Chris Hogg

Phenotypic Variation in Enhanced S-cone Syndrome

PURPOSE To characterize the clinical, psychophysical, and electrophysiological phenotype of 19 patients with enhanced S-cone syndrome (ESCS) and relate the phenotype to the underlying genetic mutation. METHODS Patients underwent ophthalmic examination and functional testing including pattern ERG, full-field ERG, and long-duration and short-wavelength stimulation. Further tests were performed in some patients, including color contrast sensitivity (CCS), multifocal ERG, fundus autofluorescence imaging (FAI), optical coherence tomography (OCT), and fundus fluorescein angiography (FFA). Mutational screening of NR2E3 was undertaken in 13 patients. RESULTS The fundus appearance was variable, from normal to typical nummular pigment clumping at the level of the retinal pigment epithelium in older patients. Nine patients had foveal schisis, and one had peripheral schisis. Pattern ERG was abnormal in all patients. In all patients, ISCEV Standard photopic and scotopic responses had a similar waveform, the rod-specific-ERG was undetectable and the 30-Hz flicker ERG was markedly delayed with an amplitude lower than the photopic a-wave. Most ERG responses arose from short-wavelength-sensitive mechanisms, and a majority of patients showed possible OFF-related activity. Multifocal ERG showed relative preservation of central function, but reduced responses with increased eccentricity. Mutations were identified in NR2E3 in 12 of 13 patients including four novel variants. CONCLUSIONS The phenotype in ESCS is variable, both in fundus appearance and in the severity of the electrophysiological abnormalities. The ERGs are dominated by short-wavelength-sensitive mechanisms. The presence, in most of the patients, of possible OFF-related ERG activity is a finding not usually associated with S-cones.

The incidence of negative ERG in clinical practice

Introduction: A negative electroretinogram (ERG) is one in which there is a selective reduction in amplitude of the b-wave, such that it does not exceed that of the a-wave. The purpose of this study was to determine the incidence and clinical causes of negative ERGs at a tertiary referral centre. In addition, interesting and previously unreported aetiologies are described. Patients and methods: Retrospective review of all ERGs done at Moorfields Eye Hospital from November 1995 to December 1998 under ISCEV standard conditions. Many patients had photopic ON- and OFF-response recording in addition to conventional ISCEV Standard ganzfeld ERG. Results: A total of 2,640 ERGs were performed during the study period. 128 cases (4.8%) showed a negative ERG. The causes, where a firm clinical diagnosis was possible, include X-linked juvenile retinoschisis, congenital stationary night blindness, central retinal artery occlusion, birdshot chorioretinopathy and melanoma-associated retinopathy (MAR). Unilateral negative ERG waveforms with normal fundal appearances were seen in 7 patients. Photopic ON- responses could be selectively affected. Conclusions: The incidence of negative ERGs over a 34-month period presenting to a large tertiary centre was almost 5%. The presence of a negative ERG may be instrumental in demonstrating the site of visual dysfunction, with many cases showing minimal or no fundus abnormality. ON- and OFF-response recording yielded additional information regarding photopic post-receptoral/phototransduction function.

Treatment with 670 nm light up regulates cytochrome C oxidase expression and reduces inflammation in an age-related macular degeneration model

Inflammation is an umbrella feature of ageing. It is present in the aged retina and many retinal diseases including age-related macular degeneration (AMD). In ageing and in AMD mitochondrial function declines. In normal ageing this can be manipulated by brief exposure to 670 nm light on the retina, which increases mitochondrial membrane potential and reduces inflammation. Here we ask if 670 nm exposure has the same ability in an aged mouse model of AMD, the complement factor H knockout (CFH−/−) where inflammation is a key feature. Further, we ask whether this occurs when 670 nm is delivered briefly in environmental lighting rather than directly focussed on the retina. Mice were exposed to 670 nm for 6 minutes twice a day for 14 days in the form of supplemented environmental light. Exposed animals had significant increase in cytochrome c oxidase (COX), which is a mitochondrial enzyme regulating oxidative phosphorylation.There was a significant reduction in complement component C3, an inflammatory marker in the outer retina. Vimetin and glial fibrillary acidic protein (GFAP) expression, which reflect retinal stress in Muller glia, were also significantly down regulated. There were also significant changes in outer retinal macrophage morphology. However, amyloid beta (Aβ) load, which also increases with age in the outer retina and is pro-inflammatory, did not change. Hence, 670 nm is effective in reducing inflammation probably via COX activation in mice with a genotype similar to that in 50% of AMD patients even when brief exposures are delivered via environmental lighting. Further, inflammation can be reduced independent of Aβ. The efficacy revealed here supports current early stage clinical trials of 670 nm in AMD patients.

Age-related retinal inflammation is reduced by 670 nm light via increased mitochondrial membrane potential

The mitochondrial theory of aging argues that oxidative stress, caused by mitochondrial DNA mutations, is associated with decreased adenosine triphosphate (ATP) production leading to cellular degeneration. The rate of this degradation is linked to metabolic demand, with the outer retina having the greatest in the body, showing progressive inflammation, macrophage invasion, and cell loss, resulting in visual decline. Mitochondrial function shifts in vitro after 670-nm light exposure, reducing oxidative stress and increasing ATP production. In vivo, it ameliorates induced pathology. Here, we ask whether 670 nm light shifts mitochondrial function and reduces age-related retinal inflammation. Aged mice were exposed to only five 90-second exposures over 35 hours. This significantly increased mitochondrial membrane polarization and significantly reduced macrophage numbers and tumor necrosis factor (TNF)-alpha levels, a key proinflammatory cytokine. Three additional inflammatory markers were assessed; complement component 3d (C3d), a marker of chronic inflammation and calcitonin, and a systemic inflammatory biomarker were significantly reduced. Complement component 3b (C3b), a marker of acute inflammation, was not significantly altered. These results provide a simple route to combating inflammation in an aging population with declining visual function and may be applicable to clinical conditions where retinal inflammation is a key feature.

A Survey of Color Discriminatlon in German Ophthalmologists: Changes Associated with the Case of Lasers and Operating Microscopes

Color vision tests were performed on 211 German ophthalmologists during their annual meeting at Essen. The subjects also answered detailed questionnaires about their use of lasers and operating microscopes, and their ocular and general health. It was found that 33% of doctors who use lasers or operating microscopes have decreased color discrimination for colors in a tritan color-confusion axis (greater than 2 standard deviations above normal). There is a relationship between number of patients treated and the degree of threshold elevation. Thirty hours of using the operating microscope produces an increase in tritan threshold equivalent to one panretinal photocoagulation.

Ultraviolet Vision and Avoidance of Power Lines in Birds and Mammals

The avoidance by mammals and ground-nesting birds of habitat up to several kilometers from high-voltage power lines is a major consequence of infrastructure development in remote areas, but the behavior is perplexing because suspended cables are neither an impenetrable physical barrier nor associated with human traffic (e.g., Vistnes & Nellemann 2008; Pruett et al. 2009; Degteva & Nellemann 2013). Moreover, avoidance may persist >3 decades after construction (Nellemann et al. 2003; Vistnes et al. 2004), suggesting behavioral reinforcement. Integration of new information on visual function with the characteristics of power line function provides compelling evidence that avoidance may be linked with the ability of animals to detect ultraviolet light (UV). Ultraviolet discharges on power lines occur both as standing corona along cables and irregular flashes on insulators. The discharge spectrum (200–400 nm; Maruvada 2000) is below the normal lower limit of human vision, UV being attenuated by the human cornea and lens, but in birds, rodents, and reindeer/caribou (Rangifer tarandus) (hereafter reindeer) the cornea and lens are UV permissive. The former have specific UV sensitive opsins (Bowmaker 2008) and, hence, power line corona may be assumed visually salient in these. Reindeer have no specific UV opsin, but we obtained robust retinal responses to 330 nm mediated by other opsins (Hogg et al. 2011 and unpublished) and propose that corona flashes are both visually salient and a cause of this species avoiding power lines. Recent demonstration of UV responses in reindeer retinae was based on electrophysiological corneal recordings (Hogg et al. 2011). These, however, are approximately 3 log units less sensitive than psychophysical measurements of visual perception (Ruseckaite et al. 2011). They demonstrate an ability to see UV discharge but are poor indicators of visual threshold and underestimate visual sensitivity. Furthermore, reindeer and some birds have a reflective surface directly behind the retinal photoreceptors (the tapetum lucidum) which ensures that light not captured as it passes through them is reflected back for a second pass, consequently, increasing retinal sensitivity in dark (i.e., very low light) environments (Johnson 1968). In reindeer, the winter adapted tapetum scatters light among photoreceptors rather than reflecting it which enhances photon capture and increases retinal sensitivity by approximately 3 log units at winter threshold (Stokkan et al. 2013). Other factors increase the likelihood that reindeer see coronal discharges in the dark. First, retinal sensitivity is maximized in reindeer because their retinae are almost permanently dark adapted during the extended dusk of Arctic winters, and, given that the mammalian visual range is approximately 9 log units, fully dark adapted eyes are capable of responding to the stimulus of a single photon. Second, the reindeer eye is larger than the human eye and thus provides greater image magnification, and the pupil, which dilates to 21 mm compared with approximately 10 mm in humans, is likely to be permanently dilated in winter consequently increasing retinal sensitivity approximately 4-fold. Third, dilation exposes more of the peripheral retina that is sensitive to sudden changes in the visual environment. The stimulus is also important. Ultraviolet discharge is both strongly (approximately 90%) reflected and scattered by snow. Hence, in a snowy landscape the corona is likely to appear brighter to animals responsive to UV than in conventional imaging which focuses on source discharge. Second, and crucially, the pattern of occurrence of corona flashes is temporally random, which is likely to impede habituation. These observations constitute a strong argument that reindeer, like birds and rodents, may see corona UV. By extension, we suggest that in darkness these animals see power lines not as dim, passive structures but, rather, as lines of flickering light stretching across the terrain. This does not explain avoidance by daylight or when lines are not transmitting electricity—although, interestingly, electrically earthed cables are more hazardous to galliformes (which detect UV to 355 nm; Lind et al. 2014), perhaps precisely because without corona definition is lost (Bevanger & Broseth 2001)—but it may be an example of classical conditioning in which the configuration of power lines is associated with events regarded as threatening.

Shifting mirrors: adaptive changes in retinal reflections to winter darkness in Arctic reindeer

Arctic reindeer experience extreme changes in environmental light from continuous summer daylight to continuous winter darkness. Here, we show that they may have a unique mechanism to cope with winter darkness by changing the wavelength reflection from their tapetum lucidum (TL). In summer, it is golden with most light reflected back directly through the retina, whereas in winter it is deep blue with less light reflected out of the eye. The blue reflection in winter is associated with significantly increased retinal sensitivity compared with summer animals. The wavelength of reflection depends on TL collagen spacing, with reduced spacing resulting in shorter wavelengths, which we confirmed in summer and winter animals. Winter animals have significantly increased intra-ocular pressure, probably produced by permanent pupil dilation blocking ocular drainage. This may explain the collagen compression. The resulting shift to a blue reflection may scatter light through photoreceptors rather than directly reflecting it, resulting in elevated retinal sensitivity via increased photon capture. This is, to our knowledge, the first description of a retinal structural adaptation to seasonal changes in environmental light. Increased sensitivity occurs at the cost of reduced acuity, but may be an important adaptation in reindeer to detect moving predators in the dark Arctic winter.

Macular colour contrast sensitivity in ocular hypertension and glaucoma: evidence for two types of defect.

Colour contrast sensitivity (CCS) of a large cohort of glaucomatous patients, ocular hypertensive patients (OH), and normal persons was measured at six-month intervals during a two-year period. The OHs were graded into high, medium, and low risk groups. 69% of glaucomatous patients and 32% of all OHs had CCS thresholds greater than the mean plus 2 SDs of the controls. Satisfactory specificity and sensitivity could not be obtained by adjusting the criterion of threshold. In abnormal eyes, progressive small increases of threshold occurred during the study, but glaucomatous eyes with normal thresholds on the first visit retained normal thresholds in the subsequent visits. Although our system is very sensitive and precise, the proportion of abnormalities detected is no greater than with other techniques. In some glaucomatous patients there is a true preservation of colour vision which does not merely reflect the limitations of the test employed.

Near-infrared light increases ATP, extends lifespan and improves mobility in aged Drosophila melanogaster

Ageing is an irreversible cellular decline partly driven by failing mitochondrial integrity. Mitochondria accumulate DNA mutations and reduce ATP production necessary for cellular metabolism. This is associated with inflammation. Near-infrared exposure increases retinal ATP in old mice via cytochrome c oxidase absorption and reduces inflammation. Here, we expose fruitflies daily to 670 nm radiation, revealing elevated ATP and reduced inflammation with age. Critically, there was a significant increase in average lifespan: 100–175% more flies survived into old age following 670 nm exposure and these had significantly improved mobility. This may be a simple route to extending lifespan and improving function in old age.

Mitochondrial decline precedes phenotype development in the complement factor H mouse model of retinal degeneration but can be corrected by near infrared light.

Mitochondria produce adenosine triphosphate (ATP), critical for cellular metabolism. ATP declines with age, which is associated with inflammation. Here, we measure retinal and brain ATP in normal C57BL/6 and complement factor H knockout mice (Cfh(-/-)), which are proposed as a model of age-related macular degeneration. We show a significant premature 30% decline in retinal ATP in Cfh(-/-) mice and a subsequent shift in expression of a heat shock protein that is predominantly mitochondrial (Hsp60). Changes in Hsp60 are associated with stress and neuroprotection. We find no differences in brain ATP between C57BL/6 and Cfh(-/-) mice. Near infrared (NIR) increases ATP and reduces inflammation. ATP decline in Cfh(-/-) mice was corrected with NIR which also shifted Hsp60 labeling patterns. ATP decline in Cfh(-/-) mice occurs before inflammation becomes established and photoreceptor loss occurs and may relate to disease etiology. However, ATP levels were corrected with NIR. In summary, we provide evidence for a mitochondrial basis for this disease in mice and correct this with simple light exposure known to improve mitochondrial function.