Uveitis and Equine Recurrent Uveitis

Brian C. Gilger, DVM, MS, Diplomate ACVO Authors address: College of Veterinary Medicine, North Carolina State University, Raleigh, NC; e-mail: bgilger@unity.ncsu.edu.

Take Home Message Equine recurrent uveitis (ERU) is a major ophthalmic disease of the horse and is the most common cause of blindness in horses.1-4 This immune-mediated, pan-uveitis has approximately a 2 to 25% prevalence rate, depending on the breed.1,5 Fortunately, recent advances in the treatment of horses with ERU have led to the successful management of this disease. Introduction The equine industry in the United States has an estimated annual worth of 112 billion dollars and provides approximately 1.4 million full time jobs across the country.6 Because ERU has a prevalence rate of approximately 2 to 25% across horse breeds in the United States, the impact of this disease on the equine industry could be as high as a billion dollars a year. ERU causes these large economic losses in the equine industry because it disrupts training, decreases performance, and disqualifies horses from competition (due to medication use, etc). Furthermore, horses with ERU have decreased value as a result of vision deficits or blindness. Finally, treatment, veterinary care, and personnel costs add to the economic impact of the disease. The purpose of this lecture is to review important facts about ERU, its causes, and new treatment options for the affected horse. Clinical Signs of ERU ERU is characterized by episodes of intraocular inflammation that develop weeks to months after an initial uveitis episode subsides;1-4,7 however, not every case of initial equine uveitis will develop into ERU (see below in diagnosis). Horses can develop ERU at any age, but the peak time of the initial uveitis episode is 4-6 years, a time when most horses are at or nearing their prime performance years.5 Three main clinical syndromes are observed in ERU, the classic, insidious, and posterior type of ERU. Classic ERU is most common and is characterized by active inflammatory episodes in the eye followed by periods of minimal ocular inflammation. The acute, active phase of ERU predominantly involves inflammation of the iris, ciliary body, and choroid, with concurrent involvement of the cornea, anterior chamber, lens, retina, and vitreous. Following treatment with nonspecific anti-inflammatory medications such as corticosteroids, the signs of active, acute uveitis can recede and the disease enters a quiescent or chronic phase. After variable periods of time, the quiescent phase is generally followed by further and increasingly severe episodes of uveitis. It is the recurrent, progressive nature of the disease that is responsible for development of cataract, intraocular adhesions, and phthisis bulbi (Scarred eye).1-4,7 In the

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insidious type of ERU, however, the inflammation never completely resolves and a low grade inflammatory response continues that leads to progression to chronic clinical signs of ERU. Frequently, these horses do not demonstrate overt ocular discomfort and owners of these horses may not recognize the presence of disease until a cataract forms or the eye becomes blind. This type of uveitis is most commonly seen in Appaloosa and draft breed horses. The posterior type of ERU has clinical signs existing entirely in the vitreous and retina, with little or no anterior signs of uveitis. In this syndrome, there are vitreal opacities and retinal inflammation and degeneration. This is the least common type of uveitis, which was seen almost exclusively in Europe, but is becoming more common in the USA. Typical clinical signs of active ERU are similar to signs of uveitis in other species: photophobia, blepharospasm, corneal edema, aqueous flare, hypopyon, miosis, vitreous haze, and chorioretinitis (Fig. 1). Clinical signs of chronic ERU include corneal edema, iris fibrosis and hyperpigmentation, posterior synechia, corpora nigra degeneration (smooth edges), miosis, cataract formation, vitreous degeneration and discoloration, and peripapillary retinal degeneration (Fig. 2). Either type of ERU (classic or insidious) can have either predominantly anterior (cornea, iris, lens, and ciliary body inflammation) or posterior (ciliary body, vitreous, and chorioretinal inflammation) segment involvement.1,2,4,8-14 Ultimately, even with aggressive treatment, many horses develop a chronically painful eye and blindness as a result of secondary cataract, synechia (intraocular adhesions), scarring, glaucoma, and development of phthisis bulbi.1-4,7

Fig. 1. Acute flare-up of ERU.

Fig. 2. Chronic ERU.

Infectious Agents Associated with Initial Uveitis (and Possibly ERU) Several organisms have been associated with the intiation of equine uveitis. In some instances, but not all, the uveitis associated with these systemic infections may develop into immunemedicated uveitis, or ERU. One of the most commonly associated systemic diseases associated with uveitis is leptospirosis.11-14 Roberts demonstrated that ERU can develop after primary infection (and acute uveitis) of leptospirosis; however, ERU typically did not develop until 1 year after the systemic infection. Therefore, measuring titers in cases of documented ERU is generally not beneficial for management of the condition unless there is a herd or barn outbreak of the uveitis. Onchocerciasis is another systemic disease associated with equine uveitis. This disease is much less common now with the widespread use of ivermectin; however, it is still a

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common initiator of uveitis. Other systemic infectious causes of uveitis include Streptococcus equi infection, brucellosis, toxoplasmosis, equine herpes virus (EHV-1, 2), equine viral arteritis, parainfluenza type 3, and generalized septicemia, endotoxemia, neoplasia, tooth root abscess, or trauma. Pathogenesis of Recurrent Episodes of Uveitis ERU is a 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. As mentioned above, there is a long list of infectious and non-infectious agents responsible for causing acute uveitis in the horse. Although any of these causes of uveitis may allow horses to develop ERU, not all of these acute uveitis cases will develop into ERU. The recurrent episodes typical of ERU are thought to develop because of one of two pathogeneses:1,2,4 1. Incorporation of an infectious agent or antigen into the uveal tract following the initial uveitis episode. These inciting antigens become established in the ocular tissues and their continued presence causes periodic episodes of inflammation.2,4 Several studies have suggested that Leptospira organisms may be one of the sequestered antigens.15,16 In these studies, however, only 2615 to 70%16 of the eyes had Leptospira detected, suggesting that other antigens and/or organisms also play a role. Persistence of an immune competent sensitized T-lymphocyte in the uveal tract that reactivates when given a signal. T-lymphocytes have been demonstrated to be the predominant infiltrating cell type in chronic ERU eye17-19 and cell-mediated immunity to uveal antigens has been demonstrated in ERU horses.12,18

2.

Diagnosis of ERU The clinical diagnosis of ERU is based on the presence of characteristic clinical signs (corneal edema, aqueous flare, posterior synechia, corpora nigra atrophy, cataract formation, vitreous degeneration, retinal edema or degeneration with or without signs of associated ocular discomfort such as epiphora, periocular swelling, and blepharospasm) and history of documented recurrent or persistent episodes of uveitis. Both features are required to make this clinical diagnosis, especially to differentiate from non-ERU uveitis and other causes of recurrent or persistent ocular inflammation, such as herpesvirus keratitis or immune-mediated keratitis. Treatment of Equine Recurrent Uveitis The main goals of therapy for ERU are to preserve vision and reduce and control ocular inflammation in an attempt to limit permanent damage to the eye. In horses where a definite inciting cause has been identified, treatment is directed at eliminating the primary problem, and initial tests to isolate an inciting agent are performed. These tests may consist of a complete blood count, biochemistry profile, conjunctival biopsy, and serology for bacterial and viral agents. More often, however, one particular cause cannot be isolated. In these instances, therapy is directed at the allaying of symptoms and reducing ocular inflammation.

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Practical and Stable Management Practices to Decrease ERU Practices that decrease ocular injury or minimize the inflammatory stimuli may decrease or eliminate the development of recurrent episodes of uveitis in ERU (Table 1). It may be possible to eliminate environmental triggers (e.g., allergens, antigens, etc) of the recurrent episodes of uveitis by changing the horses pasture, pasture mates, or stable, increasing insect and rodent control, decrease sun exposure, or change bedding type. Trauma to the eye(s) can also be decreased by eliminating sharp edges, nails, and hooks in the stable, removing low tree branches in the pasture, lighten training and show schedule, minimize trailering, and constant use of a quality fly mask. Finally, ensuring that the horse has proper hoof care, optimal vaccination and anthelmintic schedule, and proper diet may also minimize uveitis episodes.
Table 1. Practical and Stable Management Practices to Decrease ERU

Classification
Environmental

Practice to Institute
Change pasture/stable/pasture mates Increase insect and rodent control Decrease dust Decrease sun exposure Change bedding type Proper hoof and dental care Optimal anthelmintic and vaccination schedule Proper diet/minimize weeds in pasture Soften stable (Eliminate sharp objects) Eliminate low tree branches in pasture Decrease training and show schedule Minimize trailering Do not feed from hay nets Use quality fly mask

Health Maintenance

Decrease Ocular Trauma

Medical Therapy for ERU Because vision loss is a common long-term manifestation of ERU, initial therapy must be aggressive. In acute cases, treatment in the form of systemic and local therapy consisting of antibiotics, corticosteroids and anti-inflammatory drugs is used, many times simultaneously (Table 2). Initial therapy is instituted for at least two weeks, and should be tapered off over an additional two weeks after the resolution of clinical signs. In severe cases, local subconjunctival injections of corticosteroids may be indicated as an adjunct to therapy. In most instances, a subpalpebral lavage catheter is placed to facilitate delivery of topical medications. Many horses respond well to intermittent topical and/or systemic therapy of their active episodes of ERU. Other horses, however, do not respond to traditional therapy and may experience frequent recurrences of uveitis. Traditional treatments used for ERU (i.e., corticosteroids and non-steroidal anti-inflammatory medications) are aimed at reducing inflammation and minimizing permanent ocular damage at each active episode. They are not effective in preventing recurrence of disease. Other medications used to prevent or decrease severity of recurrent episodes, such as aspirin, phenylbutazone, and various herbal treatments have limited efficacy and potential detrimental
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effects on the gastrointestinal and hematologic systems when used chronically in the horse. There have been some anecdotal reports of intravitreal injections of gentamicin (4 mg) having an effect on preventing recurrent episodes. Use of this therapy is not recommended until further clinical and experimental studies are done.
Table 2. Medical Therapy for Equine Recurrent Uveitis

Medications
Topical Medications Prednisone Acetate 1%

Dose

Indication

Caution

q 1-6 hours

Dexamethasone HCL 0.5-1% Flurbiprofen 0.03%, Diclofenac 0.1% (Voltaren), (or other topical NSAIDS) Cyclosporine A 0.022% Atropine HCL 1%

q 1-6 hours

q 1-6 hours

Potent anti-inflammatory medication with excellent ocular penetration Potent anti-inflammatory medication with excellent ocular penetration Anti-inflammatory medications with good ocular penetration

Predisposes for corneal fungal infection Predisposes for corneal fungal infection Decreases corneal epithelialization

q 6-12 hours

Strong immunosuppressant

q 6 48 hours

Cycloplegic, mydriatics (pain relief and minimize synechia formation)

Poor eye penetration, weak anti-inflammatory effect May decrease gut motility and predispose to colic

Systemic Medications Flunixin Meglumine 0.5 mg/kg PO IV, or IM for 5 days then 0.25 mg/kg PO 4.4 mg/kg PO or IV 100-300 mg/day PO or IM 5-10 mg / day PO or 2.5 5 mg daily IM 1-2 mg Potent ocular anti-inflammatory medication Long-term use may predispose to gastric and renal toxicity Long-term use may predispose to gastric and renal toxicity Frequent side effects, laminitis formation Must taper off dose. Frequent side effects, laminitis formation Must taper off dose. Severe predisposition for bacterial or fungal keratitis, cant remove therapy once given. Severe predisposition for bacterial or fungal keratitis, cant remove therapy once given.

Phenylbutazone

Anti-inflammatory medication

Prednisone

Potent anti-inflammatory medication Potent anti-inflammatory medication Repositol, potent antiinflammatory medication with a 7-10 duration of action Potent anti-inflammatory medication with a 30-60 day duration of action

Azium

Subconjunctival triamcinolone

Intravitreal triamcinolone

5 to 10 mg

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Surgical Therapy for ERU Surgical procedures are aimed at preventing the recurrence of uveitis and therefore provide longterm control of the disease: sustained release cyclosporine devices (CsA) and vitrectomy (CV). Suprachoroidal Placement of a CsA Releasing Device Horses with ERU were implanted with a 6 mm diameter, 25 mg, reservoir matrix CsA implant in the deep sclera adjacent to the suprachoridal space.20,21 Horses with follow-up greater than 1 year were examined for frequency of flares, long-term complications, and need for repeat implantation. Data from 171 eyes of 138 horses that had CsA devices implanted to control ERU was reviewed. Mean follow-up was 32 months (1 to 7 years). Horses with implants had significantly fewer flares after surgery than prior to implantation.21 The most common complication was development of glaucoma, which was in 14% horses. Only 3 eyes required a repeat implant, all 4 years or longer after the first implant. The deep sclera/suprachoroidal placement of the CsA device resulted in excellent long-term control of ERU, with few complications. A recent study of 131 horses implanted 4 years or longer, demonstrated the longterm maintenance of vision of horses with ERU implanted with a cyclosporine implant.22 Because the cyclosporine implant is not FDA approved or commercially available, research continues to search for an available and effective method for the long-term control of ERU Long-Term Prognosis for ERU In general, the prognosis for eyes afflicted with ERU is poor. Most horses with the disease have multiple recurrent episodes that eventually lead to vision deficits. Diligent observation and treatment is required by the owner in many cases to maintain vision long-term. Some horses have progressively increased severity and frequency of their bouts of inflammation and these horses are ones that may benefit from surgical therapy or another method for long-term drug release. References 1. 2. 3. 4. 5. 6. 7. Schwink KL. Equine Uveitis. Vet Clin NA: Equine Pract 1992;8:557-574. Miller TR, Whitley RD. Uveitis in horses. Mod Vet Pract 1987:351-357. Davidson MG. Anterior uveitis In: NE Robinson, ed. Current Therapy in Equine Medicine. Philadelphia: W.B. Saunders, 1992;593-594. Abrams KL, Brooks DE. Equine recurrent uveitis: current concepts in diagnosis and treatment. Equine Pract 1990;12:27-35. Nelson M. Equine recurrent uveitis, a report of 68 horses in the United States and Canada. ERU Network 1995. Rebhun WC. Diagnosis and treatment of equine uveitis. J Am Vet Med Assoc 1979;175:803-808. Commission. Economic impact of the equine racing industry. Public Sector Gaming Study Commission 1999.

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8.

9. 10. 11.

12. 13. 14.

15. 16.

17. 18. 19.

20. 21. 22.

Burgess EC, Gillette D, Pickett JP. Arthritis and panuveitis as manifestations of borrelia burgdorferi infection in a wisconsin pony. J Am Vet Med Assoc 1986;189:1340-1341. Cook CS, Peiffer RL, Harling DE. Equine recurrent uveitis. Equine Vet J 1983;3:57-60. Davidson MG, Nasisse MP, Roberts SM. Immunodiagnosis of leptospiral uveitis in two horses. Equine Vet J 1987;19:155-157. Dwyer AE, Crockett RS, Kalsow CM. Association of leptospiral seroreactivity and breed with uveitis and blindness in horses: 372 cases (1986-1993). J Am Vet Med Assoc 1995;207:1327-1331. Hines MT, Halliwell REW. Autoimmunity to retinal S-antigen in horses with equine recurrent uveitis. Progress in Vet & Comp Ophthalmol 1991;1:283-290. Morter RL, Williams RD, Bolte H, et al. Equine leptospirosis. J Am Vet Med Assoc 1969;155:436-442. Sillerud CL, Bey RF, Ball M, et al. Serologic correlation of suspected leptospira interrogans serovar pomona-induced uveitis in a group of horses. J Am Vet Med Assoc 1987;191:1576-1578. Brem S, Gerhards H, Wollanke B, et al. 35 leptospira isolated from the vitreous boudy of 32 horses with recurrent uveitis. Berl Munch Tierarztl Wochenschr 1999;112:390-393. Faber N, Crawford M, LeFebvre R, et al. Detection of leptospira spp. in the aqueous humor of horses with naturally acquired recurrent uveitis. J Clin Microbiol 2000;38:2731-2733. Romeike A, Brugmann M, Drommer W. Immunohistochemical studies in equine recurrent uveitis (ERU). Vet Pathol 1998;35:515-26. Hines MT, Jarpe A, Halliwell RE. Equine recurrent uveitis: immunization of ponies with equine retinal S antigen. Prog Vet Comp Ophthalmol 1992;2:3-10. Gilger BC, Malok E, Cutter KV, et al. Characterization of T-lymphocytes in the anterior uvea of eyes with chronic equine recurrent uveitis. Vet Immunol Immunopathol 1999;71:17-28. Gilger BC, Malok E, Stewart T, et al. Effect of an intravitreal cyclosporine implant on experimental uveitis in horses. Vet Immunol Immunopathol 2000;76:239-255. Gilger BC, Salmon JH, Wilkie DA, et al. A novel bioerodible deep scleral lamellar cyclosporine implant for uveitis. Invest Ophthalmol Vis Sci 2006:47:2596-2605. Gilger BC, Wilkie DA, Clode AB, et al. Long-term outcome after implantation of a suprachoroidal cyclosporine drug delivery device in horses with recurrent uveitis. Vet Ophthalmol 2010;13(5):294-300.

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