Recent Advances in Treatment of Equine Eye Diseases Recent
7/7/2020
Recent advances in treatment of equine eye diseases
Brian C. Gilger, DVM, MS, DACVO, DABT Professor of Ophthalmology Equine Ophthalmology Service College of Veterinary Medicine North Carolina State University
July 2020
I have the following disclosures related to my presentation:
• Funding Sources – NC Biotechnology Center – NC Translational and Clinical Sciences Institute – National MPS Society – National Institutes of Health, EY030832-01 R41 • Financial Interests – Active Patents • Immunosuppressive gene therapy for the eye (with Matt Hirsch, NC State University, UNC Chapel Hill) • Gene therapy for corneal storage diseases • Ocular injection needle device (with Samir Patel, Vladimir Zarnitsyn, NC State University) – Company affiliations • RainBio, Inc., Gene therapy applications (co-founder) • Theia Medical, Inc., Ocular drug delivery (co-founder) • Other Interests – Consultant • Powered Research, Ophthalmic CRO, Research Triangle Park, NC
Lecture outline
Recent advances in treatment of equine eye diseases
• Objectives: – Over the past several years, dedicated research of the pathogenesis and treatment of diseases of the equine eye have provided practical methods to treat some of the most frustrating conditions. The objective of this lecture is to review some of these advancements, including those that you can use immediately in your practice. • Synopsis: – Diseases we will review will include some of the most common in equine practice. We will discuss the step by step management of non-healing (indolent ulcers) and then discuss advances in treatment of fungal keratitis, periocular squamous cell carcinoma, and equine recurrent uveitis.
1 7/7/2020
Clinical and Translational Medicine20176:30 https://doi.org/10.1186/s40169‐017‐0158‐1
Common types of corneal disease in horses
• Corneal ulcers: – Single most common ocular disease in horses – Initiating factor almost always trauma – Infection follows break in corneal epithelium – Clinical signs typical of discomfort
Common types of corneal disease in horses
. Two main types:
. Superficial uncomplicated corneal ulcer
. Complicated corneal ulcer
2 7/7/2020
Common types of corneal disease in horses Complicated Corneal Ulcers • Do NOT heal within 3-7 days • Have a mechanical obstruction to healing – foreign body, indolent, dry • Are infected – Bacteria – Fungus – Virus • Have a collagenase component (i.e., melting corneal ulcers). • Are in danger of perforation
Treatment First line anti-bacterial therapies Antibiotic Formulations Combination Antibiotic Preparation Bacitracin Polyfax ointment Chloramphenicol Solution, 0.5% Ciprofloxacin Solution, 0.3% Fusidic acid Solution, 1% Gentamicin Solution, 0.3% Gramicidin Neosporin solution Lomefloxacin Solution, 0.3% Neomycin Solution, ointment, 0.5% Neosporin solution Ofloxacin Solution, 0.3% Neosporin solution, Polytrim, Polyfax ointment Polymyxin B Neosporin solution, Polytrim, Polyfax ointment Trimethoprim Polytrim solution, ointment Oxytetracycline Ointment Terramycin (with neomycin) Standard of care
Treatment Second line anti-bacterial therapies
• Ideally based on culture results
Antibiotic Manufacturer Preparation Fluoroquinolones Besifloxacin 0.6% Besivance, Bausch & Lomb Suspension Moxifloxacin 0.5% Vigamox, Alcon Solution Gatifloxacin 0.5% Zymaxid, Allergan Solution
Other Antibiotics Azithromycin 1% AzaSite, Akorn Solution
Ofloxacin. Cephalosporin
Standard of care
3 7/7/2020
Indolent corneal ulcers - horses
• Chronically non-healing superficial • Redundant epithelial edge – Fluro seeps under • No infection, minimal inflammation
Photos courtesy of Drs. Dennis Brooks and Andy Matthews
Indolent ulcer treatment
Three-step approach 1. Debridement and terramcyin – Any loose epithelium is removed – Cannot remove normal epithelium with a dry Q-tip – Repeat no more frequently than every 7 days (Give it a chance to heal) – Topical terramycin • Every 8 hours (tid) – Pain meds as needed
Diamond Burr Keratectomy
Three-step approach 2. Diamond Burr Keratectomy and contact lens – Following failure of debridement to heal (2-4 weeks) – DB keratectomy (outpatient) – Placement of contact lens (an-vision, Inc) – Topical terramycin • Every 8 hours (tid) – Pain meds as needed – Recheck 7 days *Utter Vet Ophth Algerbrush II, Lago Vista, TX 10 FEB 2014 DOI: 10.1111/vop.12148
4 7/7/2020
Indolent corneal ulcers
Three-step approach Immediate 3. Superficial keratectomy Post-op – Following failure of DB to heal (2-4 weeks) – Standing surgical procedure – +/- Placement of contact lens (an-vision, Inc) – Topical terramycin • Every 8 hours (tid) – Pain meds as needed – Recheck 7 days
Standing keratectomy 10 days post-op
Diagnosis of ocular infections
What is the cause:
• Disruption of homeostasis – Injury (trauma, foreign body, contact lens, etc) – Tear film deficiencies – Immunosuppression – Overwhelming organism exposure – Drug exposure Courtesy of Ann Dwyer Corneal laceration
Infectious keratitis
Fungal spores
Agriculture
5 7/7/2020
Treatment
Anti-fungal Therapeutics • Triazole antifungals – fluconazole, itraconazole, posaconazole, voriconazole • Imidazole antifungals – clotrimazole, econazole, miconazole, ketoconazole tioconazole, luliconazole • Polyene antifungals: – amphotericin, nystatin, natamycin • Echinocandin antifungals – anidulafungin, caspofungin and micafungin • Other antifungals – flucytosine, griseofulvin, terbinafine, amorolfine Standard of care
Minimum inhibitory concentrations
MIC (μg/ml) 0.125 0.25 0.5 1 2 4 8 16 32 64 >128
A. flavus TER VOR AMB THB NAT
A. fumigatus VOR TER AMB NAT THB
F. falciforme THB VOR TER AMB NAT
F. keratoplasticum THB VOR NAT TER AMB
TER: terbinafine AMB: amphotericin NAT: natamycin VOR: voriconazole THB: thiabendazole
Cullen M, et al. Multi‐locus DNA Sequence Analysis, Anti‐fungal Agent Susceptibility, and Fungal Keratitis Outcome in Horses from the Southeastern United States. Plos One 2019. https://doi.org/10.1371/journal.pone.0214214.
Minimum inhibitory concentrations
TER: terbinafine AMB: amphotericin NAT: natamycin VOR: voriconazole THB: thiabendazole
Roberts D, et al. In vitro susceptibility of anti‐fungal drugs in isolates from equine fungal keratitis. Vet Ophthalmol. 2020;10.1111/vop.12774. doi:10.1111/vop.12774
6 7/7/2020
Treatment
Amphoteracin B subconjunctivally
• 0.2 mL of a 5 mg/mL solution q 48 hours (usually 3 to 4 treatments)
• 27 gauge needle and 1 cc syringe.
• The injections are painful and cause the eye to be irritated.
• Most commonly done in the superior conjunctiva.
• Clinically – results are promising Advanced therapies
Treatment
Intra-corneal injections : Voriconazole • Indicated for deep corneal abscesses (fungal) • Medication does not penetrate well – intact epithelium • Direct injection to lesion every 24-48 hours • Efficacy unknown – several publications • Described using a 27-31 gauge needle
Smith et al. Treatment of 6 cases of equine corneal stromal abscessation with intracorneal injection of 5% voriconazole solution. Vet Advanced therapies Ophthalmol 2014
Treatment Intra-corneal injections : Voriconazole
Intrastromal Injection
Microneedle
Smith et al. Treatment of 6 cases of equine corneal stromal abscessation with intracorneal injection of 5% voriconazole solution. Vet Ophthalmol 2014 Advanced therapies
7 7/7/2020
Mass LesionsTreatment of the Eyelid
• Neoplasia Advanced• therapiesNon-neoplastic – “Sarcoid” – Granulation tissue • Corneal– Squamous cross linking cell carcinoma / photodynamic therapy– Habronemiasis (SCC) – Other parasitic – Lymphosarcoma – Melanoma – Mast cell tumor – Neurofibromas – Hemangioma/sarcoma
Squamous Cell Carcinoma
• Occurs commonly at third eyelid, lower eyelid, lateral limbus • Poorly pigmented horses - appaloosa, paints • Common in draft horses – Haflingers – Belgians
Equine SCC pathogenesis
UV irradiation Giuliano E. Equine Vet. J., 42 • associated with ultraviolet (UV) light exposure (2010), pp. 9-18. • targets the tumor-suppressor gene p53 which is altered in equine SCC
Genetic Predisposition A missense variant in the gene damage specific DNA binding protein 2 (DDB2, p.Thr338Met) on ECA12 was identified as a risk factor for the development of limbal SCC in Haflinger horses
R/R 5.5 times more likely to develop ocular SCC than R/Nor N/N Genetic risk is the same for the development of both limbal and nictitating membrane SCC in Haflinger horses Bellone R. Cancer Genetics 2017;141:342-353 Risk factor for ocular SCC in Belgian horses (esp. chestnut) Singer-Berk M. Animal Genetics • A missense variant, DDB2 c.1013C>T, p.Thr338MetA 2018; 49: 457-460. Knickelbein K, EVJ 2019. DOI: 10.1111/evj.13116
8 7/7/2020
https://www.vgl.ucdavis.edu/ services/horse.php
Treatment - SCC
• Surgical excision – 50% recurrence – Laser excision Therapy Number of cases Non‐recurrence rate • Topicals – “Xterra” - do not get near the eye CO ablation (eyelid) 4 0% (cornea) 20 83% – 5-Fluorouracil (5-FU) – Imiquimod 5% cream (Aldara) Cryotherapy(eyelids) 6 33% – Mitomycin C (MMC) 5 100% • Immunotherapy 3 67% –BCG Cisplatin (eyelids) 7 71% – Repeat injections q 2 to 4 wks Sx excision 18 56% • Intralesional chemotherapy – Cisplatin or carboplatin MMC (cornea) 18 81% – Cisplatin Beads Iridium brachytherapy 52 81.8% – Electro-chemotherapy (lids) • Hyperthermia / cryotherapy PDT 10 100% • Photodynamic therapy (PDT) - HRT • Brachytherapy Data from Guiliano, et al. Equine Ophthalmology 3rd Ed 2017
Treatment of SCC by Site
Photo courtesy of Riccardo Stoppini • Third eyelid – 1. Surgical excision of third eyelid – 2. Adjunctive therapy • Intralesional Chemotherapy • Cryotherapy • Topical MMC or 5 fluoruracil (5-FU)
.Lower eyelid .1. Surgical Excision .2. Adjunctive therapy .Intralesional chemotherapy .Cryotherapy (early) .Brachytherapy .Photodynamic therapy
9 7/7/2020
Treatment of SCC by Site
Completely freeze (‐40C) Thaw Repeat (double –freeze – thaw)
Squamous Cell Carcinoma
Treatment of SCC by Site
• Lateral limbus / Cornea 1. Surgical debulking 2. Mitomycin-C (MMC) 3. Strontium 90 irradiation
4. CO2 laser
Squamous Cell Carcinoma
Treatment of SCC by Site
• Lateral limbus / Cornea 1. Surgical debulking 2. Mitomycin-C (MMC) 3. Strontium 90 irradiation (25 Gy) 4. Co2 laser
• Mitomycin C Therapy – Once re-epithelialized – 0.4mg/ml (0.04%)mitomycin C) – q8H for 7 days (repeat 2-3X with 7 days off) – 83% nonrecurrence (Clode, Vet Ophth 2012)
10 7/7/2020
Photodynamic therapy
• Surgically debulk eyelid lesion
• Infiltrate wound bed with Visudyne (Verteporfin, Novartis) (1 mg/cm2 tissue)
• Red light at a wavelength of 688 nm +/- 10 nm is then delivered to the wound bed by a light emitting diode (LED, Quantum Devices Inc).
• Each 3 cm treatment spot requires 15 minutes
Courtesy of Dr. E. Guiliano
Photodynamic therapy
Treatment
Photodynamic therapy (IMMK or Fungal)
. Photothermal Therapy (PTT) Courtesy of Dr. Richard . Indocyanine Green McMullen, Auburn University . EmunDo® (A.R.C., Nürnberg, Germany) . Rose Bengal 0.1%
. Activation with 532 or 810nm light
. Excitation = vibrational energy . Long-term results pending
Future therapies
11 7/7/2020
Equine Recurrent Uveitis (ERU)
• ERU is a primary, non-specific, immune-mediated condition that results in recurrent or persistent inflammatory episodes in the eye. • To diagnose the syndrome of ERU, you must differentiate it from non-ERU uveitis • ERU is the leading cause of blindness in horses • Has been recognized a disease in horses since classical antiquity
1st Clinical Syndrome “Classic” Anterior uveitis • Recurring bouts of inflammation and pain • Followed by variable length periods of quiescence • Classic signs – Active – Chronic
Clinical Syndromes - ERU
2nd Clinical Syndrome of ERU Subclinical Uveitis
• No observed bout of inflammation/pain • Eye(s) have typical signs of chronic ERU – Cataract formation – Phthisis bulbi • Common in Appaloosa – Draft breeds
12 7/7/2020
3rd Clinical Syndrome of ERU Primary Posterior Uveitis
• Least common of three syndromes • Mild to no anterior clinical signs • Severe vitreal opacity, degeneration, infiltration • Common to have retinal detachment • Most common in warmbloods
Clinical Syndromes - ERU
Equine Recurrent Uveitis
Ocular insults Normal eye First episode •Trauma •Infections (Leptospirosis) •Corneal dz •etc Acute uveitis
Immune Rxn = Most Multiple recurrent episodes Horses ERU 1. Genetics 2. Type of insult 3. Environment
ERU Prognosis
• 224 horses / 338 eyes with ERU – 28% eyes blind on initial exam and 47% blind at last followup – Poor prognostic indicators for long-term vision: • Appaloosa breed • Elevated intraocular pressure • Positive leptospiral titer in serum or aqueous – Especially if C>4 – Prevention may be the key!!
Gerding J, Gilger B. Prognosis and impact of recurrent uveitis. Equine Vet J 2015
13 7/7/2020
Standard of Care Topical Medical Therapy
• Pred Acetate 1% • Dex HCL 0.5-1% • Difluprednate (Durazol) • NSAIDS Flurbiprofen, bromfenac, nepafenac – May decrease corneal epithelialization • Must taper off dose.
Topical medical therapy for ERU
Topical Medical Therapy
Atropine HCL 1% – q 12 – 48 hours – Cycloplegic, mydriatics (pain relief and minimize synechia formation) – May decrease gut motility and predispose to colic
Topical medical therapy for ERU
Standard of Care Systemic Medications - NSAIDS
• Flunixin Meglumine (Banamine) – 0.5 mg/kg po, IV for 5 days then 0.25 mg/kg po – Potent ocular anti-inflammatory medication – Long-term use may predispose to gastric and renal toxicity • Phenylbutazone – 4.4 mg/kg po – Good ocular anti-inflammatory medication • Ketoprofen? • Firocoxib (Previcoxr) - primarily COX-2 • Must taper off dose.
Systemic medical therapy for ERU
14 7/7/2020
Systemic Medications -Steroids
• Prednisolone – 100-300 mg/day po or IM • Dexamethasone (Azium) – 5-10 mg / day po or 2.5 – 5 mg daily IM
• Potent anti-inflammatory medication • Possible side effects, laminitis, etc • Use with caution and only if no response to NS. • Must taper off dose.
Systemic medical therapy for ERU
Prevention of new ERU episodes
• Leptospiral Vaccination – (Zoetis, Innovator Lepto) – L. pomona only – A single study showed no harm (even with ERU) – May help prevent LAU • When to recommend the vaccine – If a farm is clearly a high risk for leptospirosis: • Wet pasture • Wildlife and/or rodent exposure • Other horses on farm have developed LAU or abortions • Never vaccinate a horse with uveitis of any type
Microneedle Injection – suprachoroidal Space
• Porcine Acute Uveitis Model Gilger BC, et al. Treatment of posterior uveitis by injection of triamcinolone acetonide into the suprachoroidal space using microneedles. Invest Ophthalmol Vis Sci 2013;54(4):2483- 2492
15 7/7/2020
Methods for TA SCS injection - Horses
• Horses with active ERU poorly responsive to medications • 5 mg of TA injected into SCS – 1100um length 30G microneedle (Clearside Bio, Alpharetta, GA) – TA = Triesence® (Alcon laboratories, Fort Worth, TX) – Surgical preparation (5% betadine) – Topical proparacaine HCL – 8-10 cm posterior to dorso-temporal limbus
47
Results
• Injected 12 horses to date • Single injection (n=10) • 2 injections (n=2) • 4 times (n=1) • 3 horses injected bilaterally (and 4 eyes receiving multiple injections). –Horses selected were those poorly responsive to topical steroids +/- NSAIDs –Fifteen eyes total were treated. –Injections were performed in standing horses without difficulty –Cyclosporine implants were subsequently placed in 7 horses when uveitis appeared quiescent.
16 7/7/2020
Results - Outcome
• Immediate reduction in signs of uveitis were noted as early as 1 week after injection. • Uveitis recurrence was observed in 5 horses at mean 3.4 months (range 1-6 months) after injection. • Three horses eventually had enucleation for recurrence of uveitis (1, 3 and 11 months after injection). • One horse died of colic 2 months after injection. • Repeat injections were performed every 4 months (mean 4.3 months) in 4 eyes of 3 horses, of which 3 remain visual. • Overall, at last examination, 9/15 (60%) eyes remained visual
Low dose intravitreal gentamicin
Gentamycin – 4 mg intravitreally (0.4 cc 100mg/ml) – Can be given in active or inactive disease – Appears to have immediate effect – Need preservative-free gentamycin – Reports of acute blindness, retinal degeneration, rapid onset cataracts following administration – Mechanism of action – unknown – Use with caution and only with well-informed owners
Things to remember
• Indolent ulcers – Warn owners of the long healing time, take the 3 step approach • Fungal keratitis – always after an injury (minimize injury) – New antifungals and treatment approaches show promise) • Equine periocular SCC – Site of SCC dictates what types of treatment – Electrochemotherapy and photodynamic therapy • Equine recurrent uveitis – Consider low dose systemic steroids – Suprachoroidal steroid injections – Low dose intravitreal gentamicin
17 7/7/2020
Questions?
Thank you!
Please contact me at [email protected] with additional questions
18