Equine recurrent uveitis (Proceedings)

Herpes virus keratitis

     • Prevalence:

          o EHV-2 has a high overall seropositive rate (90%) that does not have a defined correlation with clinical disease

          o Affects foals and adults

     • Clinical Appearance:

          o Variable pain, blepharospasm, epiphora, edema, vascularization

          o Common: classic appearance of multiple multifocal opacities which may be rose bengal positive (superficial erosion) or fluorescein stain positive (superficial ulcer); does not have to have stain retention

          o EHV-1 manifestations (blindness, optic neuritis, strabismus) distinctly different

     • DDX:

          o Influenced by region

          o Immune-mediated - Midwest

          o Early fungal – primary differential for many

          o Other ulcerative – traumatic, foreign body, KCS

          o Non-ulcerative keratitis – immune-mediated keratitis, corneal degeneration, calcific band keratopathy

          o Conformation difficult – high seropositive in normal population

          o Primarily – Rule out diagnosis combined with positive response to tx

          o Electron microscopy, virus isolation,

     • Pathogenesis:

          o EHV-2 is a gamma herpesvirus producing lifelong infections characterized by variable periods of disease recrudescence and latency.

          o Reactivation associated with stress (shipping, training, breeding)

          o Latency established in lymphocytes and trigeminal and ciliary ganglia

     • TX:

          o Anti-viral efficacy for equine EHV-2 have not been tested in vivo or in vitro

          o Anti-viral medications considered virostatic and must be administered at high frequency (4-6 times daily)

          o Topical NSAID

          o Topical prophylactic antibacterial

          o Systemic NSAID

          o Lysine – 10-30 grams orally once daily

          o Topical cycloplegic – mydriatic for reflex keratouveitis

          o Topical steroid?

     • Prognosis: Variable, often taking time and patience

Bacterial ulcerative keratitis

     • Prevalence:

          o Frequent problem

          o Streptococcus, Staphlococcus, Pseudomonas sp.

          o Numerous others also reported including anaerobic (clostridium sp)

          o Mixed infections, evolving infections common

     • Clinical Appearance:

          o Non-specific: blepharoedema, pain, epiphora, mucopurulent discharge, corneal opacification

          o Specific: stromal involvement will produce cellular infiltration, marked edema, and deepening of the ulcer bed +/- keratomalacia ("melting")

          o Anterior uveitis: often severe (hypotony, miosis, flare, hypopyon, synechia)

          o Corneal neovascularization

          o Vision reduction / loss

     • DDX:

          o Infectious ulcerative keratitis (fungal, viral)

          o Traumatic / foreign body

          o Non-infectious ulcerative keratitis (superficial, eosinophilic,

          o Non-ulcerative conditions (stromal abscess, immune-mediated keratitis)

          o **Perform cytology and bacterial culture / sensitivity

     • Pathogenesis:

          o Loss of the epithelial barrier allows pathogenic and non-pathogenic bacteria to invade the stroma

               • Protease production by bacteria, epithelial cells, inflammatory cells, and stromal fibroblasts results in extensive keratomalacia

               • MMP-2,MMP-9, neutrophil elastase

     • Medical TX:

          o Control inflammation, control infection, control pain, decrease proteolysis

          o Placement of subpalpebral lavage system

          o Topical antibiotic selection based on culture; administered q 2-6 hours

               • Gram Negative – aminoglycosides, chloramphenicol (not for Pseudomonas sp.), ciprofloxacin, ofloxacin, neomycin / polymyxin B

               • Gram Positive - chloramphenicol, mofloxacin, neomycin, bacitracin

          o Topical mydriatic – cycloplegic (1% atropine)

               • Reduces risk of posterior synechia and secondary glaucoma

               • Degree of mydriasis correlates with degreed of cycloplegia

                    √ More severe reflex keratouveitis requires more frequent tx

          o Systemic NSAIDs –

               • Flunixin meglumine (1.1 mg / kg) PO or IV q 12 hrs

               • Taper dose with control of disease

                    √ Often tapered too soon

          o Systemic steroids – not preferred due to increased risk

          o Omeprazole (Gastrogard) –

               • preventative dose = 2 mg/kg PO qd

               • treatment dose = 4 mg/kg PO qd

          o Topical antiproteases – Used to control upregulated protease activity

               • Autologus serum: serine protease entrapment

               • EDTA 0.2%: calcium / zinc chelation of MMPs

               • Tetracyclines: Ca / Zn chelation of MMPs (can also be oral)

               • N-Acetylcysteine 5-10%: Ca / Zn chelation of MMPs

          o Oral / parenteral antibiotics

               • Penetration of drug into tear film, cornea, and anterior chamber unknown

               • Corneal neovascularization and inflammation may increase drug delivery

               • TMS, Potassium Penicillin, Gentamicin

               • Doxycycline –

                    √ Antibiotic

                    √ Anti-inflammatory

                    √ Anticollagenolytic

                    √ Studies:

                         • Healthy @ 10 mg/kg BID x 5 days – drug not found

                         • Healthy @ 20 mg/kg BID x 5 days – drug found intraocular

                         • Healthy @ 20 mg/kg QD x 5 days – drug found in tears

          o Subconjunctival antibiotic / mydriatic – not ideal

               • Incited inflammatory response

               • Limited space

               • Unpredictable drug bioavailability as often need 2-3 times daily tx to achieve topical levels

     • Surgical TX: Utilize when medical tx delayed or ineffective

          o Provides:

               • Immediate vascular supply

                    √ Growth factors

                    √ Fibroblasts

                    √ Protease inhibitors

               • Structural support

          o Indications:

               • Ulcers with ≥ 50% stromal loss

               • Ulcers with ≤ 50% stromal loss but associated with progressing malacia

               • Descemetocele

               • Corneal perforation / iris prolapse

               • Monitor level of uveitis

          o Procedures:

               • Conjunctival grafts (pedicle, bipedicle, hood, free island, bridge, 360°)

               • Lamellar corneal grafts (corneoscleral or corneoconjunctival transposition)

               • Natural (amnion, autologous cornea) or synthetic/biosynthetic tissue (A-Cell, Biosys) grafts

          o After sx, medical tx should continue as previously administered

     • Prognosis: Variable!

          o Must control infection, corneal digestion, and associated inflammation

          o Different studies found 50-76% rate of visual success with a comfortable eye

Fungal ulcerative keratitis

     • Prevalence:

          o Regionally frequent (warm months, humid climates)

          o Regional species variability – need for culture / ID

     • Clinical Appearance:

          o Superficial keratomycosis

               • Microerosion

                    √ Multifocal subepithelial whitish opacities

                    √ Rose bengal positive +/- ulceration

                         • Epithelial devitalization

                    √ Pain, secondary uveitis variable

               • Superficial ulceration

                    √ More severe presentation

                    √ Defined epithelial loss with white / yellow cellular infiltration

                    √ Pain, secondary uveitis, neovascularization variable

               • Plaque formation ("cake-frosting" appearance)

                    √ Whitish-yellow necrotic plaque of stroma with ulceration

          o Stromal ulcerative keratomycosis – most common; 50-80% of cases with even more severe pain and anterior uveitis

               • Corneal furrowing

                    √ Curvilinear region of stromal loss @ ulcer edge

                    √ Rapidly occurs @ any time

               • Melting

               • Perforation

          o Stromal abscess

     • DDX: Cytology; cultures (bacterial / fungal); PCR?

          o Trauma / foreign bodies

          o Infiltrative ulcerative diseases

               • Bacterial

               • Eosinophilic

               • Herpesvirus

               • Immune-mediated

          o Mixed bacterial / fungal

               • 20-35% of infectious cases

          o Calcific band keratopathy

          o Corneal degeneration

          o Corneal neoplasia

     • Pathogenesis:

          o Loss of the epithelial barrier allows ocular surface and environmental fungal organisms to adhere, invade, and infect the stroma

          o Protease production by fungii, epithelial cells, inflammatory cells, and stromal fibroblasts results in extensive keratomalacia

          o Fungal organisms have been shown to inhibit in vitro angiogenesis

          o Deep stromal disease perpetuated by fungal affinity for the glycosaminoglycans near Descemet's membrane

          o Predisposing factors

               • Topical antibiotics

                    √ Healthy gram-positive microflora which produces balanced antifungal and antibacterial substances shifts to gram-negative in corneal ulcers

                    √ Antibiotic use can exacerbate this use

               • Topical steroids

               • Not all factors understood

               • Studies

                    √ 1998 UF (Andrew S): Fungal cases - 82% received topical AB; 15.4% received topical steroid prior to referral

                    √ 2009 (Galan A): Fungal cases - 60% received topical AB; 20% received topical steroid prior to referral

     • Medical TX:

          o Target fungi, secondary bacterial infection, corneal digestion, secondary anterior uveitis, and ocular pain

          o Antifungal medications:

               • Most antifungal drugs = fungistatic because of an inability to achieve adequate concentrations in the presence of an intact corneal epithelium

                    √ Epithelial loss – increases drug concentration

                    √ High frequency administration – increases drug concentration

               • Aggressive frequency

                    √ Does this result in clinical deterioration?

                         • Intense inflammatory reaction

                    √ Potential weighed against primary disease

               • Therapeutic debridement

                    √ Increase drug penetration

                    √ Debulk organism

               • Three general antifungal classes

                    √ Polyenes:

                         • Preferentially bind ergosterol, cell membrane sterol unique to fungi

                         • Increases cell permeability and leakage; oxidative damage

                         • Able to bind to cholesterol, mammalian membrane sterol potentially creating toxicities

                         • Broad spectrum

                         • Best for ulcerative disease

                         • Good efficacy against filamentous and yeast fungi

                         • Frequency: q 2-4 hrs initially, then taper

                         • Amphotericin B:

                              o Topical 0.075 – 0.2% solution in sterile water; refrigerate, dark bottle

                              o Increased epithelial toxicity vs Natamycin

                              o Subconjunctival – 0.2 mL of 5 mg / mL solution q 48 hrs for 3 doses

                         • Natamycin:

                              o 5% suspension

                              o Only commercial ophthalmic antifungal

                    √ Azoles:

                         • Preferentially binds to fungal specific enzyme in the cytochrome P450 system

                         • Inhibits ergosterol synthesis, increases membrane permeability, alters fungal cell enzyme systems

                         • Frequency: q 2-4 hrs initially, then taper

                         • Imidazoles

                              o Ketoconazole: 1%

                                   • Best for ulcerative disease

                                   • Poorer efficacy than other azoles

                              o Miconazole:

                                   • Topical 1%

                                   • Good penetration through intact epithelium

                                   • Subconjunctival 1% - 5 to 10 mg q 24 to 48 hrs

                         • Triazoles

                              o Fluconazole:

                                   • Topical 0.2% solution

                                   • Poorer efficacy vs other azoles against filamentous and yeast organisms

                                   • Systemic = 14 mg / kg PO once, then 5 mg / kg PO q 24 hrs

                                   • Good intraocular penetration with or without inflammation

                                   • More limited spectrum than other azoles

                              o Itraconazole:

                                   • Topical 1% in 30% DMSO suspension

                                   • Good penetration through intact epithelium

                                   • Systemic = 1.5 mg / kg IV q 24 hrs; 5.0 mg / kg PO q 24 hrs

                                   • Poor intraocular penetration

                                   • If using PO, use IV solution since capsules have highly variable absorption

                              o Voriconazole:

                                   • Topical 1% solution in sterile water

                                   • Refrigerate

                                   • Good penetration through intact epithelium

                                   • Systemic = 3 mg / kg PO q 12 hrs

                                   • Good intraocular penetration with or without inflammation

                                   • More limited spectrum than other azoles

                    √ Nucleoside analogs:

                         • Nucleoside analog, flucytosine, is enzymatically altered within the fungal cell to the cytotoxic principal fluorouracil

               • Others

                    √ Silver sulfadiazine

                         • 1% ointment

                         • Frequency: q 12-24 hrs

                         • Metal ions bind microbial DNA and inhibit synthesis

                    √ Povidone – iodine

                         • 2% solution

                         • Frequency: q 24 hrs

                         • Germicide

          o Topical antibiotics:

               • Targeted ideal

               • Prophylactic if primary organism not identified

          o Topical mydriatic – cycloplegic: see above (bacterial keratitis)

          o Systemic NSAIDs: see above (bacterial keratitis)

          o Systemic steroids: see above (bacterial keratitis)

          o Omeprazole (Gastrogard): see above (bacterial keratitis)

          o Topical antiproteases: see above (bacterial keratitis) –

          o Oral / parenteral antibiotics: see above (bacterial keratitis)

          o Subconjunctival antibiotic / mydriatic: see above (bacterial keratitis)

     • Surgical TX: Utilize when medical tx delayed or ineffective

          o Goals:

               • Remove infectious organisms and inflammatory cells

               • Immediate vascular supply

                    √ Growth factors

                    √ Fibroblasts

                    √ Protease inhibitors

               • Structural support

          o Indications:

               • Ulcers with ≥ 50% stromal loss

               • Ulcers with ≤ 50% stromal loss but associated with progressing malacia

               • Descemetocele

               • Corneal perforation / iris prolapse

               • Monitor level of uveitis

          o Procedures:

               • Conjunctival grafts (pedicle, bipedicle, hood, free island, bridge, 360°)

               • Lamellar corneal grafts (corneoscleral or corneoconjunctival transposition; posterior lamellar (PLK) or deep lamellar endothelial keratoplasty (DLEK), penetrating keratoplasty) +/- conjunctival grafting

               • Natural (amnion, autologous cornea) or synthetic/biosynthetic tissue (A-Cell, Biosys) grafts

          o After sx, medical tx should continue as previously administered

     • Prognosis: Variable!

          o Must control infection, corneal digestion, and associated inflammation

          o Treatment often very prolonged / costly

               • Range – 21 to 190 days

          o Globe retention: 70-95%

               • Visual: 50-90%

Questions