Uveodermatologic syndrome or VKH-like syndrome of dogs may affect as many as 4.1% of Akitas and has been sporadically reported for other breeds.1–6 This condition causes immune-mediated damage to melanin-laden tissues, and UDS is a more appropriate term than VKH syndrome for dogs because dogs generally lack the neurologic involvement that characterizes VKH syndrome in humans.2 However, optic nerve meningitis has been histologically detected in dogs with UDS.a
Although the precise pathophysiologic mechanisms underlying UDS remain unknown,7 data suggest that the restricted genetic diversity in Akitas is a contributing factor.1 A genetic predisposition for UDS may be related to specific inherited canine leukocyte antigen alleles and their interaction with melanocyte receptors, leading to the attraction of excess T lymphocytes1 or B lymphocytes.2 Certain alleles such as canine leukocyte antigen DQA1*00201 have been identified as risk factors for UDS1; however, no simple genetic test is available to screen for a UDS risk allele in Akitas. A similar syndrome can be experimentally induced in Akitas, rats, and monkeys through inoculation with tyrosinase-related proteins.8,9 The presence of serum anti-retinal antibody has been reported in an Akita with UDS.10
Diagnosis of UDS in dogs is based heavily on clinical signs, which include bilateral panuveitis with pigment dispersion within the anterior chamber of the eye, retinal detachment, response to immunosuppressive treatment, and breed (most commonly Akita, but a predisposition in Siberian Huskies and Samoyeds is also suspected).7,11,12 When necessary for patient comfort, enucleation is performed and the histologic evaluation of affected enucleated eyes reveals lymphogranulomatous panuveitis and can confirm the diagnosis.2,13 Inflammation commonly targets melanocytes, and melanophages are a frequent finding. Secondary sequelae include glaucoma, preiridal fibrovascular membranes, posterior synechiae, cataract, optic nerve cupping or degeneration, retinal detachment, and retinal atrophy.14,b Bilateral ocular involvement is expected unless uveal pigmentation is asymmetric.7,15
Dermatologic signs of UDS include leukoderma and leukotrichia with erythema, ulceration, and crusting (often visible on the nasal planum or eyelids).6 Histologic evaluation of the skin reveals granulomatous lichenoid dermatitis with a prominent melanophage component and is a useful diagnostic test when skin lesions are present.3 Although disease involving nonocular or dermal sites is uncommon in dogs with UDS, lymphoplasmacytic and histiocytic polymyositis has been reported for a Rat Terrier with chronic UDS,4 and lymphocytic infiltrate within the subarachnoid space reportedly occurs with experimental induction of UDS in dogs.8 In addition, low tear production has been reported for 3 dogs (not Akitas) with UDS7,11,16 and a predisposition for KCS has been reported for humans with VKH syndrome.17
Clinically useful prognostic information pertaining to UDS in the veterinary medical literature is limited owing to small numbers of reported cases. The purpose of the study reported here was to retrospectively evaluate clinical data pertaining to a large group of dogs with UDS to provide detailed information regarding signalment, prognosis, and treatment and identify factors associated with visual prognosis.
Materials and Methods
Case selection criteria
Electronic medical records of the William R. Pritchard Veterinary Medical Teaching Hospital of the University of California-Davis, the veterinary teaching hospitals of the University of Minnesota and North Carolina State University, and Animal Eye Specialists of El Cerrito, Calif, were searched to identify all dogs with a diagnosis of UDS or VKH-like syndrome. Database search terms included VKH, Vogt-Koyanagi-Harada, and uveodermatologic. Akitas were included if they had been evaluated by an ophthalmologist and had characteristic clinical signs of bilateral panuveitis with pigment dispersion without another identified cause. Dogs other than Akitas (ie, non-Akitas) were included if they had clinical signs consistent with UDS and a histologic diagnosis based on a skin biopsy specimen or enucleated globe. Dogs with markedly incomplete patient data were excluded.
Medical records review
Data were extracted from the medical records regarding dog age at initial ophthalmic examination, breed, sex, neuter status, and body weight at all examinations on record; owner-reported duration of clinical signs prior to initial examination; STT results and IOP at initial examination; anterior and posterior segment findings by the attending veterinary ophthalmologist; dermatologic signs; whether dermatologic or ophthalmic signs were identified first; and biopsy results when available. Treatment data were collected, including highest daily dose of orally administered ketoconazole; highest and lowest daily doses of orally administered prednisone, azathioprine, and cyclosporine; nature of any adverse effects of medication and whether any dosage changes were necessary; and topical medications used throughout all documented visits. In addition, data related to prognosis were collected, including status of vision and glaucoma at the time of initial ophthalmic examination, time to onset of previously undiagnosed glaucoma relative to initial examination, time to onset of previously undiagnosed permanent blindness in each eye relative to initial examination, duration of follow-up, and surgeries performed (when recorded).
For the purposes of medical record review, blindness was defined as the lack of a menace response or dazzle reflex or an observed inability to navigate the examination room. Dogs were considered to have had glaucoma if they had an IOP ≥ 25 mm Hg or required ongoing treatment with an antiglaucoma medication. Because prednisone and azathioprine had been administered to some patients every other day, the lowest daily dose associated with these medications was calculated by multiplying the every-other-day dose by 0.5. Highest and lowest body weights over all visits during the study period were recorded for each dog, and then the mean of these values was calculated for each dog.
Order of affected eyes (first or second) was assigned on the basis of the order in which eyes were deemed to have developed an outcome following the initial ophthalmic examination. The following ocular outcomes were recorded for statistical use: whether glaucoma or blindness was noted in the first or second eye (yes or no), time from initial examination to onset of glaucoma in the first and second eye, whether glaucoma or permanent blindness developed in one or both eyes, and time to permanent blindness or glaucoma in the first and second eye.
Statistical analysis
The same statistical softwarec was used for all analyses. The Fisher exact test (for categorical variables) and Mann-Whitney U test (for continuous variables) was used to determine whether differences existed between Akitas and non-Akitas regarding sex distribution, age, duration of clinical signs, highest daily doses of administered prednisone or azathioprine, and whether prednisone was discontinued. The Fisher exact test was used to determine whether breed (Akita or non-Akita) and sex (male or female) were associated with glaucoma or blindness at initial ophthalmic examination. Data for Akitas and non-Akitas were subsequently combined to maximize statistical power.
Kaplan-Meier analysis was performed to estimate median time to development of glaucoma or blindness (32 patients) in the first or second eye. The log-rank test for event-time analyses was used to evaluate associations between time to development of glaucoma or permanent blindness (dependent variable) and breed (Akita or non-Akita), sex (male or female), any use of azathioprine or cyclosporine (yes or no), and whether prednisone was discontinued (yes or no). Cox proportional hazards regression was used to evaluate associations between time to development of glaucoma or permanent blindness and duration of clinical signs, age, highest dose of prednisone administered, and highest dose of azathioprine administered. For all analyses, values of P ≤ 0.05 were considered significant.
Results
Signalment
Fifty dogs, evaluated between January 1, 1985, and December 31, 2013, met the criteria for inclusion in the study. Sites of evaluation included the University of California-Davis (n = 41), North Carolina State University (5), University of Minnesota (2), and Animal Eye Specialists (2). Dogs included 15 (30%) castrated males, 13 (26%) sexually intact males, 5 (10%) males of unknown neuter status, 13 (26%) spayed females, 3 (6%) sexually intact females, and 1 (2%) female of unknown neuter status. Median age at initial ophthalmic examination was 4.1 years (range, 0.8 to 12.7 years); 6 of 50 (12%) dogs had received the UDS diagnosis when ≥ 8 years of age.
Dogs were classified as Akita (n = 37 [74%]), Siberian Husky (3 [6%]), Samoyed (2 [4%]), Labrador Retriever (2 [4%]) mixed breed (2 [4%]), Saint Bernard (1 [2%]), Chow Chow (1 [2%]), Australian Shepherd (1 [2%]), and Basset Hound (1 [2%]). The median value for mean body weight (calculated from the highest and lowest values during the study period) for all dogs was 38 kg (83.6 lb), and all dogs weighed ≥ 20 kg (44 lb). In 10 of 40 (25%) dogs with body weights recorded on multiple visits, body weight varied by ≥ 10 kg (22 lb) over the study period.
No significant difference was detected between Akitas and non-Akitas with respect to sex distribution (P = 0.17) or median age (P = 0.91). However, median mean body weight differed significantly (P = 0.003) between Akitas (42 kg [92.4 lb]; range, 30 to 76 kg [66.0 to 167.2 lb]) and non-Akitas (30 kg [66.0 lb]; range, 20 to 72 kg [44.0 to 158.4 lb]).
History, clinical signs, and diagnostic tests
Median duration of ophthalmic signs in all dogs prior to initial examination was 2 weeks (range, 0 to 104 weeks), and no significant (P = 0.15) difference in median values was identified between Akitas (1 week; range, 0 to 104 weeks) and non-Akitas (3 weeks; range, 0 to 104 weeks). Of the 46 dogs for which vision status was recorded at initial evaluation, 26 (57%) were blind in both eyes, 4 (9%) were blind in 1 eye, and 16 (35%) had vision in both eyes. No significant associations were identified between blindness at initial examination and breed (Akita or non-Akita; P = 0.42), sex (P = 0.91), age (P = 0.14), and duration of clinical signs (P = 0.88).
Of 36 eyes (18 dogs) for which STT results were available for the initial examination, a result ≤ 15 mm/min was recorded for 10 eyes of 7 dogs.18 Only 1 of 7 dogs with a subnormal STT result received a clinical diagnosis of KCS. Of 13 dogs with recorded results of fluorescein staining, 2 had unilateral corneal ulceration.
Of 78 eyes (39 dogs) treated with various ophthalmic medications for which IOP had been recorded at initial examination, 25 (32%) had an IOP ≤ 11 mm Hg, 31 (40%) had an IOP between 11 and 25 mm Hg, and 22 (28°%) had an IOP ≥ 25 mm Hg. In 18 of 50 (36°%) dogs, glaucoma had been diagnosed in at least 1 eye at initial examination owing to a high IOP or ongoing treatment with antiglaucoma medication. No significant associations were identified between glaucoma at initial examination and breed (Akita or non-Akita; P = 0.35), sex (P = 1.00), age (P = 0.53), or duration of clinical signs (P = 0.57).
Observed intraocular signs included aqueous flare (uveitis; n = 35 [70%]), iris abnormalities (eg, rubeosis iridis, iridal edema, synechiae, or pigment deposition on anterior lens capsule; 29 [58%]), retinal detachment (23 [46%]), choroidal depigmentation or chorioretinal infiltrate (10 [20%]), retinal degeneration (9 [18%]), and cataract (6 [12%]; Figures 1 and 2).
Photograph of the right eye of a spayed female Akita with pigment deposition on the anterior lens capsule and Haab striae (arrows) from secondary glaucoma due to UDS. Uveodermatologic syndrome was diagnosed in this patient at 11 months of age, and the dog had been treated medically for several years before this photograph was obtained. After this photograph was obtained and prior to last recheck examination, the eye shown required a gentamicin intravitreal injection because of uncontrolled glaucoma. At the final recheck examination, this dog was 5.8 years old and had vision in the left eye, was blind in the right eye, and was receiving azathioprine (1.4 mg/kg [0.64 mg/lb], PO) and prednisone (0.2 mg/kg [0.09 mg/lb], PO) every other day as well as dorzolamide twice a day for the left eye.
Citation: Journal of the American Veterinary Medical Association 252, 10; 10.2460/javma.252.10.1263
Photograph of the right eye of a spayed female Akita with pigment deposition on the anterior lens capsule and Haab striae (arrows) from secondary glaucoma due to UDS. Uveodermatologic syndrome was diagnosed in this patient at 11 months of age, and the dog had been treated medically for several years before this photograph was obtained. After this photograph was obtained and prior to last recheck examination, the eye shown required a gentamicin intravitreal injection because of uncontrolled glaucoma. At the final recheck examination, this dog was 5.8 years old and had vision in the left eye, was blind in the right eye, and was receiving azathioprine (1.4 mg/kg [0.64 mg/lb], PO) and prednisone (0.2 mg/kg [0.09 mg/lb], PO) every other day as well as dorzolamide twice a day for the left eye.
Citation: Journal of the American Veterinary Medical Association 252, 10; 10.2460/javma.252.10.1263
Photograph of the right eye of a spayed female Akita with pigment deposition on the anterior lens capsule and Haab striae (arrows) from secondary glaucoma due to UDS. Uveodermatologic syndrome was diagnosed in this patient at 11 months of age, and the dog had been treated medically for several years before this photograph was obtained. After this photograph was obtained and prior to last recheck examination, the eye shown required a gentamicin intravitreal injection because of uncontrolled glaucoma. At the final recheck examination, this dog was 5.8 years old and had vision in the left eye, was blind in the right eye, and was receiving azathioprine (1.4 mg/kg [0.64 mg/lb], PO) and prednisone (0.2 mg/kg [0.09 mg/lb], PO) every other day as well as dorzolamide twice a day for the left eye.
Citation: Journal of the American Veterinary Medical Association 252, 10; 10.2460/javma.252.10.1263
Fundus photographs of the right eye of a 5-year-old castrated male Akita with UDS at initial ophthalmic examination (A) and 14 days later (B). A—Acute bullous retinal detachment can be seen in the inferior retina. B—Sharply demarcated depigmentation of the retinal pigment epithelium and choroid is evident, which is characteristic of a chronic UDS lesion. At initial examination, this patient had bilateral retinal detachments, was blind in both eyes, and was treated with prednisone (2 mg/kg [0.9 mg/lb], PO) and azathioprine (1 mg/kg [0.45 mg/lb], PO) daily and 1 drop of 1% prednisolone acetate ophthalmic suspension in both eyes 3 times daily. This patient regained vision 8 days after treatment was initiated and retained vision until the final follow-up visit 3.25 years after diagnosis, when an inconsistent menace response was identified in both eyes.
Citation: Journal of the American Veterinary Medical Association 252, 10; 10.2460/javma.252.10.1263
Fundus photographs of the right eye of a 5-year-old castrated male Akita with UDS at initial ophthalmic examination (A) and 14 days later (B). A—Acute bullous retinal detachment can be seen in the inferior retina. B—Sharply demarcated depigmentation of the retinal pigment epithelium and choroid is evident, which is characteristic of a chronic UDS lesion. At initial examination, this patient had bilateral retinal detachments, was blind in both eyes, and was treated with prednisone (2 mg/kg [0.9 mg/lb], PO) and azathioprine (1 mg/kg [0.45 mg/lb], PO) daily and 1 drop of 1% prednisolone acetate ophthalmic suspension in both eyes 3 times daily. This patient regained vision 8 days after treatment was initiated and retained vision until the final follow-up visit 3.25 years after diagnosis, when an inconsistent menace response was identified in both eyes.
Citation: Journal of the American Veterinary Medical Association 252, 10; 10.2460/javma.252.10.1263
Fundus photographs of the right eye of a 5-year-old castrated male Akita with UDS at initial ophthalmic examination (A) and 14 days later (B). A—Acute bullous retinal detachment can be seen in the inferior retina. B—Sharply demarcated depigmentation of the retinal pigment epithelium and choroid is evident, which is characteristic of a chronic UDS lesion. At initial examination, this patient had bilateral retinal detachments, was blind in both eyes, and was treated with prednisone (2 mg/kg [0.9 mg/lb], PO) and azathioprine (1 mg/kg [0.45 mg/lb], PO) daily and 1 drop of 1% prednisolone acetate ophthalmic suspension in both eyes 3 times daily. This patient regained vision 8 days after treatment was initiated and retained vision until the final follow-up visit 3.25 years after diagnosis, when an inconsistent menace response was identified in both eyes.
Citation: Journal of the American Veterinary Medical Association 252, 10; 10.2460/javma.252.10.1263
The first identified clinical signs of UDS were ocular abnormalities (n = 33 [66%]) and dermatologic lesions (8 [16%]). Ophthalmic and dermatologic lesions had developed concurrently or in an undetermined order in 9 (18%) dogs. Dermatologic signs included leukoderma (n = 28 [56%]); scaling or erythema (12 [24%]); alopecia (8 [16%]); mucocutaneous erosions often centered around the nasal planum, mouth, eyelids, or periocular skin (8 [16%]); and leukotrichiae (7 [14%]). A 6.5-year-old spayed female Labrador Retriever with initial periocular erythema and alopecia and unremarkable intraocular examination findings subsequently developed poliosis and bilateral uveitis 1 and 10 months after initial examination, respectively (Figure 3). Eleven of 13 (85%) non-Akitas and 22 of 37 (59%) Akitas had dermatologic manifestations recorded at initial examination.
Photograph of a 6.5-year-old spayed female Labrador Retriever mix with marked periocular erythema and crusting (A) at initial examination, followed by leukotrichia 3 months later (B). This UDS patient initially had no intraocular clinical signs but developed marked bilateral uveitis I0 months after initial examination. Secondary glaucoma developed in the right eye that necessitated enucleation 24 months after initial examination. This patient required phacoemulsification after a cataract developed in the left eye 31 months after initial examination and retained vision through to the final recheck examination (at 57 months) while receiving 0.1% diclofenac ophthalmic solution, prednisone (0.2 mg/kg, PO), cyclosporine (4 mg/kg [1.8 mg/lb], PO), and ketoconazole (8 mg/kg [3.6 mg/lb], PO), all once daily.
Citation: Journal of the American Veterinary Medical Association 252, 10; 10.2460/javma.252.10.1263
Photograph of a 6.5-year-old spayed female Labrador Retriever mix with marked periocular erythema and crusting (A) at initial examination, followed by leukotrichia 3 months later (B). This UDS patient initially had no intraocular clinical signs but developed marked bilateral uveitis I0 months after initial examination. Secondary glaucoma developed in the right eye that necessitated enucleation 24 months after initial examination. This patient required phacoemulsification after a cataract developed in the left eye 31 months after initial examination and retained vision through to the final recheck examination (at 57 months) while receiving 0.1% diclofenac ophthalmic solution, prednisone (0.2 mg/kg, PO), cyclosporine (4 mg/kg [1.8 mg/lb], PO), and ketoconazole (8 mg/kg [3.6 mg/lb], PO), all once daily.
Citation: Journal of the American Veterinary Medical Association 252, 10; 10.2460/javma.252.10.1263
Photograph of a 6.5-year-old spayed female Labrador Retriever mix with marked periocular erythema and crusting (A) at initial examination, followed by leukotrichia 3 months later (B). This UDS patient initially had no intraocular clinical signs but developed marked bilateral uveitis I0 months after initial examination. Secondary glaucoma developed in the right eye that necessitated enucleation 24 months after initial examination. This patient required phacoemulsification after a cataract developed in the left eye 31 months after initial examination and retained vision through to the final recheck examination (at 57 months) while receiving 0.1% diclofenac ophthalmic solution, prednisone (0.2 mg/kg, PO), cyclosporine (4 mg/kg [1.8 mg/lb], PO), and ketoconazole (8 mg/kg [3.6 mg/lb], PO), all once daily.
Citation: Journal of the American Veterinary Medical Association 252, 10; 10.2460/javma.252.10.1263
Histologic evaluation of skin biopsy specimens (n = 16) or enucleated eyes (5) was performed for 19 dogs (6 Akitas and all 13 non-Akitas). All dermal biopsy specimens had evidence of histiocytic or lichenoid dermatitis, whereas all enucleated eyes had evidence of lymphoplasmacytic or lymphogranulomatous uveitis. Dermal histologic evaluation also revealed a lymphocytic inflammatory component (n = 7), pigmentary incontinence (6), folliculitis (3), acanthosis (2), furunculosis (2), hyperkeratosis (2), or a suppurative inflammatory component (1). Enucleated eyes also had secondary glaucoma (3), preiridal fibrovascular membranes (2), retinal detachment (2), and retinal atrophy (2).
Treatment
The most common topical ocular anti-inflammatory medication prescribed was 1% prednisolone acetate (n = 34 [68% of all dogs]). The most common topical ocular antiglaucoma medications prescribed were dorzolamide (n = 15 [30%]) and timolol (10 [20%]). Dogs also orally received prednisone (n = 42) and azathioprine (22), and dosages of these drugs varied throughout the treatment course. Median highest and lowest daily doses of prednisone were 2.0 mg/kg (0.9 mg/lb) and 0.26 mg/kg (0.12 mg/lb), respectively. Median highest and lowest daily doses of azathioprine were 1.6 mg/kg (0.7 mg/lb) and 0.68 mg/kg (0.31 mg/lb; Figure 4). No significant association was identified between Akitas and non-Akitas with regard to highest daily dose of prednisone administered (P = 0.87), highest daily dose of azathioprine administered (P = 0.85), and whether prednisone administration was discontinued (P = 0.33).
Box-and-whisker plots of the highest and lowest daily doses of prednisone (n = 42 and 38 dogs, respectively) and azathioprine (22 and 21 dogs, respectively) administered PO to dogs with UDS. The central black and white lines within each box represent the median and mean, respectively; lower and upper boundaries of each box represent the 25th and 75th percentiles, respectively; whiskers represent the 10th and 90th percentiles; and circles indicate outlier values.
Citation: Journal of the American Veterinary Medical Association 252, 10; 10.2460/javma.252.10.1263
Box-and-whisker plots of the highest and lowest daily doses of prednisone (n = 42 and 38 dogs, respectively) and azathioprine (22 and 21 dogs, respectively) administered PO to dogs with UDS. The central black and white lines within each box represent the median and mean, respectively; lower and upper boundaries of each box represent the 25th and 75th percentiles, respectively; whiskers represent the 10th and 90th percentiles; and circles indicate outlier values.
Citation: Journal of the American Veterinary Medical Association 252, 10; 10.2460/javma.252.10.1263
Box-and-whisker plots of the highest and lowest daily doses of prednisone (n = 42 and 38 dogs, respectively) and azathioprine (22 and 21 dogs, respectively) administered PO to dogs with UDS. The central black and white lines within each box represent the median and mean, respectively; lower and upper boundaries of each box represent the 25th and 75th percentiles, respectively; whiskers represent the 10th and 90th percentiles; and circles indicate outlier values.
Citation: Journal of the American Veterinary Medical Association 252, 10; 10.2460/javma.252.10.1263
Of the 42 dogs that orally received prednisone, 15 (36%) had adverse effects that necessitated a dosage reduction or discontinuation. These effects included polyuria or polydipsia (n = 6), hepatopathy (4), muscle wasting or weakness (2), diarrhea (2), lethargy (2), urinary tract infection or cystitis (2), anorexia (1), inappropriate urination (1), and polyphagia (1). Oral azathioprine administration was discontinued for 8 dogs owing to hepatopathy (n = 3), lethargy (2), pancytopenia (1), and thrombocytopenia (1). In 13 dogs, oral prednisone administration was discontinued completely, often following introduction of azathioprine (n = 5) or cyclosporine (2). Four patients were treated by oral cyclosporine administration, at highest daily doses of 5.0, 5.1, 5.7, and 7.65 mg/kg (2.27, 2.32, 2.59, and 3.48 mg/lb). Ketoconazole was orally administered to 2 dogs at highest daily doses of 8.2 and 8.6 mg/kg (3.73 and 3.91 mg/lb) to decrease the amount of cyclosporine required.
Follow-up
Eight (16%) dogs had no follow-up information available. Median duration of follow-up for the remaining 42 (84%) dogs was 10 months (0.3 to 59 months). Twenty-seven (64%) dogs with available follow-up information had no glaucoma in either eye at initial examination, and 3 (7%) dogs had glaucoma in only 1 eye. Median time to development of glaucoma in the first and second eyes for dogs initially free of glaucoma in at least 1 eye was 9 months (range, 0.5 to 51 months; n = 27) and 9.5 months (range, 0.3 to 54 months; 30), respectively (Figure 5). None of the following variables were significantly associated with time to development of glaucoma in the first and second eyes, respectively, of dogs with vision at initial examination: breed (P = 0.49 and P = 0.35), sex (P = 0.55 and P = 0.44), any use of azathioprine (P = 0.82 and P = 0.68) or cyclosporine (P = 0.09 and P = 0.22), whether prednisone administration was discontinued (P = 0.54 and P = 0.73), duration of clinical signs prior to initial examination (P = 0.32 and P = 0.52), age (P = 0.90 and P = 0.74), highest daily dose of prednisone administered (P = 0.60 and P = 0.95), and highest daily dose of azathioprine administered (P = 0.93 and P = 0.98).
Kaplan-Meier plots depicting time from initial ophthalmic examination to development of glaucoma (A; n = 30 dogs initially free of glaucoma in at least 1 eye) or blindness (B; 32 dogs initially with vision in at least 1 eye) in the first affected (dashed line) and second affected (solid line) eyes of dogs with UDS for which follow-up information was available. In panel A, the probability of remaining glaucoma free decreased to 0 because the dog with the longest follow-up duration developed glaucoma approximately 50 months after initial examination.
Citation: Journal of the American Veterinary Medical Association 252, 10; 10.2460/javma.252.10.1263
Kaplan-Meier plots depicting time from initial ophthalmic examination to development of glaucoma (A; n = 30 dogs initially free of glaucoma in at least 1 eye) or blindness (B; 32 dogs initially with vision in at least 1 eye) in the first affected (dashed line) and second affected (solid line) eyes of dogs with UDS for which follow-up information was available. In panel A, the probability of remaining glaucoma free decreased to 0 because the dog with the longest follow-up duration developed glaucoma approximately 50 months after initial examination.
Citation: Journal of the American Veterinary Medical Association 252, 10; 10.2460/javma.252.10.1263
Kaplan-Meier plots depicting time from initial ophthalmic examination to development of glaucoma (A; n = 30 dogs initially free of glaucoma in at least 1 eye) or blindness (B; 32 dogs initially with vision in at least 1 eye) in the first affected (dashed line) and second affected (solid line) eyes of dogs with UDS for which follow-up information was available. In panel A, the probability of remaining glaucoma free decreased to 0 because the dog with the longest follow-up duration developed glaucoma approximately 50 months after initial examination.
Citation: Journal of the American Veterinary Medical Association 252, 10; 10.2460/javma.252.10.1263
For the 27 dogs with vision in both eyes at initial examination, median time to permanent blindness in the first eye was 12 months (range, 0.4 to 52 months). For dogs with vision in at least 1 eye, median time to permanent, complete blindness in both eyes was 13.5 months (range, 0.4 to 59 months; n = 32). Twenty-five (50%) dogs had vision in at least 1 eye at the last documented visit, representing 78% of the 32 dogs that had vision at initial examination or regained vision during the follow-up period. Of the 32 aforementioned dogs, 12 (38%) dogs that initially had vision retained that vision, 3 (9%) dogs with an initially ambiguous vision status later had and maintained vision, 10 (31%) dogs that were initially blind regained vision, and 7 (22%) dogs that initially had vision became blind. Of the 17 dogs that initially had vision in at least 1 eye and that had ≥ 6 (n = 13) or 12 (4) months of follow-up, 10 and 3 dogs, respectively, retained vision in at least 1 eye through to the final visit during the study period. Ten of 100 (10%) eyes were enucleated (3 dogs had bilateral enucleation), and 1 (1%) eye was treated with an intravitreal gentamicin injection over the duration of the study. None of the following variables were significantly associated with time to development of blindness in the first or second eye, respectively, in dogs with vision in at least 1 eye at initial examination: breed (P = 0.40 and P = 0.14), sex (P = 0.33 and P = 0.43), any use of azathioprine (P = 0.29 and P = 0.47), any use of cyclosporine (P = 0.16 and P = 1.00), whether prednisone administration was discontinued (P = 0.57 and P = 0.39), duration of clinical signs prior to initial examination (P = 0.83 and P = 0.82), age (P = 0.47 and P = 0.70), highest daily dose of prednisone administered (P = 0.30 and P = 0.23), and highest daily dose of azathioprine administered (P = 0.22 and P = 0.25).
Discussion
The present study expanded upon information provided in prior reports5–7,11–13,16,19–22 involving fewer dogs, yielding detailed clinical information for 50 dogs with UDS, including 37 Akitas and 13 non-Akitas. Breeds with reported UDS include Siberian Husky,6,22 Australian Sheepdog,6 Saint Bernard,6 Shetland Sheepdog,6,23 Old English Sheepdog,6 Golden Retriever,6 Dachshund,21 Bassett Hound,24 Samoyed,19 Fox Terrier,25 Irish Setter,19 Chow Chow,11 Brazilian Fila,5 Jack Russell Terrier,4 Rat Terrier,11 Miniature Poodle,16 German Shepherd Dog,12 and Bernese Mountain Dog.26 Mixed-breed dogs can also have UDS.3 Although suggested previously,a the Labrador Retriever with UDS in the present study adds to this list. Consistent with previous reports,1,6,8 dogs with UDS in the present study were typically young to middle aged, with a median age of 4.1 years, and most were male (66%) and Akitas (74%).
In dogs, bilateral uveitis combined with dermatologic abnormalities and anterior uveal pigment dispersion or choroidal depigmentation is highly suggestive of UDS. However, 66% of dogs with UDS in the present study had ophthalmic signs prior to dermatologic signs, supporting the suggestion11 that uveitis is more often observed prior to dermatologic signs. Consequently, UDS should be considered as a differential diagnosis for all dogs with uveitis for which an underlying cause cannot be identified by physical examination, infectious disease testing, or systemic imaging. Histologic evaluation of skin biopsy specimens can be useful in the diagnosis of UDS in dogs with dermatologic lesions.
Schirmer tear testing, fluorescein staining, and IOP monitoring are considered an important part of UDS management. Low tear production, possibly due to concurrent immune-mediated lacrimal gland adenitis, has been reported for several non-Akita UDS patients7,11,16 and was identified in several patients in the present study. There is no known direct link between UDS and KCS, but preliminary research in human medicine suggests that patients with autoimmune disease of the uvea (VKH syndrome) may be at higher risk of autoimmune KCS than the general human population.17 Intraocular pressure at initial ophthalmic examination of the dogs in the present study varied, and some dogs were receiving antiglaucoma medications at the time of this examination. Approximately one-third of the dogs had an IOP in each category (≤ 11 mm Hg, 11 to 25 mm Hg, and ≥ 25 mm Hg) at this point, emphasizing the variability of IOP in UDS patients. Over the course of the study, secondary glaucoma was the most common potentially blinding complication, diagnosed in at least 1 eye of approximately half of all dogs.
Other factors associated with blindness in dogs with UDS in the present study were difficult to discern through the retrospective design, but retinal detachment and lens abnormalities including cataract were detected in 46% and 12% of all dogs, respectively. The number of dogs with these signs may have been underestimated owing to anterior segment disease or incomplete medical records. Variables including age, sex, breed, duration of clinical signs prior to examination, or treatment regimen had no measurable association with time from initial examination to development of glaucoma or blindness in either eye. Because most dogs received some form of oral immunosuppressive treatment, this factor could not be included in statistical analysis. Of dogs with vision at initial examination, a shorter duration of clinical signs prior to examination was not associated with an improved outcome. Despite this finding, rapid referral to an ophthalmologist is recommended for dogs with suspected UDS. Any effect of clinical sign duration on outcomes in the present study may have been disguised by variable speed of onset or bias introduced if blind dogs were brought in for evaluation earlier than nonblind dogs.
Immunosuppressive treatment, beginning with corticosteroid administration, is the primary treatment for dogs with UDS as documented here and is similar to the situation for humans with VKH syndrome. In physician-based ophthalmic practice, intravitreal steroid administration, use of implantable ocular devices, and initial pulse therapy with methylprednisolone are common.27 Study of these treatment modalities is warranted for dogs with UDS. Median highest (generally initial) and lowest daily doses for oral prednisone administration in the present study were 2 and 0.26 mg/kg, respectively. Immunosuppressive treatment in humans can reportedly be discontinued after a minimum of 6 months.28 However, in dogs, UDS can recur and may be more difficult to detect; thus, recurrence can be ophthalmologically devastating. If bilateral enucleation has been performed, long-term treatment with immunosuppressants is not usually necessary in dogs unless skin lesions are noticed that are more severe than depigmentation.7,11,29
Adverse effects are a major treatment consideration for dogs with UDS, with approximately one-third of patients in the present study requiring a prednisone dosage adjustment because of adverse effects. In 25% of dogs, body weight varied by ≥ 10 kg over the study period. This weight gain likely reflected an adverse effect of oral prednisone administration, which causes polyphagia.30 Body weight monitoring is important during treatment of these dogs to allow for dietary control of weight gain, to ensure appropriate dosage of medication, and to avoid clinically important comorbidities, such as orthopedic injury.31
The study reported here represents the first in which the use of orally administered cyclosporine was documented in multiple dogs with UDS, aside from a single case report11 in a Rat Terrier with UDS. Cyclosporine is a logical adjunctive treatment for UDS owing to its T-cell inhibitory effect27,32,33; however, minimal transcorneal absorption necessitates oral administration.34 Because cyclosporine treatment can be expensive, particularly in large-breed dogs, 2 dogs also received an oral ketoconazole formulation with the aim of decreasing metabolism of cyclosporine by inhibiting cytochrome P450, which allows for reduction of the cyclosporine dose by 75%.35 Therapeutic drug monitoring may assist management of UDS in dogs receiving oral cyclosporine treatment, particularly those receiving cytochrome P450 inhibitors and those that do not respond to treatment as expected. Other relevant immunosuppressant medications used in human medicine with potential use for dogs with UDS include cyclophosphamide, chlorambucil, and mycophenolate mofetil.27,28,36 In a case report,16 mycophenolate mofetil was used, albeit unsuccessfully, in a Miniature Poodle with UDS and concurrent KCS. Successful use of mycophenolate mofetil has also been reported as a steroid-sparing agent for people with VKH syndrome.28,36
Dogs needed only a menace response or ability to navigate a room to be considered to have intact vision in the present study. Many dogs with vision had clinically important (partial) vision deficits not reflected in the statistical findings. Only 25 (50%) of all dogs had vision in 1 or both eyes at the last documented visit. For these reasons, visual prognosis may be considered guarded for UDS. The number of eyes with vision at follow-up was relatively small and may have contributed to an inability to detect statistical differences between groups. Specific medications or daily doses used were not significantly associated with improved outcomes as far as glaucoma or vision, which may have reflected variability in treatment regimens, individual responses to medication, or the small sample size. Ultimately, no prognostic factors were identified and no particular treatment regimen was clearly superior to another.
In the present study, 10 eyes were enucleated to provide long-term comfort for affected dogs. However, additional enucleation surgeries may have been performed at the referring practices after these patients were lost to follow-up, likely making this number artificially low. Of dogs with vision when first examined by a veterinary ophthalmologist, 78% retained vision in at least 1 eye when subsequently monitored by an ophthalmologist over a long period. This high vision retention rate may have been inflated if clients were less likely to return for follow-up visits after their dogs became blind. Nonetheless, this finding suggested that some dogs with UDS can effectively be managed to retain vision for a prolonged period.
The limitations of the study reported here were typical of retrospective studies, including heterogeneous data, treatments, and follow-up. To maximize the number of patients included in the study, the medical records from multiple academic and private practice facilities were used and no histologic diagnosis of UDS was required for Akitas. Because the study included only dogs taken to veterinary ophthalmologists, the findings may have underrepresented UDS patients in which dermatologic signs were clinically more apparent than ophthalmic signs. Despite these limitations, the present study yielded detailed clinical information to further understanding of UDS in dogs and clinically relevant prognostic data. The findings could be useful in the design and implementation of prospective studies on UDS in this species.
Acknowledgments
Supported by the National Institutes of Health (grant No. K08 EY021142).
Presented in abstract form at the American College of Veterinary Ophthalmologists 2015 Annual Conference, Coeur d'Alene, Idaho, October 2015.
ABBREVIATIONS
| IOP | Intraocular pressure |
| KCS | Keratoconjunctivitis sicca |
| STT | Schirmer tear test I |
| UDS | Uveodermatologic syndrome |
| VKH | Vogt-Koyanagi-Harada |
Footnotes
Beckwith-Cohen B, Dubielzig RR. The clinical vs histopathological diagnosis of VKH: are we getting it right (oral presentation)? Comparative Ocular Pathology Society 1st Annual Meeting, Madison, Wis, September 2013.
Dubielzig R, Comparative Ocular Pathology Laboratory of Wisconsin, Madison, Wis: Personal communication, 2013.
Stata/IC, version 10.1, StataCorp LP, College Station, Tex.
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