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The objectives of this study were to determine the demographics of horses with equine recurrent uveitis (ERU) presenting to the Western College of Veterinary Medicine and to describe and compare the prognosis of ERU in the Appaloosa with that in other breeds. Horses diagnosed with ERU by a veterinary ophthalmologist between 2002 and 2015 were included. Eye lesions were classified as mild, moderate, or severe based on clinical manifestations. Breed, age, severity, blindness, and final outcome were evaluated. Thirty-two horses fit the inclusion criteria; 62.5% were Appaloosas. Mean age at presentation was 12.13 ± 4.6 years. Equine recurrent uveitis was bilateral in 93.6% of horses and was severe in 59.4% of eyes at presentation. Bilateral blindness was present in 59.4% of horses at last follow-up. Of 27 horses available for follow-up, 63% were euthanized due to ERU. No significant differences in age, severity, blindness, or rate of euthanasia were noted between Appaloosas and other breeds. The Appaloosa is at increased risk for ERU, which is a devastating ocular disease.
Uvéite équine récurrente dans les provinces de l’Ouest canadien : étude rétrospective (2002–2015). L’objectif de cette étude consistait à déterminer les données démographiques des chevaux atteints d’uvéite équine récurrente (UER) présentés au Western College of Veterinary Medicine et de décrire et de comparer le pronostic de l’UER chez les chevaux Appaloosa avec celui des autres races. Les chevaux diagnostiqués entre 2002 et 2015 comme étant atteints de l’UER par un ophtalmologiste vétérinaire ont été inclus. Les lésions à l’œil étaient classées comme étant légères, modérées ou graves selon les manifestations cliniques. La race, l’âge, la gravité, la cécité et le résultat final ont été évalués. Trente-deux chevaux correspondaient aux critères d’inclusion : 62,5 % étaient des chevaux Appaloosa. L’âge moyen à la présentation était de 12,13 ans ± 4,6 années. L’uvéite équine récurrente était bilatérale chez 93,6 % des chevaux et était grave pour 59,4 % des yeux à la présentation. La cécité bilatérale était présente chez 59,4 % des chevaux au dernier suivi. Parmi les 27 chevaux disponibles pour le suivi, 63 % ont été euthanasiés en raison de l’UER. Aucune différence significative au niveau de l’âge, de la gravité, de la cécité ou du taux d’euthanasie n’a été signalée entre les chevaux Appaloosa et les autres races. Les chevaux Appaloosa présentent un risque accru d’UER, qui est une maladie oculaire dévastatrice.
(Traduit par Isabelle Vallières)
Equine recurrent uveitis (ERU) is a common condition with worldwide distribution, high prevalence, and is the leading cause of blindness in horses (1). It is characterized by chronic insidious or recurring bouts of inflammation of the uveal tissue which leads to secondary changes ultimately resulting in blindness (1). Three clinical forms of ERU have been described: classic, insidious, and posterior (1). Classic ERU is the most common form and is characterized by active inflammatory episodes followed by periods of minimal observable ocular inflammation. Insidious ERU is characterized by constant and subtle intraocular inflammation that does not typically manifest as outwardly painful episodes. The clinical impression is that the insidious form is most commonly seen in the Appaloosa and draft breeds (1). In posterior uveitis the inflammation is predominately in the posterior segment, and this syndrome is most common in Warmbloods, draft breeds, and horses imported from Europe to the USA (1).
The pathophysiology of ERU is complex and not completely determined. It is known to be an autoimmune disease; however, the mechanisms of the inciting cause and recurrence of inflammatory episodes are not completely understood. The association of Leptospira spp. with ERU is well-known but not fully understood (2–12). It is theorized that for at least some horses, infection with Leptospira spp. may be the inciting cause of uveitis (2–5,12,13). The cells infiltrating the uvea of horses with ERU are predominantly CD4+ T-cells and a T-helper type 1 (Th1)-mediated disease process is implicated (14–17). As ERU has an immune-mediated pathogenesis, it is possible that the genetic make-up of the individual plays an important role in determining the susceptibility to potential inciting infections, as well as the development and severity of subsequent uveitis episodes. Genetic associations for ERU have been confirmed in both the Appaloosa and the German Warmblood horse breeds and remain under investigation (18–20).
The frequency of ERU in the Appaloosa horse is reportedly much higher than in the general population and uveitis is thought to be more severe and more likely to cause blindness in this breed (2,11,21). Although the overall prognosis for ERU is thought to be poor, objective data are limited to few retrospective studies reporting the long-term visual prognosis for the disease (2,11,22). These studies originate in the northeastern and southeastern United States and there are no objective data originating in Canada. The objectives of this study were to determine the demographics of horses with ERU presenting to a referral center in western Canada, and to describe and compare the prognosis of ERU in the Appaloosa horse with that in other breeds.
A search of the medical records of the Western College of Veterinary Medicine (WCVM) at the University of Saskatchewan was completed to identify all horses with a confirmed diagnosis of ERU between the period of 2002 and 2015. Diagnosis of ERU required complete ocular examination performed by a Diplomate of the American College of Veterinary Ophthalmologists (DACVO). Ocular examination in all horses included neuro-ophthalmic examination, followed by sedation with IV xylazine hydrochloride (Rompun; Bayer, Toronto, Ontario), 0.5 to 1.0 mg/kg body weight (BW) and auriculopalpebral nerve blocks performed using 2 mL of a 2% lidocaine hydrochloride injectable solution (Bimeda-MTC Animal Health, Cambridge, Ontario). Schirmer tear test (Schirmer Tear Test Strips; Alcon Canada, Mississauga, Ontario), rebound (Tonvet; Tiolat, Helsinki, Finland) or applanation tonometry (Tonopen XL; Biorad Ophthalmic Division, Santa Clara, California, USA), and fluorescein staining (Fluorets; Bausch & Lomb Canada, Markham, Ontario) were completed on all horses. Direct transilluminator, biomicroscopic (Osram 64222; Carl Zeiss Canada, Don Mills, Ontario or SL-14, Kowa, Tokyo Japan) and indirect ophthalmoscopic (Heine Omega 200; Heine Instruments Canada, Kitchener, Ontario) examinations were completed following mydriasis with tropicamide 1% solution (Mydriacyl; Alcon Canada, Mississauga, Ontario).
Equine recurrent uveitis was confirmed if there was presence of active uveitis in addition to historical or clinical evidence of previous episodes or continuous uveal inflammation. Eyes were classified as having mild, moderate, or severe ERU based on recorded clinical manifestations. Eyes with conjunctival hyperemia, aqueous flare, miosis, and ocular hypotony (defined as ≤ 10 mmHg or 10 mmHg difference between eyes) were considered to have mild ERU. Eyes with signs of mild ERU and 1 or more of posterior synechia, cataract, vitritis, or uveal pigmentation changes (depigmentation or hyperpigmentation) were considered to have moderate ERU. Eyes with secondary glaucoma, phthisis bulbi, retinal detachment, and/or blindness due to sequela of ERU were considered to have severe ERU. Breed, age, severity, final outcome, and causes of blindness were evaluated. If final outcome was not recorded in the medical record, owners were contacted to arrange for re-evaluation, if possible, or to determine if the horse had been euthanized due to ERU.
Statistical analysis was completed using SAS Version 9.3 software (StataCorp, College Station, Texas, USA). Outcomes for Appaloosa horses were compared to the combined outcomes of other breeds due to low numbers in the latter group. Median age was compared using the Kruskal-Wallis test. The Fisher exact test was used to compare the stage of ERU at presentation, the probability of having 1 or 2 eyes with blinding ERU at presentation and at final outcome, and to evaluate the probability of euthanasia due to the diagnosis of ERU. The number of Appaloosa horses diagnosed with ERU was compared to non-Appaloosa horses with ERU within the total equine hospital population at risk, and for each breed presenting with ERU using the Fisher exact test. Relative risk of Appaloosa horses versus non-Appaloosa horses having ERU was calculated for the at-risk population examined by the ophthalmology service. The “at-risk” population was designated as horses ≥ 4 y of age as this was the youngest age of horse diagnosed with ERU.
Thirty-two horses fit the criteria of the study; 20 (62.5%) Appaloosa horses, and 12 (37.5%) other breeds consisting of 4 Quarter Horse (QH)/QH-cross, 3 Thoroughbred (TB)/TB-cross, 2 Pony of the Americas (POA), 1 miniature horse, 1 Percheron, and 1 Hanoverian. For the Appaloosa, 13 were castrated males and 7 were female. In other breeds 7 were castrated males and 4 were female. Age at presentation ranged from 4 to 23 y. Mean age at presentation was 12.13 (± 4.6) y. Median age at presentation was not significantly different between Appaloosa horses (12 y) and other breeds (11.5 y).
For horses that were not euthanized immediately after diagnosis, clinical follow-up ranged from 1 to 9 y (mean: 3.81 ± 2.97 y). Information on final outcome with respect to euthanasia was available for 27 horses; 3 Appaloosas, and 2 other breeds were lost to follow-up. Serological testing for leptospirosis was completed on 3 horses; 1 Appaloosa for which the result was negative and 2 non-Appaloosa horses for which there was a positive leptospirosis titer (≥ 1:400).
During the period under study, 145 Appaloosa horses were presented to the WCVM for all reasons of a total 5091 equine consultations, accounting for 2.8% of the clinic population. Within the Appaloosa breed, horses presenting with ERU represented 20 of 145 (13.8%) total Appaloosa consultation examinations performed in the hospital. Twelve of the 4946 non-Appaloosa horses presented to the WCVM with ERU (0.24%). The odds ratio (OR) for an Appaloosa horse presenting to the hospital for ERU compared to the total non-Appaloosa hospital population was 65.79 [95% confidence interval (CI): 31.47 to 137.52; P < 0.001]. The odds of the Appaloosa horse presenting to the WCVM with ERU were significantly greater than that of other breeds diagnosed with ERU with the exception of the POA, and Hanoverian (Table 1). Appaloosa horses represented 26 of 178 (14.6%) equine ophthalmology consultations and 20/26 (76.9%) Appaloosas examined by the ophthalmology service were diagnosed with ERU. Of the horses examined by the ophthalmology service, the relative risk of an Appaloosa being diagnosed with ERU was 9.74 (95% CI: 5.44 to 17.44; P < 0.0001).
At presentation, ERU was bilateral in 30 (93.6%) and unilateral in 2 horses, both of which were TB breed. Both of these TB horses were available for re-evaluation examination and ERU was confirmed to remain unilateral 2 and 8 y after initial diagnosis. The majority of eyes were classified as having severe ERU at presentation and severe bilateral ERU was present in most horses at last follow-up (Table 2). There were no significant differences in severity at presentation or at last follow-up between the Appaloosa and other breeds.
The majority of eyes (56.2%) were blind at initial presentation (Table 3). At initial examination, 24 of 32 (75%) horses were blind in one or both eyes and this increased to 28 of 32 (87.5%) horses at last follow-up. There were no significant differences between the Appaloosa and other breeds related to blindness in one or both eyes at presentation and last examination.
Blindness was most commonly associated with cataract (26 Appaloosa eyes; 11 other breed eyes), phthisis bulbi (13 Appaloosa eyes; 4 other breed eyes), and glaucoma (11 Appaloosa eyes; 4 other breed eyes) (Figure 1). Other noted sequelae of ERU included lens luxation (5 Appaloosa eyes: 3 other breed eyes), posterior synechia (13 Appaloosa eyes, 8 other breed eyes), and retinal detachment as diagnosed by indirect ophthalmoscopy (4 other breed eyes). All blind eyes had more than 1 sequela of ERU.
A variety of treatments were employed including topical (diclofenac, flurbiprofen) and systemic (flunixin meglumine, phenylbutazone, aspirin) non-steroidal anti-inflammatory medications, topical corticosteroids (prednisolone acetate, dexamethasone), topical atropine, and topical antiglaucoma medications when indicated (dorzolamide, dorzolamide/timolol).
Three Appaloosa horses and 1 non-Appaloosa horse had 1 eye enucleated due to severe ERU. Euthanasia due to ERU was the final outcome in 17/27 (63%) (9 Appaloosa; 8 other breed) horses. Nine horses were euthanized at the time of initial diagnosis. Median time to euthanasia for other horses was 3.5 y (0.5 to 8 y). One Appaloosa was euthanized for reasons other than ERU but was bilaterally blind at the time. No significant differences existed in rate of euthanasia due to ERU between Appaloosas and other breeds.
Of the 6 Appaloosa horses known to be alive to date, 2 are bilaterally blind and 4 remain visual in both eyes; these horses have been followed clinically for 6 mo to 2 y. Of the 3 non-Appaloosa horses known to be alive to date, 2 are unilaterally blind, the other visual in both eyes. These horses have both been followed clinically for 2 to 8 y.
The prevalence of ERU in our hospital population was much higher in the Appaloosa horse (13.8%) compared to other breeds (0.24%) and the OR for the Appaloosa presenting for ERU was very high compared to the general hospital population. These numbers must be interpreted with caution as ophthalmic examinations were not completed on all horses presenting to the hospital and it is likely that ERU was present and undiagnosed in some horses in the general population. The relative risk for a diagnosis of ERU in the Appaloosas examined by the ophthalmology service was 9.74, demonstrating ERU was much more likely to be diagnosed in the Appaloosa than in other breeds examined. Of the 32 horses with confirmed ERU, the Appaloosas represented 62.5% of the ERU population which is much higher than 24% and 25% reported in previous retrospective studies (2,11).
Our study found a higher overall frequency of bilateral disease (93.5%) compared to a recent retrospective (67.5%) (11). A higher proportion overall of blind eyes at presentation (56.2% compared to 28.4%) as well as bilateral blindness on follow-up (59.4% compared to 28.9%) was also noted in our study. Similar to previous reports, blindness was most commonly associated with cataract, phthisis bulbi, and secondary glaucoma (2,11). At last follow-up 87.5% of horses (85% Appaloosa and 91.6% non-Appaloosa horses) were blind in at least 1 eye. This is higher than previous studies which reported 43.8% and 63.4% of horses blind in one or both eyes (2,11). Bilateral blindness occurred in 50% of Appaloosa horses and 75% of non-Appaloosa horses examined. The proportion of bilaterally blind Appaloosa horses in our study falls within the range of 39% to 58% reported previously (2,11). However, we report a much higher frequency of bilateral blindness in non-Appaloosa horses compared to the 35.7% and 8.3% reported previously (2,11).
The retrospective nature of this study did not allow us to objectively and assuredly assign a diagnosis of insidious, classic, or posterior uveitis. Most horses presented with moderate to severe forms of the disease and some had never been treated for ERU prior to referral. The resulting clinical manifestations may represent insidious uveitis, or a classic form which was undiagnosed and untreated. Additionally, posterior uveitis may not have been recognized due to the severity of anterior segment disease. Diagnosis of the form of uveitis would have required earlier referral, and long-term management which was not possible in many of our cases.
There may be many reasons for the noted disparities in our study compared to previous reports. The age at presentation was virtually identical to previous reports; therefore, this is unlikely to have played a role (2,11). However, geographic location, horse population, and hospital case load are potential factors that may have impacted our results. The number of horses in our study is smaller compared to previous reports; however, our study employed strict inclusion criteria for ERU. The study by Dwyer et al (2) investigated the association of leptospiral seroreactivity and breed with uveitis and blindness. The inclusion criteria were not limited to cases with confirmed recurrent or continuous uveitis. Thus, it is possible that a number of horses, which may not have had ERU as we have defined it, were included in that study and direct comparisons of visual outcome may not be possible. In the report by Gerding et al (11) 46.2% of horses with ERU received cyclosporine implants as a therapy for ERU (11). This therapy has been reported to reduce recurrence of uveitis episodes and improve long-term maintenance of vision in horses with ERU (23). These devices are recommended for horses with vision and lacking significant ocular conditions suggestive of advanced ERU and are not recommended for horses with active, inflamed eyes that cannot be controlled with topical or systemic anti-inflammatory medications (23). Cyclosporine implants were not available at the WCVM until the later years of our study; however, most horses in our study would not have fit the criteria for implantation due to severity as 59.4% of eyes presented in the severe stage of disease. Additionally, the insidious nature of the disease seen commonly in the Appaloosa may limit the utility of this therapy in the breed. Although we were unable to apply an ERU classification, Appaloosa horses accounted for 62.5% of ERU cases in this series and it is possible many of these horses had the insidious form of the disease.
The association of Leptospira spp. with ERU is well-known, particularly Leptospira interrogans serotype Pomona; however, this association is not completely understood. It is theorized that for at least some horses, infection with Leptospira spp. is the inciting cause of uveitis (2,4,5,12,13). Its role in chronic recurrences of the disease is debated, but likely involves interaction with the immune system (16,17,24–28). Previous studies have reported an increased incidence of vision loss in seropositive horses, particularly in Appaloosas (2,11). Leptospira interrogans serotype Pomona was reported to be enzootic in the equine population in Saskatchewan in 1979; however, recent surveys are lacking (29). Testing for leptospirosis was minimal at our practice and thus, conclusions regarding the potential role for this agent in ERU in our equine population cannot be made.
Equine recurrent uveitis has been shown to have significant personal, occupational, and economic impact (11). Unfortunately, euthanasia was the most common final outcome for most horses in this study. This was higher (63%) than in 1 previous report (14.9%) and may be related to smaller numbers of horses, increased incidence of blindness, and differences in economic status and decisions made by owners in different regions (11). Poor outcomes for this population may also indicate a lack of early recognition of the condition, delayed referral, and therefore diminished therapeutic options and success.
Although our study shows that ERU is more common in the Appaloosa, we could not retrospectively make objective conclusions regarding the number and breed of horses with insidious versus classic ERU. The clinical impression is that the insidious form of ERU is more common in the Appaloosa than in other breeds. The reasons for this difference are unknown but may reflect different pathogeneses. Recent investigations using a candidate gene approach identified 3 genetic markers significantly associated with insidious ERU in Appaloosa horses (18). These included a single nucleotide polymorphism (SNP) within intron 11 of the TRPM1 gene on ECA1, an MHC class I microsatellite (472-260), and an MHC class II microsatellite (eqMHC1) both located in intron 1 of the DRA gene on ECA20 (18). The relative risk of ERU was 2 to 3 times higher with each allele for the TRPM1 SNP (18). The TRPM1 gene is responsible for the Leopard complex (LP) spotting patterns for which the Appaloosa has been selected (30,31). Expression of this gene is reduced in the retina and skin of Appaloosa horses (30,31). Reduced expression in the retina of LP/LP horses is the cause of congenital stationary night blindness (CSNB); however, its role in pigmentation is not understood (30–32). The TRPM1 gene may play a role in immune function as it is also known to be expressed in human B- and T-lymphocytes, monocytes, and hematopoietic cell lines (33,34); however, these potential roles have yet to be investigated in the equine species.
Although overall numbers of POAs within the hospital population were low (6), our data suggest that the POA may also be overrepresented for ERU. The POA is a breed developed in the United States with a foundation stallion that was an Arabian/Appaloosa/Shetland pony cross; POAs have characteristic LP spotting patterns. Other breeds with LP spotting include the Knabstrupper, Noriker, American miniature, and British spotted pony. Increased risk of ERU has not been reported in these breeds; however, it may be worth investigating along with the potential role of TRPM1 in ERU. Anecdotally, there is a suggested association between severity of ERU and extent of roaning in Appaloosa horses. Unfortunately, phenotype with respect to spotting patterns and roaning was not available for most horses in this study and thus, a relationship of phenotype and ERU could not be determined.
Our data also suggest over-representation of the Hanoverian breed for ERU. This warmblood horse breed, which originates in Germany, is known to have a high frequency of ERU in which heredity has been shown to play a role (19,20,35). There is an association between ERU and equine MHC class I haplotypes in the Hanoverian (35). In addition, genome wide association studies (GWAS) have identified a significant SNP on ECA20 located close to the candidate genes IL-17A, and IL-17F. The IL-17 cytokine is pro-inflammatory and is associated with cell damage during autoimmune disease including uveitis (15,36).
This study demonstrates that ERU in western Canadian Prairie Provinces is a devastating ocular disease that is most commonly bilateral, frequently results in bilateral blindness, and that euthanasia is a common final outcome. Most horses present to veterinary ophthalmologists at middle-age with advanced stages of disease which may limit therapeutic options and effectiveness. Thus, early recognition of the disease and referral may improve outcomes. The Appaloosa, and possibly the POA and Hanoverian are over-represented for ERU in western Canada. Future investigation of the association of ERU with LP as well as genes involved in immune system function may improve our understanding of the pathogenesis of this disease in the Appaloosa horse.
The authors acknowledge Drs. Laura Field and Vanessa Holly for their contributions to data collection and analysis. CVJ
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