International Congress of the Italian Association of Companion Animal Veterinarians

Transcription

1 International Congress of the Italian Association of Companion Animal Veterinarians 2 - May, 201 Rimini, Italy Next Congress : SCIVAC International Congress Ma -, 201 -, Italy Reprinted in IVIS with the permission of the Congress Organizers

2 69 CONGRESSO INTERNAZIONALE MULTISALA SCIVAC RIMINI MAGGIO 2011 Uveal Disease: from Clinical Case to Diagnosis and Therapy David Donaldson BVSc (Hons) DipECVO MRCVS, Animal Health Trust, Newmarket, Suffolk, UK What is the uvea? vascular tunic of the eye choroid(c), ciliary body (cb) & iris (i) contains large capillary beds major site of ocular lymphoid tissue intimate association of choroid and retina These characteristics help explain the pathogenesis of disease affecting the uvea: blood borne elements trapped within the uveal capillary beds (e.g. micro organisms, neoplastic cells) may initiate uveitis the uvea is the location of both specific and non specific immunological reactions involving the eye inflammation of the choroid is always associated with inflammation of the retina i.e. chorio-retinitis What is the blood ocular barrier? A set of structures which prevents large, high-molecular-weight proteins from entering the intra-ocular fluid The capillaries of the iris are non fenestrated and are an important part of the blood ocular barrier Disruption of this barrier (e.g. uveitis, neoplasia) leads to large molecules such as lipoproteins entering the normally clear fluid of the eye 136

3 Lipid aqueous in a cat large lipoproteins cannot normally pass into the anterior chamber due to the non-fenestrated structure of iris capillaries the presence of lipid aqueous indicates breakdown of this barrier. In contrast to the iris the capillaries of the choroid are considered to be more leaky. Leakage from the choroidal vessels will lead to fluid accumulating under the retina, which may lead to detachment of the retina. The fluid may be serous, transudate or exudate or if the capillaries are severely disrupted blood - some idea of the type of fluid present is usually possible if it is visible through the semitransparent retina the intimate contact between the choroid and retina means inflammation of the choroid will always be associated with concurrent inflammation of the retina Serous retinal detachments in a dog the retina (x) is detached and coming anterior into the vitreous, (note deviation of the blood vessels). UVEITIS Uveitis may be classified on the basis of: Anatomical location (e.g. anterior vs. posterior) Duration (acute vs. chronic) (chronic > 3 months) Aetiopathogenesis (exogenous vs. endogenous) In the context of this discussion division of uveitis based on pathogenesis is useful in determining which diagnostic tests should be considered. exogenous uveitis - causes include trauma (blunt or penetrating) and corneal ulceration endogenous uveitis - develops from within the eye or from the bloodstream The initial assessment of a uveitis patient includes taking a thorough history, physical and ophthalmic examinations. 137

4 69 Congresso Internazionale Multisala SCIVAC Exogenous causes of uveitis including trauma (blunt or penetrating) and corneal ulceration, are usually diagnosed on ophthalmic examination. It is worth noting that occasionally penetrating injuries are not obvious, especially if the wound has occurred through the conjunctiva/sclera rather than the cornea or has involved the posterior aspects of the globe. These cases are unilateral and frequently present with severe panuveitis. In such cases the history may be suggestive (e.g. recent maxillary molar tooth extraction followed by severe unilateral uveitis, or recent history of a cat fight or gunshot wounds in which adnexal injury may have been noted but no overt corneal penetration was apparent. In such cases the ocular media are frequently opaque preventing examination of the posterior segment. Initial investigations are therefore usually directed towards imaging the ocular, orbital and adnexal structures; radiography and ultrasonography being the most commonly utilized in the primary setting. CLINICAL CASE: 5yo MN X bred History painful right eye after walk something protruding from eye previous medical history (PMH) nothing significantl previous ophthalmic history (POH) - nothing significantl What is your diagnosis? Will uveitis be present in this case and if so would you classify it as endogenous or exogenous uveitis? What other ocular structures may have been damaged with this injury and how significant are they to the management and prognosis of the condition? Outline your approach to investigation and management of this case? 138

5 What is your diagnosis? Penetrating corneal foreign body Will uveitis be present in this case and if so would you classify it as endogenous or exogenous uveitis? Yes - uveitis will be present in any situation where the globe is perforated due to breakdown of the blood ocular barrier. Exogenous uveitis will be present. What other ocular structures may have been damaged with this injury and how significant are they to the management and prognosis of the condition? Lens & posterior segment damage (ciliary body, retina, posterior ocular coats) If the lens capsule has been ruptured phacoclastic lens induced uveitis (LIU) will develop. Antigenic lens protein is released causing intense uveitis. In cases suffering from LIU secondary to cat scratch intensive medical systemic and topical antiinflammatory has been shown to have a better outcome than intraocular surgery. This has not been showed in intraocular foreign bodies. Retinal damage associated with perforation or tearing is likely to lead to retinal detachment. Inoculation of bacteria and or fungi into the posterior segment increases the risk of intractable endophthalmitis Outline your approach to investigation and management of this case? Assessment of intraocular damage- some assessment may be possible if the patient is calm and co-operative, in this case general anaesthesia is needed for FB removal For examination mydriasis (tropicamide or atropine preservative free) Focal light and magnification - assess intraocular damage / rule out other foreign bodies If it is not possible to assess these structures due to opacity of the ocular media ocular ultrasound should be used. Do not use ultrasound gel if globe is not intact, a temporal approach to the globe in these cases might be useful. Medical treatment Small wounds which have sealed may be treated medically with cage rest All cases assume intraocular microbial inoculation and cover for endophthalmitis and secondary uveitis Systemic broad spectrum antibiotics e.g. amoxicillin clavulanic acid Systemic non-steroidals anti-inflammatories Cyclopegic/ mydriatic topical 1% atropine ciliary spasm & to prevent synechiae Topical broad spectrum with antibiotics with good corneal penetration Surgical treatment Direct corneal suturing only used if the defect is very small otherwise tension on the sutures is likely to lead to wound breakdown and excessive astigmatism Rotational conjunctival pedicle Lens capsule rupture - lens extraction needs to be considered depending on the size of the lesion Endogenous uveitis develops from within the eye or from the bloodstream. The known and proposed causes of canine and feline uveitis are listed in Table 1 and Table 2 respectfully. Feline uveitis The majority of feline uveitis cases will have no history or clinical findings suggestive of an exogenous cause and consideration of the endogenous causes of uveitis (Table 1) will be necessary. Excluding cases of uveitis associated with intraocular neoplasia, lens disease, lipid aqueous or the rare situation where an intraocular parasite is directly visualized (e.g. ophthalmomyiasis interna), there are no pathognomonic clinical ophthalmic changes associated with endogenous uveitis in the cat. Independent of aetiology, aqueous flare, iritis, keratic precipitates, hyphaema and hypopyon commonly develop in the anterior chamber, whilst posterior uveitis presents with signs of choroidal and retinal inflammation including exudates, haemorrhage and retinal detachment. 139

6 TABLE 1 - Feline Uveitis: Known or Proposed Causes INFECTIOUS PROTOZOAL VIRAL TOXOPLASMA GONDII LEISHMANIA DONOVANI FELINE LEUKEMIA VIRUS (FELV) FELINE IMMUNODEFICIENCY VIRUS (FIV) FELINE INFECTIOUS PERITONITIS VIRUS (FIP) FELINE HERPESVIRUS 1 (FHV-1)) BACTERIAL BARTONELLA HENSELAE MYCOBACTERIUM SPP BACTERIAL INFECTIONS CAUSING SEPTICAEMIA, ENDOTOXAEMIA, EXOTOXAEMIA OR IMMUNE COMPLEX DEPOSITION (E.G. ENDOCARDITIS, PYELONEPHRITIS AND DISCOSPONDYLITIS) MYCOSES PARASITIC CRYPTOCOCCUS NEOFORMANS HISTOPLASMA CAPSULATUM BLASTOMYCES DERMATITIDES COCCIDIOIDES IMMITIS CANDIDA ALBICANS OPHTHALMOMYIASIS INTERNA POSTERIOR (DIPTERA SP.) OCULAR FILARIASIS (DIROFILARIA IMMITIS) OCULAR LARVAL MIGRANS (TOXOCARA SPP) IMMUNE-MEDIATED LENS NEOPLASIA POORLY DEFINED GROUP LIKELY TO INCLUDE MANY AUTOIMMUNE DISEASES TO A VARIETY OF ENDOGENOUS ANTIGENS (E.G. RETINAL-S ANTIGEN) THAT EITHER INITIATE OR PERPETUATE UVEITIS CATARACTS (LENS-INDUCED UVEITIS, PHACOLITIC UVEITIS) LENS RUPTURE (PHACOCLASTIC UVEITIS) PRIMARY (MELANOMA) SECONDARY NEOPLASIA (LYMPHOSARCOMA MOST COMMON) NON-OCULAR NEOPLASIA (PARANEOPLASTIC SYNDROMES) METABOLIC HYPERLIPIDAEMIA VASCULAR HYPERTENSION TOXAEMIA ANAEMIA HYPERVISCOSITY SYNDROMES BLEEDING DIATHESIS 140

7 TABLE 2 - Canine Uveitis: Known or Proposed Causes INFECTIOUS PROTOZOAL LEISHMANIA DONOVANI TOXOPLASMA GONDII RICKETTSIAL EHRLICHIA CANIS OR PLATYS VIRAL ADENOVIRUS INFECTION (INCLUDING POSTVACCINAL BLUE-EYE ) DISTEMPER VIRUS HERPES VIRUS RABIES BACTERIAL BRUCELLA CANIS BORRELIA BURGDORFERI (I.E., LYME DISEASE) LEPTOSPIRA SP. SEPTICEMIA OF ANY CAUSE MYCOSES BLASTOMYCES DERMATITIDIS COCCIDIOIDES IMMITIS CRYPTOCOCCUS NEOFORMANS HISTOPLASMA CAPSULATUM OTHER MYCOSES PARASITIC OPHTHALMOMYIASIS INTERNA POSTERIOR (DIPTERA SP.) OCULAR FILARIASIS (DIROFILARIA IMMITIS) OCULAR LARVAL MIGRANS (TOXOCARA AND BALISASCARIS SP.) ALGAL PROTOTHECA SPP. IMMUNE-MEDIATED IMMUNE-MEDIATED THROMBOCYTOPENIA IMMUNE-MEDIATED VASCULITIS UVEODERMATOLOGIC SYNDROME (SIMILAR TO HUMAN VOGT- KOYANAGI-HARADA) LENS CATARACTS (LENS-INDUCED UVEITIS) LENS RUPTURE (PHACOCLASTIC UVEITIS) NEOPLASIA / PROLIFERATIVE HISTIOCYTIC PROLIFERATIVE DISEASE GRANULOMATOUS MENINGOENCEPHALITIS (FORMERLY RETICULOSIS) PRIMARY (MELANOMA) SECONDARY NEOPLASMS (LYMPHOSARCOMA MOST COMMON) METABOLIC DIABETES MELLITUS (PARTICULARLY DIABETIC CATARACT-INDUCED UVEITIS) HYPERLIPIDEMIA VASCULAR /HAEM HYPERTENSION TOXAEMIA ANAEMIA HYPERVISCOSITY SYNDROMES BLEEDING DIATHESIS 141

8 Cases where the cause of an endogenous uveitis may be apparent in the cat intraocular neoplasia lens disease lipid aqueous Feline diffuse iris melanoma is the most common primary neoplasm of cats and usually presents as a diffuse darkening of the entire iris although nodular forms may occur. Ophthalmic signs which increase the index of suspicion that an iridal pigmentary change represents a diffuse iris melanoma, rather than benign melanosis include: the presence of iridal thickening or mass lesions, dyscoria, anisocoria, concurrent uveitis or intra-ocular haemorrhage, and free pigment in the anterior chamber or pigment accumulation in the iridocorneal angle (+/- secondary glaucoma). In the early stages, diffuse iris melanoma differentiation from benign melanosis may be difficult, and close monitoring of the ophthalmic changes is advised (serial photographs useful). Fine needle aspiration biopsy (FNAB) from the iris is usually unrewarding in distinguishing iris melanoma from melanosis but small snip biopsies may be useful if the pigmentary change affects the pupillary zone of the iris. Primary post traumatic intraocular sarcoma is thought to originate from lens epithelial cells following lens trauma. The intraocular mass lesion may be visible ophthalmoscopically, or ultrasonographically in cases where uveitis or intra-ocular haemorrhage obscures examination. These tumours may invade locally, (e.g. optic nerve/ chiasma) or metastasize to distant sites. Therefore pre-operative imaging to determine any local and/or systemic involvement of the tumour is indicated if there is an index of suspicion for this disease (e.g. elderly cat with chronic unilateral uveitis, evidence of an intra-ocular mass and a history or clinical evidence of previous ocular trauma (e.g. corneal scar, synechia)). Ocular involvement in feline lymphoma is common and often precedes systemic manifestations. These cases may present with pale intra-ocular mass lesions or in the earlier stages, more subtle nodular iris lesions may be evident. Cytology on aqueocentesis samples or FNAB from an anterior uveal mass may be rewarding in these cases although the diagnosis is usually achieved by sampling of other affected organs or lymph nodes. The presence of large capillary beds within the uveal tract makes it a potential site for haematogenous metastasis from any distant neoplasia. One particular neoplasm which appears to have a characteristic ophthalmic presentation is bronchogenic carcinoma. An ischaemic chorioretinopathy occurs due to invasion of the choroidal vasculature leading to wedge shaped areas of tan discolouration within the tapetal fundus and serous sub-retinal exudation. These cats present with unilateral or bilateral blindness and may also have painful ischaemic necrosis of the distal extremities. Diagnosis in such cases relies on biopsy of the primary or non- ocular metastatic lesions. The discussion so far has considered causes of feline uveitis in which the clinical presentation either identifies, or is highly suggestive of, a particular causation. In other cases further investigation of causes of endogenous uveitis including infectious, immune- mediated and vascular disease, is indicated. The minimum data base obtained should be a complete blood count, serum biochemistry profile, urinalysis, thoracic radiography and abdominal ultrasound. Selection of additional diagnostic tests may be affected by other clinical findings (e.g. coagulation studies and blood pressure assessment if intra-ocular haemorrhage is present or vessel tortuosity is identified) and knowledge of the diseases endemic in a given region (e.g. blastomycosis, histoplasmosis and leishmaniasis not reported in the U.K. (?Italia) but could occur in a cat which has traveled from endemic areas). In the UK, testing for Toxoplasma gondii, feline leukemia virus (FeLV), feline immunodeficiency virus (FIV), feline coronavirus and Bartonella henselae are recommended. Aqueocentesis and vitreocentesis may be considered in cases in which granuloma formation is evident (e.g. mycotic or mycobacterial infection). Vitreocentesis is more likely to yield a diagnosis even if there is anterior chamber involvement. Cryptococcus neoformans is the most commonly reported feline mycotic infection. Frequent sites of infection are the nasal passages, skin, and central nervous system: granulomatous uveitis may also be a feature. The diagnosis of cryptococcosis can be established on the basis of cytological identification of the organism aspirated from affected tissue (non-ocular in most cases), and detection of cryptococcal antigen in serum, aqueous or vitreous using latex agglutination kits. 142

9 CLINICAL CASE: EB 29 mo FE exotic History Vaccinated (FHV-1, FIE, FCV and FeLV) flea-tick control good, indoor/outdoor, single cat household hunts and fights has not travelled away from Italia previous medical history (PMH) no abnormalities previous ophthalmic history (POH) no abnormalities Physiclal examintion no abnormalities What abnormalities can you see? What is your clinical diagnosis? What other ophthalmic findings could be seen with this condition? Is this likely to represent a case of endogenous or exogenous uveitis? What initial investigations would you recommend? What infectious diseases would you test for in ITALIA? What is the most frequently reported feline mycotic infection, at what sites does it often cause disease and how is it diagnosed? 143

10 What abnormalities can you see? Keratic precipitates, iritis, rubeosis irides What is your clinical diagnosis? Anterior uveitis What other ophthalmic findings may occur with this disease? Anterior changes: aqueous flare, ciliary flush, iris swelling (and darkening), miosis, corneal oedema, hyphaema and hypopyon Posterior changes: choroidal and retinal inflammation including exudates, haemorrhage and retinal detachment. Is this likely to represent a case of endogenous or exogenous uveitis? Endogenous: the majority of feline uveitis cases will have no history or clinical findings suggestive of an exogenous cause and consideration of the endogenous causes of uveitis including infectious, immune-mediated and vascular diseases (Table 1). What initial investigations would you recommend? Minimum data base: complete blood cell count serum biochemistry profile urinalysis thoracic radiography abdominal ultrasound Selection of additional diagnostic tests may be affected by other clinical findings (e.g. coagulation studies and blood pressure assessment if intra-ocular haemorrhage is present or retinal vascular tortuosity?) and knowledge of local endemic diseases. What infectious diseases would you test for in Italia? Toxoplasma gondii, feline leukemia virus (FeLV), feline immunodeficiency virus (FIV), feline infectious peritonitis virus (FIP) and Bartonella henselae are recommended. Aqueocentesis and vitreocentesis may be considered in cases in which granuloma formation is evident (e.g. mycotic or mycobacterial infection). Vitreocentesis is more sensitive even if there is AC involvement. What is the most frequently reported feline mycotic infection, at what sites does it often cause disease and how is it diagnosed? Cryptococcus neoformans is the most commonly reported feline mycotic infection. Frequent sites of infection are the nasal passages, skin, and central nervous system: granulomatous uveitis may also be a feature. The diagnosis can be established on the basis of cytology (aspirates from affected tissue (non-ocular in most cases)), and detection of cryptococcal antigen in serum, aqueous or vitreous using latex agglutination kits. Toxoplasmosis Causally linked with feline uveitis: uveitis has been induced in cats following inoculation with T. gondii. Pathology may occur due top replication within retina (direct cytotoxicity necrosis & granulomata) OR Immune mediated mechanisms T gondii + immune complex deposition Within uvea or antigenaemia stimulating T. gondii specific intraocular lymphocytes Clinical disease In people typical retino-choroiditis lesions = most common This occurs following reactivation of dormant tissue phase (bradyzoites) In cats the entire uvea may be involved - usually anterior uveitis? Role of reactivation of dormant phase Serological testing of cats for T. gondii should include: T gondii -specific IgM by approximately ~ 2wk post infection Negative by 16 wk but may persist longer in some cases Not all cases develop IgM T gondii specific IgG IgG may not until ~ 4 wk post infection May remain elevated for years Serological evidence of recent of reactivated infection? High T. gondii-specific IgM titres (ELISA for IgM > 256) Titres vary between labs i.e. for lab (x) an IgM > 64 may indicate active infection Narrow window for detection IgM titre so failure to show doesn t rule out recent infection 144

11 69 Congresso Internazionale Multisala SCIVAC OR Increasing (4 fold or greater) T. gondii-specific IgG titres in the serum over 2-3 wk However since seropositivity to, T. gondii-specific IgM / IgG can occur in clinically normal cats they may not correlate to clinical ocular disease in an individual cat Aqueous humour testing has been used to try and improve the specificity of testing for ocular toxoplasmosis Calculation of indices which indicate evidence of intra-ocular T. gondii-specific immunoglobulin production (e.g. Goldmann Witmer coefficient (C-value)) c values > 1 suggestive of local Ab production c values > 8 strong evidence BUT ocular T gondii -specific Ig increased in experimentally inoculated healthy cats and chronically infected cats by non-specific immune stimulation (c values > 1) therefore the c value may not improve the positive predictive value (PPV) of testing for T. gondii involvement in feline ocular disease Intraocular T. gondii specific IgM may be a better marker for clinical disease Molecular tests for T. gondii antigens or DNA in the aqueous humour assist in the diagnosis of T. gondii induced uveitis Feline leukaemia virus (FeLV) Initial testing for FeLV is usually performed using an in-house ELISA (enzyme-linked immunosorbent assay) or ICGA (immunochromatographic assay) to detect soluble protein (FeLV p27) in the plasma or serum. This indicates FeLV viral infection but does not distinguish transient or permanent viraemia. A confirmatory test such as a different type of ELISA or ICGA testing kit or an IFA (immunofluorescent antibody assay) is necessary to confirm the positive result. A positive IFA detects FeLV p27 antigen within WBCs and is likely to signify permanent FeLV infection. Testing should be repeated at 12 weeks to confirm a positive viraemia. A direct causal link between FeLV and uveitis has not been established. Therefore even in a persistently viraemic patient, direct causation between FeLV and feline uveitis cannot be assumed. Ocular involvement in feline lymphoma is common and probably represents metastasis of neoplastic cells to the uveal tract (haematogenously). Feline immunodeficiency virus (FIV) Causal link? - uveitis associated with FIV in both experimentally & naturally infected cats although direct causation not proven Proposed mechanisms: direct viral damage to tissue, immune mediated disease and predisposing to opportunistic infection and a possible association with ocular lymphoma As with FeLV, initial testing for FIV is usually performed using an in-house ELISA or ICGA to detect antibodies to FIV in the serum. Positive results need to be confirmed using an alternative testing methodology such as IFA or western blot (which also detect antibodies to FIV) or PCR. In one study all FIV-seropositive cats with uveitis were also seropositive for T. gondii emphasizing the need to screen for multiple infectious agents. CLINICAL CASE: 29 mo FE exotic 2 wk hx of cloudiness affecting the right eye FeLV ELISA Snap test TEST + 145

12 Using an in house ELISA for the P27 antigen the patient tests + for FeLV. Does this result mean the cat is persistently infected with FeLV? Does serological evidence mean FeLV is the cause of the uveitis in this cat? How would you confirm persistent infection in this case? Using an in house ELISA for the P27 antigen the patient tests + for FeLV Does this result mean the cat is persistently infected with FeLV? Initial serological testing for FeLV using an in-house ELISA or ICGA detect soluble protein (FeLV p27) in the plasma or serum. This does not distinguish between transient or permanent viraemia Furthermore no test has a 100 % sensitivity and specificity, and the reliability of a test (i.e. its predictive value) decreases as the prevalence of the disease in the population decreases. Does serological evidence mean FeLV is the cause of the uveitis in this cat? No - serological tests for infectious diseases indicate exposure (as may occur in healthy cats) to an infectious agent but do not definitively establish a direct causal link between the infectious agent & uveitis in an individual cat. Furthermore a direct causal link between FeLV and uveitis has not been established. FeLV is reported to occur at a higher prevalence in cats with anterior uveitis suggesting some role in some of these cases BUT FeLV replication within the uveal tract has not been demonstrated. Therefore even in a persistently viraemic patient, direct causation between FeLV & feline uveitis cannot be assumed. How would you confirm persistent infection in this case? A confirmatory test such as a different type of ELISA or ICGA testing kit or an IFA (immunofluorescent antibody assay) is necessary to confirm the positive result. (but this needs to be done after 6? Weeks between both to confirm infection, right?) A positive IFA detects FeLV p27 antigen within WBCs and is likely to signify permanent FeLV infection Feline Herpes Virus (FHV) In a study of naturally exposed cats, FHV-1 ocular antibody production was not detected in FHV-1 seropositive normal cats In cats for which the cause of uveitis was unknown, 22 of 44 (50%) had FHV-1 C-values >1 documenting ocular antibody production. Recently, we have detected FHV-1 in 11 of 44 (25%) However, FHV-1 (one of 13; 7.8%), DNA can be detected by polymerase chain reaction in the aqueous humour of some healthy cats. Thus, detection of organism DNA in aqueous humour does not always correlated to clinical disease. Feline infectious peritonitis (FIP) Diagnosis of FIP induced feline uveitis is hindered because serology does not distinguish between enteric and FIP-inducing strains of feline coronavirus. It is therefore important to interpret the serological findings in conjunction with other parameters to increase the accuracy of testing. In one report a combination of a coronavirus antibody titre >1:160, with concurrent lymphopaenia and hypergammaglobulinaemia had a positive predictive value of 88.9% in cases with suspected systemic FIP. Bartonella spp. The cat is the major persistent reservoir host for numerous Bartonella spp including B. henselae and B. clarridgeiae. There is increasing evidence that these agents may be involved with feline uveitis, but interpretation of serological findings is difficult due to the frequency of asymptomatic carriers (in one study 41% of cats were persistently bacteraemic but showed no clinical signs). In the future testing for Bartonella spp antigens or DNA in the aqueous humour may potentially assist in the diagnosis of feline bartonellosis. 146

13 69 Congresso Internazionale Multisala SCIVAC When performing serological tests for infectious diseases it is important to remember that they indicate exposure to an infectious agent (as may occur in healthy cats) and therefore do not definitively establish a direct causal link between the infectious agent and uveitis in an individual cat. Furthermore no test has a 100 % sensitivity and specificity, and the reliability of a test (i.e. its predictive value) decreases as the prevalence of the disease in the population decreases. In many cases a causal relationship with an infectious agent is not established and immune mediated disease uveitiides are considered Immune-mediated (including autoimmune) uveitiides, although probably common in cats (as in other species) are poorly defined and are likely to represent a significant percentage of cases which are classified as idiopathic. The diagnosis is largely one of exclusion. In human medicine there are strong associations between an increasing numbers of uveitiides with specific MHC haplotypes; responses to specific endogenous ocular antigens are now recognized to either initiate or perpetuate uveitis. An example of this is cancer-associated retinopathy (CAR) in people, which is thought to be driven at least in part by antibodies against the retinal protein recoverin. Feline uveitis may occur in association with non-ocular tumours and some of these may represent immune-mediated paraneoplastic uveitiides akin to the human CAR syndrome. Treatment of uveitis: early - aggressive and prolonged treatment required Medical Symptomatic topical anti-inflammatory therapy instituted immediately even in those patients with suspected multisystem disease Even if a diagnosis of an infectious agent is eventually made initial anti-inflammatory treatment is still mandatory to save the integrity of the eye Failure to institute prompt therapy may result in numerous adverse sequelae of uveitis, including synechiae, cataract, glaucoma and phthisis bulbi. Systemic therapy includes various combinations of anti-inflammatory, antimicrobial, and specific therapy as determined by the multisystemic disease Topical therapy alone may suffice for mild anterior uveitis, but for severe anterior uveitis and posterior uveitis, systemic therapy is also indicated Mydriatic-cycloplegic drugs Parasympathetic agents such as atropine induce mydriasis, post synechiae & provide cycloplegia (relieving pain) n.b.more frequent therapy may be required to induce cycloplegia compared to mydriasis - this explains why ciliary body spasm (pain) may still exist after the pupil is dilated Non-specific anti-inflammatory effect by stabilizing the blood aqueous barrier, therefore reducing uveitis and facilitating re-establishment of normal lops In complicated uveitis cases they must be administered with caution because of chance producing SECONDARY GLAU- COMA Mild uveitis may require therapy with atropine 1% once or twice daily, whereas more severe cases may require more frequent application (e.g., 4-6 times daily) Atropine 1% ointment is the treatment of choice for cats Side effects of frequent treatment with topical atropine may include decreased tear production, tachycardia, gut motility, & the potential to precipitate acute glaucoma Decreased tear production is a common side effect in the dog and is significant when ulcerative keratitis coexists with uveitis 10% phenylephrine can be used for recalcitrant cases when pupillary dilation is difficult to achieve especially if extensive synechiae have formed 10% phenylephrine is not particularly effective in cats compared to dogs and may cause systemic toxicity Scopolamine/phenylephrine solution (Murocoll2) may break fibrous adhesions and dilate pupils that are unresponsive to atropine, because it combines the additive effects of parasympatholytic and sympathomimetic agents Efficacy in domestic animals has not been consistently documented Suppress Inflammation Corticosteroids: TOPICALLY, SUBCONJUNCTIVALLY, SYSTEMICALLY Increase cellular membrane integrity, inhibit lysozyme release / reduce the amount of exudate Topical corticosteroids -are the primary therapy for patients with anterior uveitis, including those with suspected infectious disease in an attempt to prevent the possible blinding sequels of uveitis (synechiae, cataract & glaucoma) 1% prednisolone acetate and 0.1% dexamethasone acetate penetrate are recommended as they penetrate the intact cornea 147

14 better and are more potent than other steroid preparations An initial application frequency of q 1 to 6 hours may be required with solutions When being used longer term in small dogs (toy) and cats e.g. prednisolone acetate 0.5% may reduce risk of adrenal axis suppression *Gentle shake suspension at least 20 times before use *Elevate the nose ~ 2 minutes after application Subconjunctival corticosteroids May be administered in select cases as an adjunct to topical therapy Triamcinolone acetonide (Vetalog), methylprednisolone acetate (Depo-Medrol), betamethasone (Betasone), and dexamethasone (Azium) may be used for subconjunctival injection Subconjunctival injection in cases that cannot be treated routinely or chronic cases where treatment difficult or contraindicated Systemic corticosteroids Much greater caution is required before beginning systemic corticosteroid therapy (esp. when bacteraemia or systemic mycoses are suspected) Corneal ulceration is a contraindication to topical or subconjunctival steroid therapy, but not necessarily to systemic therapy Start with high doses e.g. prednisolone 2mg/kg SID for SEVERE cases or 1 mg/kg for moderate cases and wean slowly as the inflammation subsides NSAIDS Topical NSAIDS: When combined with corticosteroids their therapeutic effects are additive and combination therapy may be beneficial in refractory cases. NSAIDs that have been used topically on the eye include indomethacin (Indocid), flurbiprofen (Ocufen), suprofen (Profena) and diclofenac (Voltarol) Experimental study 1% suspensions of each drug, the relative blood-aqueous barrier stabilizing efficacy was: diclofenac > flurbiprofen > suprofen Experimental study using commercially available drug concentrations, the stabilizing efficacy was: 0.03% flurbiprofen > 0.1% diclofenac > 1 % suprofen however, in both these studies, the anti-inflammatory effects of diclofenac and flurbiprofen were similar, and both drugs would appear to be acceptable choices for clinical use in the dog the indications and contraindications for topical NSAIDs are suggested to be similar to those for corticosteroids flurbiprofen may delay corneal wound healing, but unlike corticosteroids, it does not appear to potentiate collagenase activity flurbiprofen has been safely used to treat eyes with concurrent uveitis and corneal ulceration BUT is contraindicated in animals with co-existing herpesvirus keratitis. Systemic NSAIDs: NSAIDs contraindicated when hyphaema or bleeding tendencies Dog aspirin dosages for uveitis are as high as 20 to 40 mg/kg two times a day, but 10 to 15 mg/kg orally two or three times a day appears to be effective Carprofen has been shown to be an effective at 2 mg/kg orally two times a day Carpofen seems to have minimal effect on platelets compared with that of other NSAIDs but hepatotoxicity has been recognized, particularly in the Labrador retriever Aspirin advocate by some as a good option for long-term management of uveitis Cats- 10 mg/kg orally every 52 hrs Dogs mg/kg orally every 12 hrs 69 Congresso Internazionale Multisala SCIVAC 148

15 CLINICAL CASE: 29 mo FE exotic 2 wk hx of cloudiness affecting the right eye FeLV ELISA Snap test TEST + Scenario 1: only anterior chamber signs are present What medication would you prescribe at what dose and for how long? What is the prognosis for the eye? Scenario 2: vitritis is present and it is difficult to see the retina What medication would you prescribe at what dose and for how long? What is the prognosis for the eye? Immunosuppressive drugs Azathioprine (Imuran ) Mainly in those cases unresponsive to conventional therapy. Imuran most com monly used in therapy for uveodermatological syndrome in the dog Frequent blood, platelet counts & liver enzyme determinations are recommended with initial therapy because of the potential hepatotoxic / myelosuppressive effects of this drug. Initial dosage is 2mg/kg per day for 3 to 5 days, followed by reduction on the basis of blood parameters and response to therapy. Cyclosporine Immunosuppressive agent that primarily affects T-lymphocyte functions. The topical formulation has gained popularity for the treatment of external ocular diseases in the dog (e.g., keratoconjunctivitis sicca), but its relatively poor intraocular penetration after topical application 0.2% ophthalmic (Optimmune ). 1 or 2% solution prepared in corn oil with the oral solution (Sandimmune ) 149

16 Systemic cyclosporine (Atopica ) can be used in order to control inflammation within the eye cyclosporine inhibits the IL-2 that stimulates T lymphocytes and has been used as immunomodulator +/- anti-inflammatory in different diseases such as: uveodermatologic syndrome, idiopathic uveitis, complicated uveitis post-phacoemulsification Should be used with caution in dogs with hepatic and renal disease CsA metabolism is reduced (hence plasma concentration increase) with the use of ketoconazol and other izoles, cimetidine, doxycycline and also with the use of allopurinol. Antimicrobial Topical antimicrobial antibiotics found in most ophthalmic preparations (i.e., aminoglycosides, bacitracin, polymyxin) do not penetrate the intact cornea readily; therefore, they would have minimal benefit in therapy for bacterial-mediated uveitis. Tetracycline may achieve therapeutic levels in the eye chloramphenicol and many topical quinolone antibiotics (e.g. ofloxacin (Exocin )) penetrate the cornea well Systemic antimicrobial may be indicated as prophylaxis or specific causative agent the blood-aqueous barrier is normally impermeable to many antibiotics, but during active uveitis, the blood aqueous barrier is compromised and drug permeability enhanced. Some drugs penetrate the normal blood aqueous barrier; these drugs are recommended for empirical therapy: Amoxicillin Trimethoprim/ sulfadiazine Cephalosporin Particular antibiotic may be indicated for example doxycylcine for ehrlichiosis clindamycin for azithromycin for toxoplasmosis doxycycline and azithromycin for bartonellosis 69 Congresso Internazionale Multisala SCIVAC 150