How to Medically Manage a Case of Equine Eosinophilic Keratoconjunctivitis

HOW-TO SESSION: OPHTHALMOLOGY

Chelsey Miller, DVM*; and Mary L. Utter, DVM

Authors’ addresses: Iron Will Mobile Veterinary Service, Chapel Hill, NC 27517 (Miller); University of Pennsylvania, 382 West Street Road, New Bolton Center, Kennett Square, PA 19348–1691 (Utter); e-mail: [email protected]. *Corresponding and presenting author. © 2013 AAEP.

1. Introduction rigorously tested and shown to be superior to any Equine eosinophilic keratitis or keratoconjunctivitis other. Irrespective of treatment, the course of the (EK) is an inflammatory disease of the conjunctiva disease is often extended, and it is not unusual for and cornea. This disease has been described in treatment to extend beyond 1 month. The excep- other veterinary species, including cats,1–6 dogs,7 tion is surgical intervention with a superficial kera- and rabbits8; however, there is a dearth of infor- tectomy, which results in a relatively rapid mation in the veterinary literature regarding this resolution once performed. 10 disease in horses.9–18 The disease appears to have In one case series, Yamagata et al reported on a seasonal component, with the majority of cases seven horses diagnosed with EK in the Midwestern occurring in summer and early fall. EK has been United States from 1976 to 1994. These horses reported in the Quarter Horse, Thoroughbred, Ara- were treated either medically or surgically. Time bian, Warmblood, Mustang, and Icelandic horse to resolution of clinical signs ranged widely, from 14 breeds and in one donkey. No definitive sex or days for one horse that was treated with a superfi- breed predisposition has been identified. The exact cial keratectomy, 90 days for one horse treated with etiology and pathogenesis of EK are still unknown, topical antibiotics only, and between 45 and 106 but EK is postulated to be the result of a hypersen- days for five horses treated with a combination of sitivity reaction to an unknown stimulus, a theory topical medications, including antibiotics and corti- supported by the response to treatment with immu- costeroids. Secondary corneal bacterial or fungal nomodulating drugs in horses and other species.1–17 infections were not identified in these cases. Al- In horses, parasitic causes, such as Onchocerca, though this is a small case series, it supports the Thelazia, and Habronema infections, have been in- hypothesis that topical corticosteroid treatment may vestigated and have not been found to play a role in increase the time to resolution, whereas surgical the development of EK.16 Although a wide range of intervention with a superficial keratectomy may treatment approaches has been used in horses, in- hasten resolution of EK. cluding systemic and topical medications and surgi- After this case series was reported, several case cal interventions, no treatment approach has been reports and case series have described EK in equids.

NOTES

160 2013 ր Vol. 59 ր AAEP PROCEEDINGS HOW-TO SESSION: OPHTHALMOLOGY A single case of EK in a 29-year-old donkey was cases of equine EK and provides additional evidence reported by Jennings.11 The donkey presented that EK is a recurrent, seasonal disease in horses. with a 2-day history of unilateral ocular discharge On the basis of this literature, medical manage- and a limbal mass. After treatment with topical ment of equine EK should include standard ulcer- dexamethasone and topical antibiotics, the lesions ative keratitis regimen (described in Treatment had resolved at the time of a follow-up appointment Approach section) in addition to a short course of 30 days after initiation of treatment. In another systemic corticosteroids to combat the plausible al- single case report of EK, bilateral conjunctival and lergic hypersensitivity component. An H1-receptor periocular skin biopsies were performed in a 17- antagonist, cetirizine, should also be prescribed as year-old Icelandic mare with a 4-week history of both an immediate treatment and future preventa- 17 bilateral conjunctivitis.12 In this mare, BPV-1/-2 tive measure. Although use of topical corticoste- DNA and oncogene E5 transcript were identified, roids in some cases of EK may result in short-term suggesting a role for a viral component in the devel- improvement, the use of topical corticosteroids in opment of EK in horses. the face of a corneal ulcer is dangerous because it The following year in a conference abstract, Sand- may increase the incidence and severity of second- 17 berg et al13 reported EK in a group of three horses ary bacterial and fungal corneal infections. recurring in the summer months over a 2-year pe- 2. Clinical Signs and History riod. All three horses responded poorly to medical therapy with topical antibiotics and topical as well Clinical signs of EK include moderate to severe oc- as systemic corticosteroids but demonstrated rapid ular pain, caseous ocular discharge, severe conjunc- resolution after a superficial keratectomy. Histo- tival hyperemia and chemosis, and pink proliferative corneal plaques, most often originating pathology and transmission electron microscopy of 9–17 the keratectomy specimens identified eosinophils in at the corneolimbal junction. White, cellular the anterior corneal stroma. Allergic dermatitis plaques may be present overlying the pink prolifer- was diagnosed in two of these horses, raising the ative lesions. Individual cases of EK can present possibility of a multi-system eosinophilic disease with clinical signs at any point along the clinical process or general immunoglobulin E–mediated hy- spectrum, from severe conjunctivitis and blepharitis with or without corneal ulceration, to geographic persensitivity disease. Kafarnik15 reported a sin- corneal ulceration with secondary bacterial and/or gle case of EK in a 7-year-old Cob gelding with a fungal involvement. The majority of horses are ex- 3-month history of bilateral corneal ulcers. Super- quisitely painful on presentation with moderate to ficial keratectomy led to resolution in 14 days, with severe epiphora and blepharospasm. The disease no recurrence reported in 6 months of follow-up. can present unilaterally or bilaterally, and severity Diamond burr debridement has been used to treat can differ between left eye and right eye when bilat- horses previously diagnosed with EK and with sub- 18 eral. Reflex uveitis is often present. There was a sequent nonhealing corneal ulcers. Taken to- clear seasonal component, with 92% of cases in one gether, these cases support the hypothesis that study having developed clinical signs from June superficial keratectomy may be associated with through October.17 more rapid resolution of clinical signs than medical Many horses present with a history of similar therapy alone. ophthalmic clinical signs observed by the owner dur- Although the superficial keratectomy has shown ing the summer and early fall months of previous the most promise for achieving rapid resolution of years. In one study, 44% of horses diagnosed with EK, surgical intervention is not the best “first-line” EK had a 1- to 5-year history of confirmed EK.17 treatment for mild or recurrent cases. In addition, An owner may also report that within a single year, even in cases with severe and prolonged disease, their horse exhibits repeated bouts of conjunctivitis, surgical intervention is often declined by owners blepharitis, and corneal ulceration, which respond because of concerns about risks of general anesthe- poorly to routine cornel ulcer management, includ- sia and/or financial constraints. Therefore, identi- ing topical antibiotics and antifungals, systemic fying the best non-surgical approach to treatment of non-steroidal anti-inflammatory drug (NSAID) med- EK is important and useful in managing a disease ication, and topical mydriatic/cycloplegic treatment. that has a seasonally reoccurring component. The Although in many cases the definitive diagnosis of most recent insight into medical management of EK EK cannot be made for previous episodes, awareness is in a retrospective study of 46 eyes in 26 horses.17 of a possible recurrent disease process may raise a In this study, the signalment, history of EK, pre- red flag to the clinician that this is not a typical case senting signs, medical therapy, time to resolution, of ulcerative keratitis. and recurrence during a follow-up period (mean, 1.9; standard deviation [SD], 1.6; range, 0.3–4.7 years) 3. Examination and Diagnosis were evaluated in horses diagnosed with EK from A complete ophthalmic examination should be per- 2008 to 2012. The results of this retrospective study formed to rule out other causes of conjunctivitis, support the use of systemic corticosteroids and a blepharitis, corneal ulceration, and anterior uveitis, systemic histamine 1(H1)-receptor antagonist in if present. Differential diagnoses for EK include

AAEP PROCEEDINGS ր Vol. 59 ր 2013 161 HOW-TO SESSION: OPHTHALMOLOGY other infiltrative, potentially ulcerative corneal dis- migrating to the conjunctiva and cornea could help eases, including fungal, bacterial, parasitic, or viral alleviate the clinical signs of EK in horses. This is keratitis, neoplasia, and calcific band keratopathy.16 supported by in vitro research in an epithelial cell A definitive diagnosis of EK is made on the basis of culture model in which epithelial cells showed signs predominance of eosinophils on corneal or conjunc- of toxicity and a decrease in the rate of wound repair tival cytology in conjunction with clinical signs.16 after treatment with the major eosinophil granule Eosinophils may be accompanied by smaller num- product, major basic protein.19,20 On the basis of bers of mast cells, lymphocytes, plasma cells, and these studies, it can be hypothesized that the pres- neutrophils, in addition to bacteria or fungal hy- ence of degranulating eosinophils on the equine cor- phae, depending on whether a secondary corneal nea could lead to corneal ulceration and failure of infection is present. A brightly eosinophilic, acel- normal corneal healing.20 Therefore, preventing lular, granular material may surround the corneal additional eosinophil recruitment and migration to plaques. On the basis of the results of a general the corneal surface could benefit horses diagnosed ophthalmic examination and cytological evaluation, with EK. Pharmacokinetic studies have identified additional microbial diagnostics should be per- a safe oral dose in horses that achieves similar formed, including bacterial culture and antimicro- plasma concentrations to those achieved in hu- bial susceptibility and fungal culture, because the mans.21 In a histamine-induced cutaneous wheal risk of secondary corneal infection is high in any formation study in horses, it was shown that pre- case of ulcerative corneal disease in horses. treatment with cetirizine inhibited wheal forma- Corneal cytological evaluation is critical to mak- tion.22 These studies support the use of cetirizine ing the diagnosis of EK. The easiest way to ini- in cases of EK as a way to reduce the severity of tially misdiagnose a case of EK as a case of “simple” clinical signs while the horse is having an active ulcerative keratitis or conjunctivitis of another eti- bout of EK or during at-risk times of year, in an ology is to fail to perform cytology. effort to reduce the recurrence rate.17 Extended treatment is the reality for the majority 4. Medical Treatment Approach of cases of equine EK, with more than 80% of cases On the basis of data from a retrospective study of 46 requiring medical treatment for at least 3 months.17 17 eyes in 27 horses, the most effective medical treat- In one retrospective study, time to resolution was ment regimen includes a short, tapering regimen significantly shorter for horses treated with sys- of systemic dexamethasone; systemic H1-receptor temic corticosteroids (mean, 2.23; SD, 1.13 months), antagonist (cetirizine); topical antibiotic and anti- relative to patients that were not so treated (mean, fungal treatment to prevent and/or treat secondary 4.20; SD, 1.47 months).17 Recurrence is common in corneal infection; topical mydriatic/cycloplegic to ad- this disease, with a 33% recurrence rate; however, dress reflex uveitis; and systemic NSAIDs after ces- 17 horses treated with cetirizine are significantly less sation of systemic dexamethasone. likely to have recurrence during the following Eosinophilic keratoconjunctivitis cases are at risk year.17 In one study, recurrence of EK was re- for secondary corneal infection, with 51% of eyes ported for only one of 13 horses (8%) treated with having a positive bacterial or fungal culture in one 17 cetirizine, relative to recurrence in eight of 14 horses study. Therefore, topical antimicrobial therapy (57%) that had not been treated with cetirizine.17 is critical. The medical management of horses diagnosed with EK is routine with respect to treating 5. Monitoring and Follow-Up corneal ulceration and reflex uveitis. Treatment should include a topical antibiotic and antifungal, It is imperative that frequent re-evaluations are topical mydriatic/cycloplegic, and systemic NSAIDs. performed on horses diagnosed with EK, just as with With the exception of mild cases of EK, a tapering any case of equine ulcerative keratitis. However, regimen of systemic dexamethasone is used as fol- following up with owners dealing with equine EK is lows: 0.04 mg/kg for 1 day, 0.03 mg/kg for 2 days, perhaps even more important compared with un- and 0.02 mg/kg for 3 to 5 days.17 The initial dose is complicated ulcerative keratitis because of the pro- typically administered intravenously, with all sub- longed treatment time often required to achieve sequent doses given orally. After treatment with resolution of clinical signs. As many veterinarians systemic dexamethasone, a significant improvement have probably seen in other cases of ophthalmic in conjunctivitis and blepharitis is typically ob- disease requiring frequent daily treatments, an served within 24 to 48 hours. owner’s inability to treat ulcerative keratitis in their Horses diagnosed with EK are also treated with horse can lead to significant worsening of the dis- systemic cetirizine given orally at a dose of 0.4 ease in a short period of time if not reported to or mg/kg twice daily.17 Cetirizine is an H1-receptor appreciated by the veterinarian. A subpalpebral antagonist used for the treatment of seasonal aller- lavage delivery system is often necessary to permit gies in humans. It acts by blocking the H1-receptor extended treatment of horses with EK. Addi- and preventing the histamine-dependent increase in tionally, serum total protein should be monitored adherence and migration of eosinophils.21 Block- weekly and serum creatinine every 2 weeks because ing additional eosinophils from being recruited and of the well-established gastrointestinal and renal

162 2013 ր Vol. 59 ր AAEP PROCEEDINGS HOW-TO SESSION: OPHTHALMOLOGY adverse effects associated with chronic NSAID 3. Andrew SE. Ocular manifestations of feline herpesvirus. administration. J Feline Med Surg 2001;3:9–16. 4. Moore PA. Feline corneal disease. Clin Techniques Small 6. Environmental Management Anim Pract 2005;20:83–93. 5. Malik R, Lessels NS, Webb S, et al. Treatment of feline The role of environmental management in the de- herpesvirus-1 associated disease in cats with famciclovir and velopment and duration of clinical signs of EK is not related drugs. J Feline Med Surg 2009;11:40–48. 6. Spiess AK, Sapienza JS, Mayordomo A. Treatment of pro- completely understood. Controlling EK by environ- liferative feline eosinophilic keratitis with topical 1.5% cyclo- mental modification is predicated on the hypothesis sporine: 35 cases. Vet Ophthalmol 2009;12:132–137. that EK is a hypersensitivity reaction to an environ- 7. de Geyer G, Raymond-Letro I. Canine chronic keratitis with mental allergen. The role of environmental modi- eosinophilic infiltrate: a retrospective study of 28 cases fication in controlling EK was reported by Utter6 on (2004–2007). Proceedings of American College of Veterinary Ophthalmologists Annual Meeting, Chicago, IL 2009. a single farm in July to August 2009. Utter re- 8. Grinninger P, Sanchez R, Kraijer-Huver IM, et al. Eosino- ported the incidence of EK in 19 Standardbred philic keratoconjunctivitis in two rabbits. Vet Ophthalmol broodmares, representing an incidence of 10% on the 2012;15:59–65. farm in a single year. With the addition of specific 9. Ramsey DT, Whiteley HE, Gerding PA Jr, et al. Eosino- philic keratoconjunctivitis in a horse. J Am Vet Med Assoc management changes, including the use of fly 1994;205:1308–1311. masks, fly repellant, night turnout, keeping pasture 10. Yamagata M, Wilkie DA, Gilger BC. Eosinophilic kerato- cut close to the ground, and longer periods of time conjunctivitis in seven horses. J Am Vet Med Assoc 1996; housed in stalls, fewer horses had EK the following 209:1283–1286. year, and overall clinical signs were less severe than 11. Jennings AF. Eosinophilic keratoconjunctivitis in a donkey. British Association of Veterinary Ophthalmology Annual during the previous year. This approach to control- Conference, Hilton Head, SC 2007. ling recurrence of EK is especially significant in 12. Kainzbauer C, Steinborn R, Mair-Scorpio G, et al. PCR- horses not treated with cetirizine because of finan- mediated detection of bovine papillomavirus E5 and L1 DNA cial constraints. in equine eosinophilic conjunctivitis/keratitis. Proceedings of American College of Veterinary Ophthalmologists Annual 7. Conclusions Meeting, Boston, MA 2008. 13. Sandberg CA, Herring IP, Schorling JJ, et al. Ulcerative Eosinophilic keratoconjunctivitis in horses is a dis- eosinophilic keratoconjunctivitis in three horses: clinical ease that can be frustrating for veterinarians, own- course and characterization by electron microscopy. Proceed- ers, and horses alike because of the severity of ings of American College of Veterinary Ophthalmologists An- nual Meeting, Boston, MA 2008. clinical signs and prolonged treatment often re- 14. Utter ME, Keenan D, Makkreel L, et al. Eosinophilic kerato- quired to achieve resolution. Additionally, it is not conjunctivitis in 19 mares on a Standardbred farm. Proceed- uncommon for horses to have additional bouts of ings of American College of Veterinary Ophthalmologists disease during the same year or later years because Annual Meeting, San Diego, CA 2010. 15. Kafarnik C. Equine eosinophilic keratitis. Companion of the high recurrence and seasonality of the dis- Anim 2010;15:4–6. ease. Correctly diagnosing the disease as EK is the 16. Clode AB. 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