Investigating non-image forming photoreception in a mouse model of autosomal dominant optic atrophy

Autosomal Dominant Optic Atrophy (ADOA) is a progressive optic neuropathy affecting mainly the retinal ganglion cells (RGCs). It is associated with mutations in the Opa1 gene and is phenotypically characterized by decreased visual acuity, central field deficits and colour vision defects. Experimental work on Opa1 mutant mice (B6; C3-Opa1Q285STOP) has permitted further characterisation of the pathophysiology of the disease. A specific functional visual deficit in the photopic negative response of the electroretinogram has been described in these mice, possibly due to altered dendritic pruning of RGCs. However, non-image-forming (NIF) visual function, which is regulated by a subset of RGCs that express the photopigment melanopsin, has not yet been extensively investigated in Opa1 mutant mice. We were interested in whether RGC dysfunction in Opa1 mutants affects NIF behaviours. We evaluated circadian behaviour, sleep behaviour and melanopsin expression in Opa1 mutant mice (Opa1+/-) and littermate controls (Opa1+/+). Opa1 mutant mice were able to entrain their behaviour rhythm to a normal 12:12 hr light/dark cycle, confining their activity to the dark phase. The suppression of activity by acute light exposure at night (negative masking) was equivalent between genotypes. Circadian phase shift responses to 480 nm or 520 nm light pulses during the subjective night were preserved in Opa1+/- mice relative to wildtype controls. The acute induction of sleep by light exposure at night was also present in Opa1+/- mice and not significantly different to Opa1+/+ animals. Immunohistochemical characterisation of melanopsin cells in flatmount retinae revealed no significant differences in cell numbers betweeen genotypes. Melanopsin (Opn4) transcript levels were also equivalent between Opa1 wildtype and mutant mice. There was also no obvious difference in melanopsin cell stratification patterns. The data overwhelmingly support the preservation of the NIF visual system in Opa1 mutant mice. The findings are consistent with patient studies suggesting increased resistance of melanopsin-expressing RGCs in conditions of mitochondrial optic atrophy. Further work is needed to extend our understanding of the possible neuroprotective mechanism involved which could lead to exciting therapeutic strategies.</p

Resistance to antivascular endothelial growth factor treatment in age-related macular degeneration

Paris Tranos,1 Athanasios Vacalis,1 Solon Asteriadis,1 Stavrenia Koukoula,1 Athanasios Vachtsevanos,1 Georgia Perganta,1 Ilias Georgalas21Retina Centre, Thessaloniki, Greece; 2Department of Ophthalmology, "G Gennimatas" Hospital of Athens, University of Athens, Athens, GreeceAbstract: Age-related macular degeneration (AMD) is the main cause of visual impairment and blindness in people aged over 65 years in developed countries. Vascular endothelial growth factor (VEGF) is a positive regulator of angiogenesis and its proven role in the pathological neovascularization in wet AMD has provided evidence for the use of anti-VEGF agents as potential therapies. In this study, we review the literature for the possible causes of failure after treatment with anti-VEGF agents and attempt to propose an algorithm of suggestive actions to increase the chances of successful management of such difficult cases.Keywords: antiVEGF, age related macular degeneration, treatmen

Specific deficits in visual electrophysiology in a mouse model of dominant optic atrophy.

Autosomal dominant optic atrophy (ADOA) is a slowly progressive optic neuropathy caused by mutations in the OPA1 gene. OPA1 is ubiquitously expressed and plays a key role in mitochondrial fusion. Heterozygous Opa1 mutant mice (B6; C3-Opa1(Q285STOP)), have previously been reported to develop visual defects and optic nerve changes. In this study, in vivo visual electrophysiological testing (ERGs and VEPs) was performed on 11-13 month old B6; C3-Opa1(Q285STOP) mice (n = 5) and age/sex matched wildtype littermate controls. Full intensity series were recorded in response to brief (4 ms) single flash stimuli delivered in a Ganzfeld dome under dark- and light-adapted conditions. The major ERG components (a-wave and b-wave) showed no detectable difference from wildtype in the amplitude or implicit time of dark-adapted ERGs across the full intensity range tested. This was also true for the components of the dark-adapted VEP. However, the light-adapted ERG responses revealed a significant reduction in the photopic negative response (PhNR) amplitude in Opa1(+/-) animals relative to wildtypes at the brighter intensities tested. Elements of the light-adapted VEP were also abnormal in mutant mice. Overall Opa1(+/-) mice display functional deficits in electrophysiology that are consistent with ganglion cell dysfunction. These deficits may correlate with a reduction in the dendritic arborisation of retinal ganglion cells, which has been previously reported to occur at a similar age in the same mutant mouse line (Williams et al., 2010). The functional phenotype we have described in this mouse model may be useful in the robust and accurate assessment of potential treatments for ADOA

A noninterventional study to monitor patients with diabetic macular oedema starting treatment with ranibizumab (POLARIS)

Purpose: Antivascular endothelial growth factor agents are increasingly used in diabetic macular oedema (DME); however, there are few studies exploring their use in DME in real-world settings. Methods: POLARIS was a noninterventional, multicentre study to monitor 12-month outcomes in patients starting ranibizumab treatment in routine practices. The primary outcome was mean change in visual acuity (VA) from baseline to month 12 (last observation carried forward approach). Other outcomes included mean change in central retinal thickness (CRT) and resource utilization. Visual acuity (VA) outcomes were also stratified by country, baseline visual acuity score (VAS), sex, age and injection frequency. Results: Outcomes were analysed from all treated patients (n = 804) and from first-year completers (patients who had a visual acuity assessment at 12 months; n = 568). The mean (SD) baseline VAS was 59.4 (15.9) letters, and the mean change in visual acuity was 4.4 letters (95% confidence interval: 3.3–5.4) at month 12 (study eye; first-year completers). The mean number of injections (study eye) was 4.9, and the mean number of all visits (any eye) was 10 (58% were injection visits) over 12 months (first-year completers). The mean (SD) baseline CRT was 410.6 (128.8) μm, and the mean change in CRT was −115.2 μm at month 12 (study eye; first-year completers). Visual acuity (VA) outcomes were generally comparable across most countries and subgroups and were greatest in patients with the lowest baseline VAS (≤60 letters). Conclusion: POLARIS showed that real-world outcomes in DME patients starting treatment with ranibizumab were lower than those observed in clinical studies, in spite of extensive monitoring. © 2018 The Authors. Acta Ophthalmologica published by John Wiley &amp; Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation