Evaluation of canine serum for the presence of antiretinal autoantibodies in sudden acquired retinal degeneration syndrome

OBJECTIVE: To determine the presence of serum antiretinal antibodies in sudden acquired retinal degeneration syndrome (SARDS) affected dogs and the size of the antigen to which these antibodies bind via the use of enzyme-linked immunosorbent assay (ELISA) and Western blot immunoassays. ANIMALS STUDIED: Serum was collected from 13 dogs affected by SARDS and five dogs with normal ocular examinations. PROCEDURES: All serum samples were subjected to ELISA with saline-soluble canine retinal tissue and Western blot analyses with SDS solubilized normal canine retinal tissue as the antigen. Antirecoverin (23 kDa) and antiheat shock cognate (65 kDa) antibodies were used as positive controls for both procedures. Affinity-purified goat antidog IgG and IgM labeled with horseradish peroxidase were used for all clinical samples and goat antirabbit IgG was used as the secondary antibody for the positive controls. RESULTS: ELISA demonstrated antibody reaction with all samples. Western blot immunoassays identified multiple bands in all canine serum samples, as well as in negative controls. Approximate sizes of the bands were 25 and 50 kDa, corresponding to IgG light and heavy chains, respectively. CONCLUSION: No antiretinal autoantibodies were identified in the serum of dogs affected by SARDS as compared to normal canine patients.     

Acute blindness in dogs: Sudden acquired retinal degeneration syndrome versus neurological disease (140 cases, 2000–2006)

Objective  To evaluate dogs with amaurosis and compare signalment, history, ophthalmic examination and neurologic abnormalities between dogs diagnosed with sudden acquired retinal degeneration syndrome (SARDS) versus neurological disease (ND). Animals Studied-140 dogs with acute vision loss and ocular abnormalities insufficient to account for visual deficits. An electroretinogram (ERG) was performed on each dog.
Procedures  Medical records were reviewed and information was collected for all dogs meeting the inclusion criteria. Dogs diagnosed with SARDS were compared to those with ND based on signalment, duration of clinical signs, past medical problems, clinicopathologic findings, and ophthalmic and physical examination abnormalities.
Results  120 dogs were diagnosed with SARDS and 20 dogs with ND based on ERG results. Mixed-breed dogs were most commonly diagnosed with SARDS as well as ND. Pure breed dogs frequently diagnosed with SARDS included the Miniature Schnauzer and Dachshund. Dogs with SARDS did not differ significantly from those with ND based on age or sex distribution. Cushing's-like symptoms were reported more frequently in SARDS dogs as well as conjunctival hyperemia and retinal vascular attenuation. Papilledema and asymmetric visual deficits were observed more frequently in dogs with ND. Dogs with ND were no more likely than SARDS dogs to have additional neurological deficits.
Conclusions  Appreciable overlap of clinical signs exists between dogs with SARDS and dogs with ND resulting in acute vision loss. As a significant portion of dogs (14%) in the present study were diagnosed with ND, an ERG to rule out ND is indicated in dogs with amaurosis.     

Evaluation of a comparative pathogenesis between cancer-associated retinopathy in humans and sudden acquired retinal degeneration syndrome in dogs via diagnostic imaging and western blot analysis

OBJECTIVE: To evaluate dogs with sudden acquired retinal degeneration syndrome (SARDS) for evidence of pituitary gland, adrenal gland, and pulmonary neoplasia and antiretinal antibodies and to evaluate dogs with neoplasia for antiretinal antibodies. ANIMALS: 57 clinically normal dogs, 17 with SARDS, and 53 with neoplasia. PROCEDURE: Thoracic radiography, ultrasonography of adrenal glands, and contrast-enhanced computed tomography of pituitary glands were performed in 15 dogs with SARDS. Western blot analysis was performed on sera of all dogs; recoverin (23 kd) and arrestin (48 kd) retinal antibodies were used as positive controls. RESULTS: Neoplasia was not detected via diagnostic imaging in dogs with SARDS. Western blot analysis revealed bands in all dogs ranging from > 48 to < 23 kd. Prominent bands with equivalent or greater density than 1 or both positive controls at the 1:1,000 dilution, and present at the 1:3,000 dilution, were detected in 28% of clinically normal dogs, 40% of dogs with neoplasia, and 41% of dogs with SARDS. No bands in dogs with SARDS had a consistent location of immune activity, and none were detected at the 23-kd site. The area around the 48-kd site had increased immune activity in all 3 groups. CONCLUSIONS AND CLINICAL RELEVANCE: The etiology of SARDS in dogs does not appear to be similar to cancer-associated retinopathy in humans on the basis of absence of differential antibody activity against retinal proteins. Although dogs with SARDS often have clinical signs compatible with hyperadrenocorticism, neoplasia of the adrenal glands, pituitary gland, or lungs was not detected.     

Sudden acquired retinal degeneration syndrome (SARDS) – a review and proposed strategies toward a better understanding of pathogenesis,early diagnosis,and therapy

Sudden acquired retinal degeneration syndrome (SARDS) is one of the leading causes of currently incurable canine vision loss diagnosed by veterinary ophthalmologists. The disease is characterized by acute onset of blindness due to loss of photoreceptor function, extinguished electroretinogram with an initially normal appearing ocular fundus, and mydriatic pupils which are slowly responsive to bright white light, unresponsive to red, but responsive to blue light stimulation. In addition to blindness, the majority of affected dogs also show systemic abnormalities suggestive of hyperadrenocorticism, such as polyphagia with resulting obesity, polyuria, polydipsia, and a subclinical hepatopathy. The pathogenesis of SARDS is unknown, but neuroendocrine and autoimmune mechanisms have been suggested. Therapies that target these disease pathways have been proposed to reverse or prevent further vision loss in SARDS‐affected dogs, but these treatments are controversial. In November 2014, the American College of Veterinary Ophthalmologists' Vision for Animals Foundation organized and funded a Think Tank to review the current knowledge and recently proposed ideas about disease mechanisms and treatment of SARDS. These panel discussions resulted in recommendations for future research strategies toward a better understanding of pathogenesis, early diagnosis, and potential therapy for this condition.     

Retinopathy associated with ivermectin toxicosis in two dogs

CASE DESCRIPTION: 2 dogs (dogs 1 and 2) were examined for sudden onset of blindness. Both dogs had mild obtundation and mydriasis in both eyes. It was thought that dog 1 may have ingested ivermectin; dog 2 had been treated with ivermectin for demodectic mange. CLINICAL FINDINGS: On initial examination, both dogs had mydriasis and decreased pupillary light reflexes in both eyes. Dog 1 had an absent menace response bilaterally. Fundic examination of both eyes in both dogs revealed regions of multifocal retinal edema and folds with low-lying retinal separation. The electroretinogram was extinguished in dog 1 and attenuated in dog 2. Ivermectin was detected in serum samples from both dogs. TREATMENT AND OUTCOME: Both dogs made a complete clinical recovery following cessation of exposure to ivermectin; electroretinographic findings improved, and retinal edema resolved with some residual chorioretinal scarring. CLINICAL RELEVANCE: To our knowledge, this is the first report of resolution of retinal edema and electroretinographic changes associated with ivermectin toxicosis in dogs. In dogs that develop blindness suddenly, fundic examination, electroretinography, and assessment of serum ivermectin concentration are diagnostically useful, even if exposure to ivermectin is unknown.     

Retinal degeneration in nine Swedish Jämthund dogs

The Jämthund is the fourth most common breed in Sweden with approximately 1600 pups registered each year. Although it has been known that some adult dogs go blind, so they cannot hunt, the Jämthund dog has historically not been screened for hereditary eye diseases. This report describes nine Swedish Jämthund dogs with retinal degeneration. These dogs represent all Jämthund dogs diagnosed with progressive retinal atrophy (PRA) by the Swedish Eye Panel and registered with the Swedish Kennel Club from January 1998 to September 2008. The dogs were examined with indirect opthalmoscopy and slitlamp biomicroscopy. Additionally, electroretinograms (ERGs) following ECVO guidelines were performed in two dogs (one affected and one normal) and the eyes from three affected dogs were examined by light‐microscopy postmortem. Typical findings were bilateral symmetric generalized retinal degeneration with tapetal hyper‐reflectivity, attenuation of blood vessels and pigment clumping in the nontapetal fundus. These retinal findings progressed with time in two dogs after re‐examination. Visual impairment, especially under dim light conditions, was observed in the affected dogs. ERG from one affected dog showed profoundly reduced rod responses, whereas cone responses were better preserved. Microscopic changes in the eyes from three dogs were characterized by a severe diffuse predominantly outer retinal degeneration and atrophy. Re‐sequencing of the prcd‐gene for eight of the nine investigated dogs revealed that none of the individuals carried disease allele that has been associated with prcd‐PRA in other breeds. In conclusion, ophthalmoscopic, electroretinographic, and light‐microscopic alterations observed in nine Jämthund dogs were compatible with PRA. The prcd mutation was excluded as a cause of this retinopathy.     

Feline retinal degeneration: clinical experience and new findings (1994-1997)

A retrospective case series of 26 cats with diffuse retinal degeneration is presented. The most common presenting complaints included bumping into objects, dilated pupils, and reluctance to jump. Ophthalmic examination findings were consistent with those reported in dogs with progressive retinal atrophy. Breed predilection of the Siamese cat was observed. Cats with primary retinal degeneration presented late in the clinical course of their disease, when vision loss was severe. Early symptoms such as night blindness and secondary ocular complications (i.e., cataract and retinal detachment), reported in dogs with progressive retinal degeneration, were not observed in this study. All cats showed excellent adaptive capabilities to blindness.     

RETINAL DEGENERATION IN GREYHOUNDS

Retinal degeneration in 10 Greyhounds with clinical and ophthalmoscopic features is described, including results of electroretinography and fluorescein angiography for one affected dog. Clinical and histologic features differed from other kinds of retinal degeneration in dogs.     

Assessment of retinal function and characterization of lysosomal storage body accumulation in the retinas and brains of Tibetan Terriers with ceroid-lipofuscinosis

OBJECTIVE: To characterize lysosomal storage body accumulation in the retina and brain of Tibetan Terriers with ceroid-lipofuscinosis and determine whether the disease in these dogs is accompanied by impaired retinal function and retinal degeneration. ANIMALS: Three 7- to 10-year-old Tibetan Terriers with ceroid-lipofuscinosis and 1 healthy 5-year-old Tibetan Terrier. PROCEDURE: Owners completed a questionnaire to identify behavioral and physical signs indicative of ceroid-lipofuscinosis. Neurologic, behavioral, and ophthalmologic evaluations, including full-field electroretinograms, were performed on each dog. Fluorescence, light, and electron microscopy were performed on specimens of retina, cerebral cortex, and cerebellum of all dogs postmortem. RESULTS: Behavioral assessments of the affected dogs revealed moderate visual impairment in low-light conditions but good vision in bright light. On funduscopic evaluation of these dogs, abnormalities detected ranged from none to signs of moderately advanced retinal degeneration. Compared with findings in the control dog, electroretinography revealed depressed rod cell function with some impairment of cone cell function in the affected dogs. Morphologically, disease-specific storage bodies were detected in retinal Müller cells and neurons, particularly in ganglion cells, and in cells of the cerebral cortex and cerebellum in affected dogs. Substantial photoreceptor cell loss and disruption of photoreceptor outer segment morphology appeared to develop late in the disease. IMPLICATIONS FOR HUMAN MEDICINE: The similarities between ceroid-lipofuscinosis in Tibetan Terriers and some forms of ceroid-lipofuscinosis in humans suggest that the canine disease may have a genetic and biochemical basis similar to that of one of the ceroid-lipofuscinosis disorders in humans.     

Familial non-rcd1 generalised retinal degeneration in Irish setters

Four Irish setters were diagnosed with bilateral retinal degeneration and cataracts at an age ranging from six to 11 years. In three of these dogs, progressive night blindness was reported from an age of eight to 11 years. In the fourth dog, aged six, no signs of visual impairment had been noticed. In all four dogs, the rod-cone dysplasia type 1 (rcd1) mutation was excluded as a cause, using an allele-specific PCR. From their three-generation pedigrees, a familial relationship was detected in three out of four dogs, which were also related to four additional Irish setter dogs with a history and clinical signs suggestive of late-onset progressive retinal degeneration. These results suggest the existence of a possibly hereditary, late-onset, progressive retinal atrophy in the Irish setter breed, that is distinct from rcd1.     

Autoantibodies against glial fibrillary acidic protein (GFAP) in cerebrospinal fluids from Pug dogs with necrotizing meningoencephalitis

Cerebrospinal fluids (CSFs) from 9 Pug dogs with necrotizing meningoencephalitis (NME: Pug dog encephalitis) were examined to identify the antigens for anti-astrocyte autoantibodies. Each CSF exhibited a positive reaction to the cytoplasm of cultured canine astrocytes by an indirect fluorescent antibody test. In an immunoblotting analysis on normal canine brain proteins, eight of 9 CSFs showed a common band of 52 kDa, corresponding to glial fibrillary acidic protein (GFAP), and all of 9 CSFs reacted with purified bovine GFAP. From these results, GFAP is one of the common autoantigens in Pug dogs with NME. On the other hand, the reactivity of CSFs to chymotrypsin-digested bovine GFAP fragments were variable among dogs, indicating that the antibodies in the CSFs recognized different epitopes on GFAP.     

Retinal degeneration in the dog and cat

Retinal degenerations in the dog and cat are an important cause of blindness in these species. Particularly in the dog, many retinal degenerations, collectively called progressive retinal atrophy, seen in clinical practice are inherited. The clinical signs, electrophysiological findings, pathology, and underlying biochemical defects in the retina vary from breed to breed. Specific categories of inherited retinal degeneration are now recognized, and classified into early onset photoreceptor dysplasias, late-onset retinal degenerations, or retinal degenerations secondary to primary RPE dystrophy. As new inherited retinal degenerations are reported in different breeds they can generally be assigned to one these categories. Other causes of retinal degeneration include nutritional deficiencies, glaucoma, inflammation, ischemia, and toxins. Idiopathic retinal degeneration occurs in the dog with some frequency.     

Clinical, electrophysiological and morphological changes in a case of hereditary retinal degeneration in the Papillon dog

An autosomal recessive retinal disease with a late onset in Swedish Papillon dogs has recently been described. A 7-year-old Papillon dog showed no obvious signs of visual impairment and only minor ophthalmoscopic changes. Cone ERG b-wave amplitudes were within normal limits, while rod responses were nonrecordable or severely abnormal. Ultrastructural examination showed a generalized retinal degenerative disease, most prominent in the peripheral areas. The inferior retina was more severely affected than the superior areas. Both rods and cones showed morphological changes. The Papillon dog is another dog breed affected by progressive rod-cone degeneration, with similarities to the canine retinal disease given the gene symbol prcd .     

Novel feline autoimmune blistering disease resembling bullous pemphigoid in humans: IgG autoantibodies target the NC16A ectodomain of type XVII collagen (BP180/BPAG2).

In humans and dogs, bullous pemphigoid (BP) is an autoimmune blistering disease associated with the production of basement membrane autoantibodies that target the 180-kd type XVII collagen (BP180, BPAG2) and/or the 230-kd plakin epidermal isoform BPAG1e (BP230). In two adult cats, an acquired dermatosis and stomatitis was diagnosed as BP subsequent to the fulfillment of the following criteria: 1) presence of cutaneous vesicles, erosions, and ulcers; 2) histologic demonstration of subepidermal vesiculation with inflammatory cells, including eosinophils; 3) in vivo deposition of IgG autoantibodies at the epidermal basement membrane zone; and 4) serum IgG autoantibodies targeting a 180-kd epidermal protein identified as type XVII collagen. In both cats, the antigenic epitopes targeted by IgG autoantibodies were shown to be situated in the NC16A ectodomain of type XVII collagen, a situation similar to that of humans and dogs with BP. Feline BP therefore can be considered a clinical, histopathologic, and immunologic homologue of BP in humans and dogs.     

Multifocal chorioretinal lesions in Borzoi dogs

OBJECTIVES: To identify the prevalence of Borzoi chorioretinopathy in western Canada, characterize lesions with fluorescein angiography, determine if lesions were progressive, clarify the association of progressive retinal atrophy and investigate the etiology. MATERIALS AND METHODS: Serial ophthalmic examination, fundus photography, electroretinography, and fluorescein angiography were used to evaluate Borzoi dogs with lesions of Borzoi chorioretinopathy. Pedigree analysis and test breeding of two affected dogs were completed to determine the heritability of Borzoi chorioretinopathy. RESULTS: One hundred three Borzoi dogs were examined between 1998 and 2003. Focal, peripheral, tapetal, hyper-reflective and pigmented areas consistent with focal retinal degeneration and RPE pigmentation were identified in 12 dogs between 7 months and 7 years of age. Seven males and five female dogs were affected. Ophthalmoscopy and fundus photography over 5 years revealed individual lesions that did not progress or coalesce in 12 affected dogs. Electroretinography of affected and normal Borzoi dogs confirmed that retinal function was similar in normal and affected dogs up to 7 years of age. Fluorescein angiography was performed in three affected dogs and confirmed intact blood-ocular barriers, focal retinal pigment epithelium hypertrophy, and focal absence of choroiocapillaris corresponding to chronic, focal lesions. Pedigree analysis precluded simple dominant, X-linked dominant, or X-linked recessive inheritance. One male dog from the test-bred litter developed bilateral lesions at 14 months of age. Simple recessive, polygenetic, and acquired etiologies of these lesions cannot be ruled out at this time. CONCLUSIONS: Borzoi chorioretinopathy is an acquired condition that initially manifests as focal retinal edema and loss of choriocapillaris and tapetum. With time the retina degenerates becoming hyper-reflective and with RPE hyper-pigmentation and clumping within the borders of the tapetal lesions. Choriocapillaris remains hypofluorescent on fluorescein angiography. Progressive retinal atrophy was excluded as an etiology of multifocal chorioretinopathy in Borzois dogs. This condition is not inherited by simple autosomal dominant or sex-linked modes of inheritance.     

EVALUATION OF DIAPHRAGMATIC MOTION IN NORMAL AND DIAPHRAGMATIC PARALYZED DOGS USING M‐MODE ULTRASONOGRAPHY

Diagnosis of unilateral diaphragmatic paralysis in dogs is currently based on fluoroscopic detection of unequal movement between the crura. Bilateral paralysis may be more difficult to confirm with fluoroscopy because diaphragmatic movement is sometimes produced by compensatory abdominal muscle contractions. The purpose of this study was to develop a new method to evaluate diaphragmatic movement using M‐mode ultrasonography and to describe findings for normal and diaphragmatic paralyzed dogs. Fifty‐five clinically normal dogs and two dogs with diaphragmatic paralysis were recruited. Thoracic radiographs were acquired for all dogs and fluoroscopy studies were also acquired for clinically affected dogs. Two observers independently measured diaphragmatic direction of motion and amplitude of excursion using M‐mode ultrasonography for dogs meeting study inclusion criteria. Eight of the clinically normal dogs were excluded due to abnormal thoracic radiographic findings. For the remaining normal dogs, the lower limit values of diaphragmatic excursion were 2.85–2.98 mm during normal breathing. One dog with bilateral diaphragmatic paralysis showed paradoxical movement of both crura at the end of inspiration. One dog with unilateral diaphragmatic paralysis had diaphragmatic excursion values of 2.00 ± 0.42 mm on the left side and 4.05 ± 1.48 mm on the right side. The difference between left and right diaphragmatic excursion values was 55%. Findings indicated that M‐mode ultrasonography is a relatively simple and objective method for measuring diaphragmatic movement in dogs. Future studies are needed in a larger number of dogs with diaphragmatic paralysis to determine the diagnostic sensitivity of this promising new technique.     

Clinical findings in early onset cone-rod dystrophy in the Standard Wire-haired Dachshund

OBJECTIVE: To describe the clinical findings and the age of onset of cone-rod dystrophy (crd) in the Standard Wire-haired Dachshund (SWHD) and to evaluate which clinical tests could be used to obtain a reliable diagnosis. ANIMALS: Sixty-eight SWHD and SWHD-derived dogs were used, including 23 affected with crd and 45 controls, respectively. PROCEDURES: The dogs were subjected to behavioral testing, examination of pupillary light reflexes (PLRs), indirect ophthalmoscopy and bilateral full field electroretinography (ERG). RESULTS: The majority of affected puppies (5-10 weeks) displayed pin-point sized pupils upon examination with focal light. All dogs in the control group, except one, displayed normal PLRs upon examination. In all crd-affected dogs there was a great variation both in age of onset and in clinical appearance of retinal changes upon fundoscopy. Two siblings displayed panretinal degeneration at the age of 10 months while other affected dogs showed early changes at the age of 3 years. Generalized bilateral retinal atrophy was the end stage of the disease. The maze test revealed no obvious differences among affected and unaffected groups. ERG recordings showed only slightly reduced rod, and mixed rod-cone responses, but severely reduced cone single flash a- and b-wave amplitudes, and cone flicker amplitudes were observed in all affected dogs. CONCLUSION: Presence of pin-point sized pupils in young SWHDs was found to be an important indicator of early onset crd. Fundoscopic changes and progression of disease at later stages resembled those previously described in the majority of progressive retinal atrophies in dog. ERG was found to be the most reliable diagnostic procedure to clinically diagnose crd in the SWHD.     

Uveitis associated with poliosis and vitiligo in six dogs

Idiopathic panuveitis with retinal detachment was associated with facial poliosis, vitiligo, and alopecia in 6 dogs; 4 were adult males. Dermatohistologic examination of affected facial sites from all dogs revealed a lichenoid dermatitis and unusual histiocytic cells. Intensive topical and systemic corticosteroid and topical mydriatic/cycloplegic therapy was successful in controlling uveitis in all dogs for variable periods. Three dogs, monitored for 12, 30, and 46 months, retained useful vision despite infrequent recurrence of uveitis. One dog was lost for subsequent examination. Two dogs were euthanatized and necropsied. Ocular histologic examination of these dogs revealed extensive granulomatous iridocyclitis and choroiditis, with retinal detachment and lenticular degeneration.     

Isotype determination of circulating autoantibodies in canine autoimmune subepidermal blistering dermatoses

Abstract The three most common canine autoimmune blistering skin diseases (AISBD), bullous pemphigoid (BP), mucous membrane pemphigoid (MMP) and epidermolysis bullosa acquisita (EBA) have recently been separated based on clinical, histological and immunological grounds. The objectives of this study were to determine the isotype profiles of circulating autoantibodies in these dermatoses. Serum was collected from 5 dogs with BP, 15 with MMP and 11 with EBA. All sera were tested using an indirect immunofluorescence method using salt-split canine gingiva as substrate. Anti-basement membrane IgG autoantibodies were detected in all patients. Among the IgG autoantibodies, IgG1 and IgG4 were encountered most frequently, while IgG2 and IgG3 were uncovered in some dogs. IgE autoantibodies were detected more often than IgA or IgM autoantibodies in any of the three entities. The predominance of IgG1, IgG4 and IgE autoantibody isotypes in dogs with AISBD is very similar to the situation found in humans with the homologous diseases.     

Canine inherited retinal degenerations: update on molecular genetic research and its clinical application

Inherited retinal degenerations in the dog include generalised progressive retinal atrophy, retinal pigment epithelial dystrophy, congenital stationary night blindness and day blindness (hemeralopia). The clinical phenotype and pathology of these diseases closely resemble some types of human inherited retinal degeneration, in particular retinitis pigmentosa, one of the most common inherited causes of blindness in man. Molecular genetic investigations aim to identify the genetic mutations underlying the canine inherited retinal degenerations. Two major research strategies, candidate gene analysis and linkage analysis, have been used. To date, candidate gene analysis has definitively identified the genetic mutations underlying nine inherited retinal degenerations, each in a different breed of dog, and linkage studies have identified genetic markers for a further retinal degeneration which is found in at least six different breeds. This review outlines the research strategy behind candidate gene and linkage studies and summarises recent results in the search for genetic causes of canine inherited retinal degenerations. The aim is to increase awareness of this rapidly changing field and to show how the research can be used to develop genetic tests for these diseases and thereby reduce the incidence of inherited eye disease in dogs.