Visual Psychophysics and Physiological Optics Vision in Observers With Enhanced S-Cone Syndrome: An Excess of S-Cones but Connected Mainly to Conventional S-Cone Pathways

Citation: Ripamonti C, Aboshiha J, Henning GB, et al. Vision in observers with enhanced S-cone syndrome: an excess of S-cones but connected mainly to conventional S-cone pathways. Invest Ophthalmol Vis Sci. 2014;55:963-976. DOI:10.1167/iovs. 13-12897 PURPOSE. The effect of increased numbers of S-cone photoreceptors in enhanced S-cone syndrome (ESCS) was investigated psychophysically in six ESCS observers to understand more about relative cone sensitivities and postreceptoral organization. METHODS. Measures of temporal sensitivity or delay were made: S-and L-cone temporal acuity (critical flicker fusion, or CFF), S-cone temporal contrast sensitivity, and S-cone delay. RESULTS. ESCS observers showed uniform enhancements of S-cone CFF of between 0.85 and 6.25 Hz, but reductions in L-cone CFF. They also showed higher S-cone temporal contrast sensitivities at medium and high S-cone adaptation levels, with sensitivity functions that peaked near 7.5 Hz but fell off at lower and higher frequencies. In contrast, the mean normal function was flat at low frequencies and fell off only at high frequencies. The S-cone signal, as in the normal, is subject to large phase delays. CONCLUSIONS. We interpret the enhancements in CFF as increases in S-cone number in ESCS of between 1.39 and 11.32 times normal density (with a mean of 3.48). The peaked ESCS contrast-sensitivity functions are consistent with S-cone signal interactions that increase sensitivity at intermediate frequencies through constructive interference but decrease it at lower and higher frequencies through destructive interference. Measurements of S-cone delays relative to L-and M-cone signals show that the predominant S-cone signals in ESCS are negative and delayed as in normal observers, but reveal another faster, positive S-cone signal. This signal is also likely to be the cause of constructive and destructive interference in the contrast-sensitivity data of ESCS observers Keywords: enhanced S-cone syndrome, flicker sensitivity, critical flicker fusion, temporal processing, NR2E3, temporal acuity, short-wavelength-sensitive cones. E nhanced S-cone syndrome (ESCS) is a rare inherited degenerative retinal disease named after the associated unusual gain in function-an increase in short-wavelengthsensitive (S) cone sensitivity. 1 The syndrome is also characterized by severely reduced rod sensitivity (night blindness), foveal schisis and macular cysts, varying degree of visual acuity loss, and atypical ERGs that show little or no responses to dim rod (scotopic) stimuli, but have large, slow responses to brighter cone (photopic) stimuli. 1-4 The photopic ERG was originally thought to be of rod origin, 5-7 but spectral measurements have shown that it is dominated by S-cones with reduced contributions from long-and middle-wavelength-sensitive (L and M) cones. 9,10,12 Hood et al. 10 More direct evidence for a relative increase in the number of Scones was provided by histological examination of a disordered ESCS retina of a 77-year-old woman, 12 in which twice the normal number of cones was found, 92% of which were Scones. A more recent study used adaptive optics imaging to attempt to visualize individual cones directly in vivo in three young adults with ESCS. The excess of S-cones can be related to a molecular defect. The gene NR2E3 codes for a photoreceptor-specific nuclear receptor NR2E

Visual Psychophysics and Physiological Optics Vision in Observers With Enhanced S-Cone Syndrome: An Excess of S-Cones but Connected Mainly to Conventional S-Cone Pathways

Citation: Ripamonti C, Aboshiha J, Henning GB, et al. Vision in observers with enhanced S-cone syndrome: an excess of S-cones but connected mainly to conventional S-cone pathways. Invest Ophthalmol Vis Sci. 2014;55:963-976. DOI:10.1167/iovs. 13-12897 PURPOSE. The effect of increased numbers of S-cone photoreceptors in enhanced S-cone syndrome (ESCS) was investigated psychophysically in six ESCS observers to understand more about relative cone sensitivities and postreceptoral organization. METHODS. Measures of temporal sensitivity or delay were made: S-and L-cone temporal acuity (critical flicker fusion, or CFF), S-cone temporal contrast sensitivity, and S-cone delay. RESULTS. ESCS observers showed uniform enhancements of S-cone CFF of between 0.85 and 6.25 Hz, but reductions in L-cone CFF. They also showed higher S-cone temporal contrast sensitivities at medium and high S-cone adaptation levels, with sensitivity functions that peaked near 7.5 Hz but fell off at lower and higher frequencies. In contrast, the mean normal function was flat at low frequencies and fell off only at high frequencies. The S-cone signal, as in the normal, is subject to large phase delays. CONCLUSIONS. We interpret the enhancements in CFF as increases in S-cone number in ESCS of between 1.39 and 11.32 times normal density (with a mean of 3.48). The peaked ESCS contrast-sensitivity functions are consistent with S-cone signal interactions that increase sensitivity at intermediate frequencies through constructive interference but decrease it at lower and higher frequencies through destructive interference. Measurements of S-cone delays relative to L-and M-cone signals show that the predominant S-cone signals in ESCS are negative and delayed as in normal observers, but reveal another faster, positive S-cone signal. This signal is also likely to be the cause of constructive and destructive interference in the contrast-sensitivity data of ESCS observers Keywords: enhanced S-cone syndrome, flicker sensitivity, critical flicker fusion, temporal processing, NR2E3, temporal acuity, short-wavelength-sensitive cones. E nhanced S-cone syndrome (ESCS) is a rare inherited degenerative retinal disease named after the associated unusual gain in function-an increase in short-wavelengthsensitive (S) cone sensitivity. 1 The syndrome is also characterized by severely reduced rod sensitivity (night blindness), foveal schisis and macular cysts, varying degree of visual acuity loss, and atypical ERGs that show little or no responses to dim rod (scotopic) stimuli, but have large, slow responses to brighter cone (photopic) stimuli. 1-4 The photopic ERG was originally thought to be of rod origin, 5-7 but spectral measurements have shown that it is dominated by S-cones with reduced contributions from long-and middle-wavelength-sensitive (L and M) cones. 9,10,12 Hood et al. 10 More direct evidence for a relative increase in the number of Scones was provided by histological examination of a disordered ESCS retina of a 77-year-old woman, 12 in which twice the normal number of cones was found, 92% of which were Scones. A more recent study used adaptive optics imaging to attempt to visualize individual cones directly in vivo in three young adults with ESCS. The excess of S-cones can be related to a molecular defect. The gene NR2E3 codes for a photoreceptor-specific nuclear receptor NR2E

Dark-Adaptation Functions in Molecularly Confirmed Achromatopsia and the Implications for Assessment in Retinal Therapy Trials

PURPOSE. To describe the dark-adaptation (DA) functions in subjects with molecularly proven achromatopsia (ACHM) using refined testing conditions with a view to guiding assessment in forthcoming gene therapy trials. METHODS. The DA functions of nine subjects with ACHM were measured and compared with those of normal observers. The size and retinal location of the stimuli used to measure DA sensitivities were varied in four distinct testing condition sets, and the effect of altering these parameters assessed. RESULTS. In three of the four testing condition sets, achromats had significantly higher mean final thresholds than normal observers, whereas in the fourth condition set they did not. A larger, more central stimulus revealed the greatest difference between the final DA thresholds of achromat and normal subjects, and also demonstrated the slowest rate of recovery among the achromat group. CONCLUSIONS. In this, the largest study of DA functions in molecularly proven ACHM to date, we have identified optimal testing conditions that accentuate the relative difference between achromats and normal observers. These findings can help optimize DA testing in future trials, as well as help resolve the dichotomy in the literature regarding the normality or otherwise of DA functions in ACHM. Furthermore, the shorter testing time and less intense adaptation light used in these experiments may prove advantageous for more readily and reliably probing scotopic function in retinal disease, and be particularly valuable in the frequent post therapeutic assessments required in the context of the marked photophobia in ACHM

Dark-Adaptation Functions in Molecularly Confirmed Achromatopsia and the Implications for Assessment in Retinal Therapy TrialsDark-Adaptation Functions in Achromatopsia

PurposeTo describe the dark-adaptation (DA) functions in subjects with molecularly proven achromatopsia (ACHM) using refined testing conditions with a view to guiding assessment in forthcoming gene therapy trials.MethodsThe DA functions of nine subjects with ACHM were measured and compared with those of normal observers. The size and retinal location of the stimuli used to measure DA sensitivities were varied in four distinct testing condition sets, and the effect of altering these parameters assessed.ResultsIn three of the four testing condition sets, achromats had significantly higher mean final thresholds than normal observers, whereas in the fourth condition set they did not. A larger, more central stimulus revealed the greatest difference between the final DA thresholds of achromat and normal subjects, and also demonstrated the slowest rate of recovery among the achromat group.ConclusionsIn this, the largest study of DA functions in molecularly proven ACHM to date, we have identified optimal testing conditions that accentuate the relative difference between achromats and normal observers. These findings can help optimize DA testing in future trials, as well as help resolve the dichotomy in the literature regarding the normality or otherwise of DA functions in ACHM. Furthermore, the shorter testing time and less intense adaptation light used in these experiments may prove advantageous for more readily and reliably probing scotopic function in retinal disease, and be particularly valuable in the frequent post therapeutic assessments required in the context of the marked photophobia in ACHM

Genotype-Dependent Variability in Residual Cone Structure in Achromatopsia: Toward Developing Metrics for Assessing Cone HealthAssessing Residual Photoreceptor Integrity in ACHM

PurposeGene therapy trials for inherited photoreceptor disorders are planned. Anatomical metrics to select the best candidates and outcomes are needed. Adaptive optics (AO) imaging enables visualization of photoreceptor structure, although analytical tools are lacking. Here we present criteria to assess residual photoreceptor integrity in achromatopsia (ACHM).MethodsTwo AOSLOs, at the Medical College of Wisconsin and Moorfields Eye Hospital, were used to image the photoreceptor mosaic of 11 subjects with ACHM and 7 age-matched controls. Images were obtained, processed, and montaged using previously described methods. Cone density and reflectivity were quantified to assess residual cone photoreceptor structure.ResultsAll subjects with ACHM had reduced numbers of cone photoreceptors, albeit to a variable degree. In addition, the relative cone reflectivity varied greatly. Interestingly, subjects with GNAT2-associated ACHM had the greatest number of residual cones and the reflectivity of those cones was significantly greater than that of the cones in the subjects with CNGA3/CNGB3-associated ACHM.ConclusionsWe present cone reflectivity as a metric that can be used to characterize cone structure in ACHM. This method may be applicable to subjects with other cone disorders. In ACHM, we hypothesize that cone numerosity (and/or density) combined with cone reflectivity could be used to gauge the therapeutic potential. As gene replacement would not be expected to add cones, reflectivity could be a more powerful AO-metric for monitoring the cellular response to treatment and could provide a more immediate indicator of efficacy than behavioral measures, which may take longer to change

A Prospective Longitudinal Study of Retinal Structure and Function in AchromatopsiaNatural History of Achromatopsia

PurposeTo longitudinally characterize retinal structure and function in achromatopsia (ACHM) in preparation for clinical gene therapy trials.MethodsThirty-eight molecularly confirmed ACHM subjects underwent serial assessments, including spectral domain optical coherence tomography (SD-OCT), microperimetry, and fundus autofluorescence (FAF). Foveal structure on SD-OCT was graded and compared for evidence of progression, along with serial measurements of foveal total retinal thickness (FTRT) and outer nuclear layer (ONL) thickness. Fundus autofluorescence patterns were characterized and compared over time.ResultsMean follow-up was 19.5 months (age range at baseline, 6-52 years). Only 2 (5%) of 37 subjects demonstrated change in serial foveal SD-OCT scans. There was no statistically significant change over time in FTRT (P = 0.83), ONL thickness (P = 0.27), hyporeflective zone diameter (P = 0.42), visual acuity (P = 0.89), contrast sensitivity (P = 0.22), mean retinal sensitivity (P = 0.84), and fixation stability (P = 0.58). Three distinct FAF patterns were observed (n = 30): central increased FAF (n = 4), normal FAF (n = 11), and well-demarcated reduced FAF (n = 15); with the latter group displaying a slow increase in the area of reduced FAF of 0.03 mm(2) over 19.3 months (P = 0.002).ConclusionsPreviously published cross-sectional studies have described conflicting findings with respect to the age-dependency of progression. This study, which constitutes the largest and longest prospective longitudinal study of ACHM to date, suggests that although ACHM may be progressive, any such progression is slow and subtle in most patients, and does not correlate with age or genotype. We also describe the first serial assessment of FAF, which is highly variable between individuals, even of similar age and genotype