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Objective To describe functional and structural features of presumed cancer‐associated retinopathy (CAR) mimicking sudden acquired retinal degeneration syndrome (SARDS) in dogs and describe treatment outcomes. Animals Subjects were 17 dogs from 8 eight US states and Canada diagnosed with SARDS or immune‐mediated retinitis (IMR) by 12 ophthalmologists. Nine eyes from seven deceased patients were used for microarray (MA), histology, or immunohistochemical (IHC) analysis. Procedures Dogs underwent complete ophthalmic examination, including retinal photography, optical coherence tomography (OCT), chromatic pupil light reflex testing (cPLR), and electroretinography (ERG), in addition to complete systemic examination. Histology, microarray, and IHC analysis were performed in CAR retinas to evaluate histological and molecular changes in retinal tissue. Results None of the patients evaluated satisfied previously established criteria for diagnosis of SARDS (flat ERG+ no red – good blue PLR), and all were diagnosed with IMR. All patients were diagnosed with a cancer: meningioma (24%), sarcoma (18%), pituitary tumor (12%), and squamous cell carcinoma (12%), other (34%). Median survival time was 6 months from diagnosis (range 1‐36 months). Most frequent systemic abnormalities were as follows: proteinuria (78%); elevated liver enzymes (47%); and metabolic changes (PU/PD, polyphagia – 24%). Immunosuppressive therapy resulted in the reversal of blindness in 44% of treated patients, with 61% of all treated patients recovering and/or maintaining vision. Median time for preservation of vision was 5 months (range 1‐35 months). Conclusions Observed changes are highly suggestive of immune‐mediated damage in IMR‐CAR eyes. A relatively high percentage of patients with CAR responded positively to immunosuppressive therapy.

Objective To perform detailed analysis of retinal changes in dogs with SARDS using optical coherence tomography (OCT), funduscopy, and molecular analysis. Animals Subjects were 29 dogs from 12 US states and Canada diagnosed with SARDS by 8 ophthalmologists. An additional 7 eyes from 5 deceased SARDS dogs were used for molecular and histological analysis. Procedures Dogs were evaluated using chromatic pupil light reflex testing (cPLR), and electroretinography (ERG); subjects underwent complete ophthalmic examination, including funduscopy, retinal photography, and OCT, in addition to complete laboratory analysis, blood pressure evaluation, abdominal and thoracic radiographs, and computerized tomography (CT) imaging to assess possible systemic abnormalities. Histology and immunohistochemistry analysis was performed in 2 SARDS eyes. Microarray analysis was performed in 5 SARDS retinas. Results Thirty‐eight percent of patients had

Antibody-mediated retinopathies may be widely present among the canine population. Early diagnosis and appropriate treatment are essential for visual preservation and reversal of blindness in these patients. The principal purpose of this review is to describe the mechanistic basis, clinical signs, diagnostic methods, and treatment options for retinal diseases causing sudden onset of blindness with absence of typical signs of intraocular inflammation or retinal degeneration-sudden acquired retinal degeneration syndrome and immune-mediated retinitis.

Contains fulltext : 154409.pdf (Publisher’s version ) (Open Access) Several dog breeds are susceptible to developing primary angle closure glaucoma (PACG), which suggests a genetic basis for the disease. We have identified a four-generation Basset Hound pedigree with characteristic autosomal recessive PACG that closely recapitulates PACG in humans. Our aim is to utilize gene mapping and whole exome sequencing approaches to identify PACG-causing sequence variants in the Basset. Extensive clinical phenotyping of all pedigree members was conducted. SNP-chip genotyping was carried out in 9 affected and 15 unaffected pedigree members. Two-point and multipoint linkage analyses of genome-wide SNP data were performed using Superlink-Online SNP-1.1 and a locus was mapped to chromosome 19q with a maximum LOD score of 3.24. The locus contains 12 Ensemble predicted canine genes and is syntenic to a region on chromosome 2 in the human genome. Using exome-sequencing analysis, a possibly damaging, non-synonymous variant in the gene Nebulin (NEB) was found to segregate with PACG which alters a phylogenetically conserved Lysine residue. The association of this variants with PACG was confirmed in a secondary cohort of unrelated Basset Hounds (p = 3.4 x 10-4, OR = 15.3 for homozygosity). Nebulin, a protein that promotes the contractile function of sarcomeres, was found to be prominently expressed in the ciliary muscles of the anterior segment. Our findings may provide insight into the molecular mechanisms that underlie PACG. The phenotypic similarities of disease presentation in dogs and humans may enable the translation of findings made in this study to patients with PACG.

Early detection of pathological changes and progression in glaucoma and other neuroretinal diseases remains a great challenge and is critical to reduce permanent structural and functional retina and optic nerve damage. Raman spectroscopy is a sensitive technique that provides rapid biochemical characterization of tissues in a nondestructive and noninvasive fashion. In this study, spectroscopic analysis was conducted on the retinal tissues of seven beagles with acute elevation of intraocular pressure (AEIOP), six beagles with compressive optic neuropathy (CON), and five healthy beagles. Spectroscopic markers were identified associated with the different neuropathic conditions. Furthermore, the Raman spectra were subjected to multivariate discriminate analysis to classify independent tissue samples into diseased/healthy categories. The multivariate discriminant model yielded an average optimal classification accuracy of 72.6% for AEIOP and 63.4% for CON with 20 principal components being used that accounted for 87% of the total variance in the data set. A strong correlation (R20.92) was observed between pattern electroretinography characteristics of AEIOP dogs and Raman separation distance that measures the separation of spectra of diseased tissues from normal tissues; however, the underlining mechanism of this correlation remains to be understood. Since AEIOP mimics the pathological symptoms of acute/early-stage glaucoma, it was demonstrated that Raman spectroscopic screening has the potential to become a powerful tool for the detection and characterization of early-stage disease.

To develop fast and reliable testing routines for diagnosing retina and optic nerve diseases in canine cataract patients based on chromatic properties of the pupillary light reflex response.Seventy-seven canine patients with a history of cataract and decreased vision (43 patients with cataracts and no evidence of retina or optic nerve disease, 21 patients with cataracts and retinal degeneration [RD], 13 patients with cataracts and retinal detachment [RDT]), 11 canine patients with optic neuritis (ON) and 23 healthy dogs were examined using chromatic pupillary light reflex (cPLR) analysis with red and blue light and electroretinography.Electroretinography analysis showed statistically significant deficits in a- and b-wave amplitudes in dogs with cataracts and RD, or cataracts and RDT, when compared to dogs with cataracts without evidence of retinal abnormalities. Evaluation of b-wave amplitudes showed that presence of 78.5-μV (or lower) amplitudes had high sensitivity of 100% (95% CI: 87.2-100%) and high specificity of 96.7% (95% CI: 88.4-100%) in RD and RDT. Evaluation of cPLR responses using red light showed that presence of the pupil end constriction diameter of 5.5 mm (or higher) had moderately high sensitivity of 76.5% (95% CI: 50.1-93.2%) and high specificity of 100% (95% CI: 91.2-100%) in detecting RD and RDT. Optic neuritis patients had absent cPLR responses, regardless of the visual status.Chromatic evaluation of the pupillary light reflex is a rapid and accurate test for diagnosing retina and optic nerve diseases in canine patients.

To perform in vivo analysis of retinal functional and structural parameters in healthy mouse eyes.Adult C57BL/6 male mice (n = 37).Retinal function was evaluated using pattern electroretinography (pERG) and the chromatic pupil light reflex (cPLR). Structural properties of the retina and nerve fiber layer (NFL) were evaluated using spectral-domain optical coherence tomography (SD-OCT).The average pERG amplitudes were found to be 11.2 ± 0.7 μV (P50-N95, mean ± SEM), with an implicit time for P50-N95 interval of 90.4 ± 5.4 ms. Total retinal thickness was 229.5 ± 1.7 μm (mean ± SEM) in the area centralis region. The thickness of the retinal nerve fiber layer (mean ± SEM) using a circular peripapillary retinal scan centered on the optic nerve was 46.7 ± 0.9 μm (temporal), 46.1 ± 0.9 μm (superior), 45.8 ± 0.9 μm (nasal), and 48.4 ± 1 μm (inferior). The baseline pupil diameter was 2.1 ± 0.05 mm in darkness, and 1.1 ± 0.05 and 0.56 ± 0.03 mm after stimulation with red (630 nm, luminance 200 kcd/m(2)) or blue (480 nm, luminance 200 kcd/m(2)) light illumination, respectively.Pattern electroretinography, cPLR and SD-OCT analysis are reproducible techniques, which can provide important information about retinal and optic nerve function and structure in mice.

To provide normative data for canine whole retinal thickness (WRT), nerve fiber layer thickness (NFL), photoreceptor layer thickness (PR), and outer nuclear layer thickness (ONL) using spectral domain optical coherence tomography.Twelve healthy adult intact female beagles.Horizontal volume scans through the area dorso-temporal from the optic nerve (superior retina), and the area ventro-temporal from the optic nerve (inferior retina) were used to evaluate the thickness of retinal NFL, PR, ONL, and WRT. Peripapillary circular scans were used to evaluate NFL thickness. Statistical analyses were performed to compare the thickness of the individual layers between the superior and inferior retina (paired t-test). One-way analysis of variance (ANOVA) was used to compare the thickness of peripapillary NFL between the superior, inferior, temporal and nasal quadrants of the circle scan.The WRT, PR, and NFL thickness were greater in the superior than in the inferior retina (198.7 ± 9.6 μm vs. 164.4 ± 6.4 μm, P0.0001; 95.5 ± 6.5 μm vs. 78.8 ± 7.4 μm, P0.0001; and 26.4 ± 1.6 μm vs. 25.0 ± 1.9 μm, P = 0.0236, respectively). No statistical difference was found between the ONL thickness of the superior and inferior retina (50.1 ± 6.4 μm vs. 44.3 ± 3.6, P = 0.0578). Peripapillary NFL thickness showed a similar tendency as the linear scans, with the superior quadrant having the greatest thickness (91.26 ± 7.0 μm) and the inferior quadrant being the thinnest (76.42 ± 9.2 μm) (P0.001).Results of our in vivo studies showed significant differences between thickness values for the superior (tapetal) and inferior (nontapetal) retinal regions.

Glaucoma is a chronic neurodegenerative disease characterized by apoptosis of retinal ganglion cells and subsequent loss of visual function. Early detection of glaucoma is critical for the prevention of permanent structural damage and irreversible vision loss. Raman spectroscopy is a technique that provides rapid biochemical characterization of tissues in a nondestructive and noninvasive fashion. In this study, we explored the potential of using Raman spectroscopy for detection of glaucomatous changes in vitro. Raman spectroscopic imaging was conducted on retinal tissues of dogs with hereditary glaucoma and healthy control dogs. The Raman spectra were subjected to multivariate discriminant analysis with a support vector machine algorithm, and a classification model was developed to differentiate disease tissues versus healthy tissues. Spectroscopic analysis of 105 retinal ganglion cells (RGCs) from glaucomatous dogs and 267 RGCs from healthy dogs revealed spectroscopic markers that differentiated glaucomatous specimens from healthy controls. Furthermore, the multivariate discriminant model differentiated healthy samples and glaucomatous samples with good accuracy [healthy 89.5% and glaucomatous 97.6% for the same breed (Basset Hounds); and healthy 85.0% and glaucomatous 85.5% for different breeds (Beagles versus Basset Hounds)]. Raman spectroscopic screening can be used for in vitro detection of glaucomatous changes in retinal tissue with a high specificity.

Purpose The pathophysiological events that occur in advanced glaucoma are not well characterized. The principal purpose of this study is to characterize the gene expression changes that occur in advanced glaucoma. Methods Retinal RNA was obtained from canine eyes with advanced glaucoma as well as from healthy eyes. Global gene expression patterns were determined using oligonucleotide microarrays and confirmed by real-time PCR. The presence of tumor necrosis factor (TNF) and its receptors was evaluated by immunolabeling. Finally, we evaluated the presence of serum autoantibodies directed against retinal epitopes using western blot analyses. Results We identified over 500 genes with statistically significant changes in expression level in the glaucomatous retina. Decreased expression levels were detected for large number of functional groups, including synapse and synaptic transmission, cell adhesion, and calcium metabolism. Many of the molecules with decreased expression levels have been previously shown to be components of retinal ganglion cells. Genes with elevated expression in glaucoma are largely associated with inflammation, such as antigen presentation, protein degradation, and innate immunity. In contrast, expression of many other pro-inflammatory genes, such as interferons or interleukins, was not detected at abnormal levels. Conclusions This study characterizes the molecular events that occur in the canine retina with advanced glaucoma. Our data suggest that in the dog this stage of the disease is accompanied by pronounced retinal neuroinflammation.

To compare the incidence of seizures in dogs with intervertebral disk disease after iopamidol or iomeprol myelography, and to assess whether the incidence of seizures differed between the 2 agents when severity of neurological deficits, location of cord compression, duration of anesthesia, site of myelogram, volume of contrast, and concentration of contrast were evaluated.Retrospective study.Veterinary teaching hospital.One hundred and sixty-one client-owned dogs with intervertebral disk disease.Subarachnoid injection of contrast medium.One hundred and sixty-one dogs with intervertebral disk disease were subjected to myelography using iopamidol (n=74) or iomeprol (n=87). Cranial myelography was performed in 31 dogs, caudal myelography in 125 and both cranial and caudal myelography in 5. Seizures occurred in 23 of 161 (14%) dogs. There was no significant difference overall between iopamidol and iomeprol myelography. However, in dogs with thoracolumbar disk extrusion and paraplegia, seizures occurred more frequently after caudal myelography using iopamidol compared with iomeprol.Both iomeprol and iopamidol are suitable for myelography in dogs. Iomeprol is recommended for caudal myelography in paraplegic dogs with thoracolumbar disk extrusion due to the higher incidence of seizures in this group when iopamidol was used.

Glaucoma is characterized as a progressive optic neuropathy with characteristic optic disc changes and progressive visual field deficits.1 Elevated intraocular pressure (IOP) is considered a primary risk factor for the initiation and progression of glaucomatous neuropathy.1,2 However, in many patients, despite adequate control of the IOP, the loss of vision continues to progress, which necessitates further identification of molecular mechanisms responsible for the glaucomatous neurodegeneration and development of novel therapeutic modalities that directly target disease-affected retinal ganglion cells (RGCs).2–4 Despite new discoveries, the underlying genetic abnormalities and environmental factors that may contribute to the development and progression of glaucoma have not been clearly defined.5,6 Glaucoma in humans is typically a chronic and slowly progressive disease that may cause significant damage to the optic nerve before any symptoms of the disease are recognized. The gradual and often silent progression of the disease creates difficulties in early diagnosis and understanding of early changes in glaucomatous eyes. To better understand early glaucomatous changes and to develop effective diagnostic and therapeutic modalities, it is essential to create animal models that recapitulate the silent and slow development of the disease characterized by a progressive loss of RGC function. Numerous inducible animal models of glaucoma have been used successfully to test different therapeutic strategies and to evaluate molecular mechanisms of RGC damage resulting from chronic elevation of IOP.2,7,8 However, the major obstacles in many of these models is a very high elevation of IOP immediately after glaucoma induction surgery,9–11 the inability to sustain elevated IOP longer than a period of a several months,12–17 and the size of the eye, which is dramatically smaller than the human eye, posing a problem for effective translation of therapeutic options to the human patients.18,19 Spontaneously occurring animal models of glaucoma in mice and dogs have also been described and have provided important information about the structural and molecular events occurring during the development of glaucomatous optic neuropathy.20–26 Spontaneously occurring large animal models of glaucoma offer a unique opportunity to collect data by using instrumentation identical to that used in human patients with glaucoma. They are an excellent tool for the rapid development and translation of novel medical and surgical therapies from animals to human patients, and they provide interesting data correlating morphologic or biochemical findings to functional parameters. The principal purpose of this manuscript was to describe the morphologic and functional changes in a canine model of hereditary primary angle-closure glaucoma (PACG). We hope this model will further advance our understanding of early functional, structural, and molecular changes in glaucomatous eyes.

Purpose To evaluate retina and optic nerve damage following experimental blast injury. Methods Healthy adult mice were exposed to an overpressure blast wave using a custom-built blast chamber. The effects of blast exposure on retina and optic nerve function and structure were evaluated using the pattern electroretinogram (pERG), spectral domain optical coherence tomography (OCT), and the chromatic pupil light reflex. Results Assessment of the pupil response to light demonstrated decreased maximum pupil constriction diameter in blast-injured mice using red light or blue light stimuli 24 hours after injury compared with baseline in the eye exposed to direct blast injury. A decrease in the pupil light reflex was not observed chronically following blast exposure. We observed a biphasic pERG decrease with the acute injury recovering by 24 hours postblast and the chronic injury appearing at 4 months postblast injury. Furthermore, at 3 months following injury, a significant decrease in the retinal nerve fiber layer was observed using OCT compared with controls. Histologic analysis of the retina and optic nerve revealed punctate regions of reduced cellularity in the ganglion cell layer and damage to optic nerves. Additionally, a significant upregulation of proteins associated with oxidative stress was observed acutely following blast exposure compared with control mice. Conclusions Our study demonstrates that decrements in retinal ganglion cell responses can be detected after blast injury using noninvasive functional and structural tests. These objective responses may serve as surrogate tests for higher CNS functions following traumatic brain injury that are difficult to quantify.