Gillian J. McLellan

Feline Glaucoma – A Comprehensive Review

Cats with glaucoma typically present late in the course of disease. It is likely that glaucoma in cats is under-diagnosed due to its insidious onset and gradual progression, as well as limitations of some commonly used tonometers in this species. Treatment of glaucoma in feline patients presents a clinical challenge, particularly as glaucoma is often secondary to other disease processes in cats. In this review, we consider the clinical features, pathophysiology, and classification of the feline glaucomas and provide current evidence to direct selection of appropriate treatment strategies for feline glaucoma patients.

Optical coherence tomography for the evaluation of retinal and optic nerve morphology in animal subjects: practical considerations.

Optical coherence tomography (OCT) is a noninvasive, noncontact imaging technique capable of producing high-resolution images of the retina and optic nerve. These images provide information that is useful for following the progression and/or resolution of posterior segment disease. Rapid advances in OCT technology allow the acquisition of increasingly detailed images, approaching the original goal of providing in vivo histopathology. Increases in scan acquisition speeds and axial resolution enhance the clinical diagnostic value of this modality. Adapting instrumentation designed for use in human patients for use in animals can be challenging. Each species has a unique set of adjustments that need to be made but it is possible to obtain reproducible, high-quality OCT images in a variety of animals, including rodents, dogs, cats, pigs, and monkeys. Deriving quantitative measurements from OCT instruments is hindered by software algorithm errors in detecting the edges of the distinct retinal layers. These segmentation errors occur in scans of human eyes as well in other species and arise with similar frequency with each of the different OCT instruments. Manual segmentation methods to derive optic nerve head and other structural indices have been developed for several species.

The effect of dorzolamide 2% on circadian intraocular pressure in cats with primary congenital glaucoma

OBJECTIVE To determine the extent of fluctuation in circadian intraocular pressure (IOP) and the efficacy of topical dorzolamide 2% q 8 h in lowering IOP and blunting circadian fluctuation in IOP in glaucomatous cats. ANIMALS STUDIED Seven adult cats with primary congenital glaucoma (PCG). PROCEDURES Measurements of IOP and pupil diameter were obtained for both eyes (OU) of each cat q 4 h for 12 days. Cats were housed in a laboratory animal facility with a 12-h light:dark cycle. Baseline values were established for 2 days. For the next 5 days, placebo (1.4% polyvinyl alcohol) was administered OU q 8 h. Dorzolamide 2% was then administered OU q 8 h for a further 5 days. A multivariate mixed linear model was fitted to the data, with parameters estimated from a Bayesian perspective. The 4 am time point was selected as the reference for the purposes of comparisons. RESULTS Estimated mean IOP for the reference time point pre-treatment was symmetric (about 33 mmHg OU). In all cats, IOP was significantly lower during the diurnal phase, relative to the 4 am measurements, with highest IOP observed 2-6 h after the onset of the dark phase. Circadian fluctuations in IOP were dampened during the treatment period. There was a significant decrease in IOP in all cats during the dorzolamide treatment period (estimated mean for the treatment period reference = 17.9 mmHg OU). CONCLUSIONS Topical dorzolamide 2% q 8 h is effective in reducing IOP and IOP fluctuation in cats with PCG.

Evaluation of rebound tonometry in red-eared slider turtles (Trachemys scripta elegans)

OBJECTIVE To evaluate feasibility and accuracy of intraocular pressure (IOP) measurement by rebound tonometry in adult red-eared slider turtles and determine the effects of manual and chemical restraint on IOP. ANIMAL STUDIED Seventeen adult red-eared slider turtles. PROCEDURES Intraocular pressure was measured with TonoLab® and TonoVet® tonometers in conscious, unrestrained turtles. To evaluate the effects of manual restraint, turtles were restrained by digital pressure on the rostral head or proximal neck. The effect of two chemical restraint protocols (dexmedetomidine, ketamine, midazolam [DKM] and dexmedetomidine, ketamine [DK] subcutaneously) on IOP was evaluated. Triplicate TonoLab® and TonoVet® readings were compared with direct manometry in three ex vivo turtle eyes. RESULTS TonoLab® correlated better with manometry at IOPs < 45 mmHg than TonoVet® (linear regression slopes of 0.89 and 0.30, respectively). Mean (±SD) IOP in unrestrained conscious turtles was significantly lower (P < 0.01) with TonoLab® (10.02 ± 0.66 mmHg) than with TonoVet® (11.32 ± 1.57 mmHg). Manual neck restraint caused a significant increase in IOP (+6.31 ± 5.59 mmHg), while manual rostral head restraint did not. Both chemical restraint protocols significantly reduced IOP (DKM: −1.0 ± 0.76 mmHg; DK: −1.79 ± 1.17) compared with measurements in conscious unrestrained turtles. CONCLUSIONS Chemical and manual neck restraint affected IOP. Rostral head restraint had no significant effect on IOP and is, therefore, recommended as the appropriate restraint technique in red-eared slider turtles. TonoLab® measurements estimated actual IOP more accurately, within physiologic range, than measurements obtained using the TonoVet®.

A Mutation in LTBP2 Causes Congenital Glaucoma in Domestic Cats (Felis catus)

The glaucomas are a group of diseases characterized by optic nerve damage that together represent a leading cause of blindness in the human population and in domestic animals. Here we report a mutation in LTBP2 that causes primary congenital glaucoma (PCG) in domestic cats. We identified a spontaneous form of PCG in cats and established a breeding colony segregating for PCG consistent with fully penetrant, autosomal recessive inheritance of the trait. Elevated intraocular pressure, globe enlargement and elongated ciliary processes were consistently observed in all affected cats by 8 weeks of age. Varying degrees of optic nerve damage resulted by 6 months of age. Although subtle lens zonular instability was a common feature in this cohort, pronounced ectopia lentis was identified in less than 10% of cats examined. Thus, glaucoma in this pedigree is attributed to histologically confirmed arrest in the early post-natal development of the aqueous humor outflow pathways in the anterior segment of the eyes of affected animals. Using a candidate gene approach, significant linkage was established on cat chromosome B3 (LOD 18.38, θ = 0.00) using tightly linked short tandem repeat (STR) loci to the candidate gene, LTBP2. A 4 base-pair insertion was identified in exon 8 of LTBP2 in affected individuals that generates a frame shift that completely alters the downstream open reading frame and eliminates functional domains. Thus, we describe the first spontaneous and highly penetrant non-rodent model of PCG identifying a valuable animal model for primary glaucoma that closely resembles the human disease, providing valuable insights into mechanisms underlying the disease and a valuable animal model for testing therapies.

Effects of unilateral topical administration of 0.5% tropicamide on anterior segment morphology and intraocular pressure in normal cats and cats with primary congenital glaucoma

OBJECTIVE To determine the effects of topical 0.5% tropicamide on anterior segment morphology (ASM) and intraocular pressure (IOP) in normal and glaucomatous cats. ANIMALS USED: Normal cats and cats with inherited primary congenital glaucoma (PCG). PROCEDURES Control IOP curves were performed in untreated normal and PCG cats. In the first experiment, tropicamide was applied OD in eight normal and nine PCG cats. IOP and pupillary diameter (PD) were measured at 0, 30, and 60 min, then hourly until 8 h post-treatment. In a second experiment, six normal and seven PCG cats received tropicamide OD. High-resolution ultrasound images were obtained at 0, 1, 5, and 10 h post-treatment to measure ASM changes. IOP and PD were measured OD at 0, 1, 2, 3, 5, 7, and 9 h. RESULTS In untreated normal cats IOP OU decreased throughout the day. In PCG cats IOP OU had wide fluctuations over time. In normal cats IOP response varied in the treated eye but did not change significantly in untreated eyes. IOP significantly increased from baseline in both eyes of all treated PCG cats. Increases in IOP were associated with some ASM changes. Cats with PCG had a significantly smaller angle recess areas, diminished ciliary clefts and decreased iris-lens contact. ASM changes were not strongly correlated with IOP in all cats. CONCLUSIONS The ASM of PCG cats is markedly different from normal cats, and clinically significant increases in IOP OU occur in cats with PCG after tropicamide treatment. The mechanism for this increase remains unclear.

Retinal Intrinsic Optical Signals in a Cat Model of Primary Congenital Glaucoma

PURPOSE To examine the impact of reduced inner retinal function and breed on intrinsic optical signals in cats. METHODS Retinal intrinsic optical signals were recorded from anesthetized cats with a modified fundus camera. Near infrared light (NIR, 700-900 nm) was used to illuminate the retina while a charge-coupled device (CCD) camera captured the NIR reflectance of the retina. Visible stimuli (540 nm) evoked patterned changes in NIR retinal reflectance. NIR intrinsic signals were compared across three subject groups: two Siamese cats with primary congenital glaucoma (PCG), a control Siamese cat without glaucoma, and a control group of seven normally pigmented cats. Intraocular pressure (IOP), pattern electroretinogram, and optical coherence tomography measurements were evaluated to confirm the inner retinal deficit in PCG cats. RESULTS Stimulus-evoked, NIR retinal reflectance signals were observed in PCG cats despite severe degeneration of the nerve fiber layer and inner retinal function. The time course, spectral dependence, and spatial profile of signals imaged in PCG cats were similar to signals measured from normal and Siamese control cats. CONCLUSIONS Despite increased IOP, reduced nerve fiber layer thickness and ganglion cell function, intrinsic optical signals persist in cats affected with PCG. The mechanisms giving rise to intrinsic signals remain despite inner retinal damage. Signal strength was reduced in all Siamese cats compared to controls, suggesting that reduced intrinsic signals in PCG cats represent a difference between breeds rather than loss of ganglion cells. These results corroborated previous findings that retinal ganglion cells are not the dominant source of intrinsic optical signals of the retina.

Allogeneic Transplantation of Müller-Derived Retinal Ganglion Cells Improves Retinal Function in a Feline Model of Ganglion Cell Depletion

Human Müller glia with stem cell characteristics (hMGSCs) have been shown to improve retinal function upon transplantation into rat models of retinal ganglion cell (RGC) depletion. However, their translational potential may depend upon successful engraftment and improvement of retinal function in experimental models with anatomical and functional features resembling those of the human eye. We investigated the effect of allogeneic transplantation of feline Müller glia with the ability to differentiate into cells expressing RGC markers, following ablation of RGCs by N‐methyl‐d‐aspartate (NMDA). Unlike previous observations in the rat, transplantation of hMGSC‐derived RGCs into the feline vitreous formed aggregates and elicited a severe inflammatory response without improving visual function. In contrast, allogeneic transplantation of feline MGSC (fMGSC)‐derived RGCs into the vitrectomized eye improved the scotopic threshold response (STR) of the electroretinogram (ERG). Despite causing functional improvement, the cells did not attach onto the retina and formed aggregates on peripheral vitreous remnants, suggesting that vitreous may constitute a barrier for cell attachment onto the retina. This was confirmed by observations that cellular scaffolds of compressed collagen and enriched preparations of fMGSC‐derived RGCs facilitated cell attachment. Although cells did not migrate into the RGC layer or the optic nerve, they significantly improved the STR and the photopic negative response of the ERG, indicative of increased RGC function. These results suggest that MGSCs have a neuroprotective ability that promotes partial recovery of impaired RGC function and indicate that cell attachment onto the retina may be necessary for transplanted cells to confer neuroprotection to the retina.

A keratoprosthesis prototype for the dog

OBJECTIVE To describe the technique for implantation of a novel keratoprosthesis (KP) prototype and evaluate its application for the treatment of corneal blindness in dogs. ANIMALS STUDIED Seven dogs, all of them being clinically blind before surgery as a result of severe corneal endothelial disease (5/7) or chronic superficial keratitis (2/7) that were unresponsive to prior therapy. PROCEDURES A silicone KP was implanted unilaterally, just anterior to Descemets membrane, after creating a stromal pocket by deep stromal lamellar dissection. RESULTS Implantation of the KP was accomplished without complication in six of seven operated dogs. In the remaining case, an intra-operative complication (perforation of Descemets membrane) was associated with extrusion of the KP 8 weeks postoperatively. All operated eyes regained limited vision after surgery. Three to six months after implantation purulent keratitis occurred in all five eyes with endothelial disease, necessitating surgical removal of the KP 6 months postoperatively in 5/7 eyes. CONCLUSIONS This KP prototype shows promise as a treatment for certain blinding corneal diseases. However, changes in the design of this KP, allowing improved stromal integration, will be necessary before its clinical application can be approved.

Phylogenetic and recombination analysis of the herpesvirus genus varicellovirus

BackgroundThe varicelloviruses comprise a genus within the alphaherpesvirus subfamily, and infect both humans and other mammals. Recently, next-generation sequencing has been used to generate genomic sequences of several members of the Varicellovirus genus. Here, currently available varicellovirus genomic sequences were used for phylogenetic, recombination, and genetic distance analysis.ResultsA phylogenetic network including genomic sequences of individual species, was generated and suggested a potential restriction between the ungulate and non-ungulate viruses. Intraspecies genetic distances were higher in the ungulate viruses (pseudorabies virus (SuHV-1) 1.65%, bovine herpes virus type 1 (BHV-1) 0.81%, equine herpes virus type 1 (EHV-1) 0.79%, equine herpes virus type 4 (EHV-4) 0.16%) than non-ungulate viruses (feline herpes virus type 1 (FHV-1) 0.0089%, canine herpes virus type 1 (CHV-1) 0.005%, varicella-zoster virus (VZV) 0.136%). The G + C content of the ungulate viruses was also higher (SuHV-1 73.6%, BHV-1 72.6%, EHV-1 56.6%, EHV-4 50.5%) compared to the non-ungulate viruses (FHV-1 45.8%, CHV-1 31.6%, VZV 45.8%), which suggests a possible link between G + C content and intraspecies genetic diversity. Varicellovirus clade nomenclature is variable across different species, and we propose a standardization based on genomic genetic distance. A recent study reported no recombination between sequenced FHV-1 strains, however in the present study, both splitstree, bootscan, and PHI analysis indicated recombination. We also found that the recently sequenced Brazilian CHV-1 strain BTU-1 may contain a genetic signal in the UL50 gene from an unknown varicellovirus.ConclusionTogether, the data contribute to a greater understanding of varicellovirus genomics, and we also suggest a new clade nomenclature scheme based on genetic distances.