A chart-based test of contrast sensitivity in noise: reference ranges, effects of age and optical abnormality.

CLINICAL RELEVANCE: Contrast sensitivity plays an important role in the comprehensive assessment of visual function; however, measurement with standard eye charts can be affected by age and optical abnormality. BACKGROUND: This study describes a novel chart-based test of letter contrast sensitivity (CS) in luminance noise (the Illinois Eye and Ear Noise CS test), defines normal reference ranges, estimates test-retest repeatability, and assesses the effects of age and simulated optical abnormalities. METHODS: Seventy-five individuals with normal visual function (age 18-85 years) participated. Subjects identified letter optotypes that spanned a broad contrast range (0.9% to 59.6%) printed in a book-based test. Letters were presented against a grey background (no-noise condition) and in luminance noise that consisted of light and dark checks (noise condition). A subset of 10 subjects repeated the test to define short-term variability and performed the test under three additional conditions: simulated cataract, +2.00D defocus, and low room illuminance. RESULTS: In the no-noise condition, CS was independent of age (mean log CS of 1.74) until approximately 54 years, and declined for older subjects (CS loss of 0.1 log unit/decade). CS measured in noise was independent of age across the range of ages tested (mean log CS of 0.91). The 95% limits of agreement for test-retest repeatability was 0.19 log units. Simulated cataract, +2.00D defocus, and reduced illumination significantly reduced CS in the no-noise condition (F = 102.6, p < 0.001), whereas these optical manipulations did not significantly affect CS in noise (F = 2.58, p = 0.074). CONCLUSIONS: Measurements of CS in luminance noise may be valuable, as these measures are largely independent of age and certain forms of optical degradation. CS measurements in noise may provide useful insight into visual function in patients who have combined neural and optical abnormality, as noise minimises CS loss from optical defects.

Dysregulated 24 h melatonin secretion associated with intrinsically photosensitive retinal ganglion cell function in diabetic retinopathy: a cross-sectional study.

AIMS/HYPOTHESIS: The aim of this study was to explore whether diabetic retinopathy is associated with alterations of the circadian system, and to examine the role of reduced intrinsically photosensitive retinal ganglion cell (ipRGC) function. METHODS: Participants with type 2 diabetes, with diabetic retinopathy (n=14) and without diabetic retinopathy (n=9) underwent 24 h blood sampling for melatonin and cortisol under controlled laboratory conditions. ipRGC function was inferred from the post-illumination pupil response (PIPR). Habitual sleep duration, efficiency and variability were assessed by actigraphy. RESULTS: Participants with diabetic retinopathy compared to participants without diabetic retinopathy had smaller PIPR (p=0.007), lower 24 h serum melatonin output (p=0.042) and greater day-to-day sleep variability (p=0.012). By contrast, 24 h cortisol profiles, sleep duration and efficiency were similar in both groups. Six individuals with diabetic retinopathy had no detectable dim-light melatonin onset. PIPR correlated with 24 h mean melatonin levels (r=0.555, p=0.007). CONCLUSIONS/INTERPRETATION: ipRCG dysfunction in diabetic retinopathy is associated with disruptions of the 24 h melatonin rhythm, suggesting circadian dysregulation in diabetic retinopathy.

Multidimensional sleep health and diabetic retinopathy: Systematic review and meta-analysis.

Diabetic retinopathy (DR) is one of the most prevalent microvascular diabetic complications. Poor sleep health and obstructive sleep apnea (OSA) are risk factors for diabetes and poor glycemic control. Recent studies have suggested associations between poor sleep health/OSA and DR. Furthermore, there have been suggestions of melatonin dysregulation in the context of DR. We conducted a systematic review and meta-analysis exploring the associations between multidimensional sleep health (duration, satisfaction, efficiency, timing/regularity and alertness), OSA and melatonin with DR. Forty-two studies were included. Long, but not short sleep, was significantly associated with DR, OR 1.41 (95%CI 1.21, 1.64). Poor sleep satisfaction was also significantly associated with DR, OR 2.04 (1.41, 2.94). Sleep efficiency and alertness were not associated with DR, while the evidence on timing/regularity was scant. Having OSA was significantly associated with having DR, OR 1.34 (1.07, 1.69). Further, those with DR had significantly lower melatonin/melatonin metabolite levels than those without DR, standardized mean difference -0.94 (-1.44, -0.44). We explored whether treating OSA with continuous positive airway pressure (CPAP) led to improvement in DR (five studies). The results were mixed among studies, but potential benefits were observed in some. This review highlights the association between poor multidimensional sleep health and DR.

Greater sleep variability is associated with higher systemic inflammation in type 2 diabetes.

Sleep irregularity and variability have been shown to be detrimental to cardiometabolic health. The present pilot study explored if higher day-to-day sleep irregularity and variability were associated with systemic inflammation, as assessed by high-sensitivity C-reactive protein, in type 2 diabetes. Thirty-five patients with type 2 diabetes (mean age 54.3 years, 54.3% female) who were not shift-workers participated. The presence of diabetic retinopathy was determined. The standard deviation of sleep duration and sleep midpoint across all recorded nights were used to quantify sleep variability and regularity, respectively, assessed by 14-day actigraphy. The presence and severity of sleep apnea were assessed using an overnight home monitor. Low-density lipoprotein, haemoglobin A1C and high-sensitivity C-reactive protein were collected. Multiple regression analysis using natural-log-transformed values was performed to establish an independent association between sleep variability and high-sensitivity C-reactive protein. Twenty-two (62.9%) patients had diabetic retinopathy. The median (interquartile range) of high-sensitivity C-reactive protein was 2.4 (1.4, 4.6) mg L-1 . Higher sleep variability was significantly associated with higher high-sensitivity C-reactive protein (r = 0.342, p = 0.044), as was haemoglobin A1C (r = 0.431, p = 0.010) and low-density lipoprotein (r = 0.379, p = 0.025), but not sleep regularity, sleep apnea severity or diabetic retinopathy. Multiple regression analysis showed that higher sleep variability (B = 0.907, p = 0.038) and higher HbA1c (B = 1.519, p = 0.035), but not low-density lipoprotein, contributed to higher high-sensitivity C-reactive protein. In conclusion, higher sleep variability in patients with type 2 diabetes who were not shift-workers was independently associated with higher systemic inflammation, conferring increased cardiovascular risk. Whether sleep interventions to reduce sleep variability can reduce systemic inflammation and improve cardiometabolic health should be investigated.

The Slow Progression of Diabetic Retinopathy Is Associated with Transient Protection of Retinal Vessels from Death.

The purpose of this study was to investigate the reason that diabetic retinopathy (DR) is delayed from the onset of diabetes (DM) in diabetic mice. To this end, we tested the hypothesis that the deleterious effects of DM are initially tolerated because endogenous antioxidative defense is elevated and thereby confers resistance to oxidative stress-induced death. We found that this was indeed the case in both type 1 DM (T1D) and type 2 DM (T2D) mouse models. The retinal expression of antioxidant defense genes was increased soon after the onset of DM. In addition, ischemia/oxidative stress caused less death in the retinal vasculature of DM versus non-DM mice. Further investigation with T1D mice revealed that protection was transient; it waned as the duration of DM was prolonged. Finally, a loss of protection was associated with the manifestation of both neural and vascular abnormalities that are diagnostic of DR in mice. These observations demonstrate that DM can transiently activate protection from oxidative stress, which is a plausible explanation for the delay in the development of DR from the onset of DM.

Improvement of retinal function in Alzheimer disease-associated retinopathy by dietary lysophosphatidylcholine-EPA/DHA.

Alzheimer disease (AD) is the most prevalent cause of dementia in the elderly. Although impaired cognition and memory are the most prominent features of AD, abnormalities in visual functions often precede them, and are increasingly being used as diagnostic and prognostic markers for the disease. Retina contains the highest concentration of the essential fatty acid docosahexaenoic acid (DHA) in the body, and its deficiency is associated with several retinal diseases including diabetic retinopathy and age related macular degeneration. In this study, we tested the hypothesis that enriching retinal DHA through a novel dietary approach could ameliorate symptoms of retinopathy in 5XFAD mice, a widely employed model of AD. The results show that 5XFAD mice have significantly lower retinal DHA compared to their wild type littermates, and feeding the lysophosphatidylcholine (LPC) form of DHA and eicosapentaenoic acid (EPA) rapidly normalizes the DHA levels, and increases retinal EPA by several-fold. On the other hand, feeding similar amounts of DHA and EPA in the form of triacylglycerol had only modest effects on retinal DHA and EPA. Electroretinography measurements after 2 months of feeding the experimental diets showed a significant improvement in a-wave and b-wave functions by the LPC-diet, whereas the TAG-diet had only a modest benefit. Retinal amyloid ß levels were decreased by about 50% by the LPC-DHA/EPA diet, and by about 17% with the TAG-DHA/EPA diet. These results show that enriching retinal DHA and EPA through dietary LPC could potentially improve visual abnormalities associated with AD.

Effects of normal aging on the mouse retina assessed by full-field flash and flicker electroretinography.

Changes in the full-field flash and flicker electroretinogram (ERG) that accompany normal aging were evaluated in mice. ERGs were recorded from a single cohort of C57BL/6J mice from 5 to 70 weeks of age using conventional techniques. Dark-adapted ERGs were recorded for flash luminances of - 3.0 to 1.5 log cd-s-m-2; a- and b-wave amplitude and implicit time (IT) were calculated from these responses. In addition, light-adapted flicker ERGs elicited by sinusoidally modulated light were measured for temporal frequencies of 2 to 31 Hz. Amplitudes and phases were extracted from the flicker responses using Fourier analysis. Linear quantile mixed models were used for statistical comparisons of the effects of age on amplitude and timing. There was a significant decrease in a-wave amplitude (p < 0.001) and b-wave amplitude (p < 0.001) over the 65 week study. From 5 to 70 weeks, the a- and b-wave amplitudes decreased by a factor of approximately 2. There was a small (2-14 ms), but significant (p < 0.001), delay in a- and b-wave IT over the 65 week study. There was also a significant decrease in fundamental amplitude (factor of 1.8, p < 0.001) and second harmonic amplitude (factor of 1.5, p < 0.001) over time. There were no significant age-related effects on the phase of these components (both p > 0.06). These results indicate that age scales the single flash and flicker ERG similarly, reducing response amplitude by a factor of approximately 2, from 5 to 70 weeks, with small or no effect on response timing. These data may be useful for guiding future longitudinal pre-clinical therapeutic studies.

Visual Field Abnormalities in Early-Stage Diabetic Retinopathy Assessed by Chromatic Perimetry.

Purpose: The purpose of this study was to define the nature and extent of sensitivity loss using chromatic perimetry in diabetics who have mild or no retinopathy. Methods: Thirty-four individuals with type II diabetes mellitus who have mild nonproliferative diabetic retinopathy (MDR; N = 17) or no diabetic retinopathy (NDR; N = 17) and 15 visually normal, non-diabetic controls participated. Sensitivity was assessed along the horizontal visual field meridian using an Octopus 900 perimeter. Measurements were performed under light- and dark-adapted conditions using long-wavelength (red) and short-wavelength (blue) Goldmann III targets. Cumulative defect curves (CDCs) were constructed to determine whether field sensitivity loss was diffuse or localized. Results: Sensitivity was reduced significantly under light-adapted conditions for both stimulus colors for the NDR (mean defect ± SEM = -2.1 dB ± 0.6) and MDR (mean defect ± SEM = -4.0 dB ± 0.7) groups. Sensitivity was also reduced under dark-adapted conditions for both stimulus colors for the NDR (mean defect ± SEM = -1.9 dB ± 0.7) and MDR (mean defect ± SEM = -4.5 ± 1.0 dB) groups. For both diabetic groups, field loss tended to be diffuse under light-adapted conditions (up to 6.9 dB loss) and localized under dark-adapted conditions (up to 15.4 dB loss). Conclusions: Visual field sensitivity losses suggest neural abnormalities in early stage diabetic eye disease and the pattern of the sensitivity losses differed depending on the adaptation conditions. Chromatic perimetry may be useful for subtyping individuals who have mild or no diabetic retinopathy and for better understanding their neural dysfunction.

Occult retinopathy following treatment of Hepatitis C with glecaprevir/pibrentasvir (Mavyret).

BACKGROUND/PURPOSE: Medication-induced ocular toxicity is an important consideration in the differential diagnosis of unexplained visual disturbance. We present a case of visual disturbance after starting treatment with glecaprevir/pibrentasvir (Mavyret), a therapy for Hepatitis C virus approved by the FDA in 2017. METHODS: A 50-year-old male with no significant ocular history experienced bilateral visual disturbance, including visual field and acuity loss, shortly after initiating treatment with Mavyret for Hepatitis C. Examination of the anterior and posterior segments was unremarkable, and no abnormalities could be identified on multimodal imaging of the eye and brain, including MRI, SD-OCT, and fundus autofluorescence. Extensive testing for inflammatory, infectious, nutritional, and genetic etiologies for optic neuropathy and retinopathy was negative. RESULTS: Electrophysiology testing was pursued to narrow the broad differential diagnosis. Full-field electroretinography and multi-focal electroretinography detected deficiencies in the rod and cone visual pathways and attenuated electrophysiologic responses in the fovea. Pattern electroretinography and visually-evoked potentials demonstrated macula dysfunction. Taken together, electrophysiologic data suggested diffuse retinal dysfunction, which was most pronounced in the macula. CONCLUSIONS: Given the temporal relationship between Mavyret administration and vision loss in our patient, and the absence of an underlying cause after extensive evaluation, we propose that Mavyret may be associated with a toxic occult retinopathy characterized by panretinal dysfunction without clinically apparent structural findings.

Rod photoreceptor activation and deactivation in early-stage diabetic eye disease.

PURPOSE: To infer rod phototransduction activation and deactivation characteristics in diabetics who have mild or no clinically-apparent retinopathy. METHODS: Fifteen non-diabetic controls, 15 diabetics with no clinically-apparent diabetic retinopathy (NDR), and 15 diabetics with mild non-proliferative diabetic retinopathy (MDR) participated. Dark-adapted flash electroretinograms (3.2 to 4.4 log scot td-s) were recorded to assess rod activation. The a-waves were fit with a Gaussian model to derive Rmp3 (maximum photoreceptor response amplitude) and S (phototransduction sensitivity). Rod deactivation was assessed with a paired flash paradigm, in which a-waves were measured for two flashes separated by inter-stimulus intervals (ISIs) of 0.125 to 16 s. The ISI needed for the a-wave amplitude of the second flash to recover to 50% of the first flash (t50) was determined. The effect of stimulus retinal illuminance on activation and deactivation was evaluated in a subset of control subjects. RESULTS: Analysis of variance indicated that both diabetic groups had significant log S reductions compared to controls (p < 0.001). Mean S was reduced by approximately 49% and 78% for the NDR and MDR groups, respectively. In contrast, log Rmp3 and log t50 did not differ significantly among the groups (both p > 0.08). Reducing stimulus retinal illuminance significantly reduced S, but did not significantly affect Rmax or t50. CONCLUSIONS: Only phototransduction sensitivity was abnormal in this sample of diabetic subjects. The normal deactivation kinetics suggests that circulating rod current is normal. These findings begin to constrain possible explanations for abnormal rod function in early diabetic retinal disease.

Two-Color Dark-Adapted Perimetry Implemented With a Commercially Available Perimeter to Characterize Rod-Pathway Sensitivity.

BACKGROUND AND OBJECTIVE: To characterize rod-pathway function across the visual field using 2-color dark-adapted perimetry (2cDAP) implemented with conventional Octopus 900 Pro perimeters. PATIENTS AND METHODS: Eighteen visually normal individuals and two retinitis pigmentosa (RP) patients participated. Thresholds were measured under dark-adapted conditions at 15 locations along the horizontal meridian using short (450 nm) and long (610 nm) wavelength stimuli. Threshold differences between the two wavelengths were used to determine rod- vs cone-mediated function. RESULTS: Among controls, peripheral and perifoveal thresholds for the short-wavelength stimulus were approximately 2 log units lower than for the long-wavelength stimulus. Foveal thresholds for the two wavelengths were similar. RP threshold profiles differed considerably from the controls, with normal foveal thresholds and high peripheral thresholds for both wavelengths. CONCLUSIONS: 2cDAP can be performed with an unmodified Octopus perimeter to evaluate rod function across the visual field and obtain information that is not available with standard automated perimetry. [Ophthalmic Surg Lasers Imaging Retina 2022;53:692-696.].

Spatial and Temporal Integration Abnormalities in X-Linked Retinoschisis.

Purpose: To evaluate spatial and temporal integration across the visual field in individuals with juvenile X-linked retinoschisis (XLRS). Methods: Nine subjects with XLRS and 10 visually normal individuals participated. Luminance thresholds were measured at 15 locations along the horizontal visual field meridian. Locations were grouped into four regions for analysis: foveal, parafoveal (2°), perifoveal (5°-10°), and peripheral (10°-60°). For spatial integration measurements, stimulus duration was 100 ms, and size ranged from 0.01 to 2.32 deg2 (Goldmann I-V). For temporal integration measurements, stimulus size was 0.15 deg2 (Goldmann III), and duration ranged from 12 to 800 ms. The effect of stimulus size and duration on the subjects' threshold was described using integration models. Results: Luminance thresholds for the XLRS group were more elevated for small targets (2.0×-12.6×) than for large targets (1.25×-3.2×) compared to controls for all locations. Likewise, thresholds for the XLRS group were more elevated for short durations (6.3×) than for long durations (4.0×) in the fovea and parafovea but were similarly elevated at all durations (2.0×-2.5×) in the perifovea and periphery. For both the size and duration experiments, thresholds measured in the fovea, parafovea, and perifovea of XLRS subjects were highly similar to those measured from the peripheral field of the controls. Conclusions: Spatial and temporal integration characteristics of the XLRS fovea, parafovea, and perifovea are similar to those of the normal periphery. The results also indicate that scaling stimulus size equates thresholds for the XLRS and control subjects throughout the visual field, but scaling duration does not.

Retinoschisin deficiency induces persistent aberrant waves of activity affecting neuroglial signaling in the retina.

Genetic disorders which present during development make treatment strategies particularly challenging because there is a need to disentangle primary pathophysiology from downstream dysfunction caused at key developmental stages. To provide a deeper insight into this question, we studied a mouse model of X-linked juvenile retinoschisis (XLRS), an early-onset inherited condition caused by mutations in the Rs1 gene encoding retinoschisin (RS1) and characterized by cystic retinal lesions and early visual deficits. Using an unbiased approach in expressing the fast intracellular calcium indicator GCaMP6f in neuronal, glial, and vascular cells of the retina of RS1-deficient male mice, we found that initial cyst formation is paralleled by the appearance of aberrant spontaneous neuro-glial signals as early as postnatal day 15, when eyes normally open. These presented as glutamate-driven wavelets of neuronal activity and sporadic radial bursts of activity by Müller glia, spanning all retinal layers and disrupting light-induced signaling. This study confers a role to RS1 beyond its function as an adhesion molecule, identifies an early onset for dysfunction in the course of disease, establishing a potential window for disease diagnosis and therapeutic intervention.Significance StatementDevelopmental disorders make it difficult to distinguish pathophysiology due to ongoing disease from pathophysiology due to disrupted development. Here, we investigated a mouse model for X-linked retinoschisis (XLRS), a well-defined monogenic degenerative disease caused by mutations in the Rs1 gene, which codes for the protein retinoschisin. We evaluated the spontaneous activity of explanted retinas lacking retinoschisin at key stages of development using the unbiased approach of ubiquitously expressing GCaMP6f in all retinal neurons, vasculature and glia. In mice lacking RS1, we found an array of novel phenotypes which present around eye-opening, are linked to glutamatergic neurotransmission, and affect visual processing. These data identify novel pathophysiology linked to RS1, and define a window where treatments might be best targeted.

Contrast Sensitivity and Equivalent Intrinsic Noise in X-Linked Retinoschisis.

Purpose: To define relationships among contrast sensitivity (CS), equivalent intrinsic noise (Neq; a measure of noise within the visual pathway), and retinal thickness in X-linked retinoschisis (XLRS). Methods: Nine XLRS and 10 visually-normal subjects participated. CS was measured in the presence and absence of luminance noise. These data were fit with a standard model to estimate Neq and sampling efficiency (an estimate of the ability to use stimulus information). Optical coherence tomography images were obtained to quantify outer nuclear layer (ONL+) and outer segment (OS+) thickness. A linear structure-function model was used to describe the relationship between CS and the product of ONL+ and OS+ thickness. Results: CS in the absence of noise (CS0) for the XLRS subjects ranged from normal to as much as 1.5× below the lower limit of normal. Four of the nine subjects with XLRS had abnormally high Neq, whereas two others had sampling efficiency that was borderline abnormal. Log CS0 for the subjects with XLRS was correlated significantly with log Neq (r = -0.78, P = 0.01), but not with log efficiency (r = 0.19, P = 0.63). CS0 and Neq, but not efficiency, conformed to the linear ONL+ × OS+ structure-function model. Conclusions: The XLRS subjects in this study who had elevated internal noise had abnormally low CS; both internal noise and CS fell within the predicted limits of a structure-function model. Translational Relevance: Internal noise measurements can provide insight into a source of CS loss in some individuals with XLRS.

Cone pathway dysfunction in Jalili syndrome due to a novel familial variant of CNNM4 revealed by pupillometry and electrophysiologic investigations.

PURPOSE: To evaluate retinal function in a family presenting with Jalili syndrome due to a previously unreported variant in CNNM4. METHODS: A family of three sisters with a novel CNNM4 variant, c.482 T > C p.(Leu161Pro), and ten visually normal, age-similar controls participated in this study. The subjects underwent detailed dental examinations and comprehensive ophthalmological examinations that included color vision testing, retinal imaging, and electroretinography. Full-field light- and dark-adapted luminance thresholds were obtained, in addition to light- and dark-adapted measures of the pupillary light reflex (PLR; pupil constriction elicited by a flash of light) across a range of stimulus luminance. RESULTS: Clinical findings of cone dysfunction and amelogenesis imperfecta were observed, consistent with Jalili syndrome. Light-adapted ERGs were non-detectable in CNNM4 subjects, whereas dark-adapted ERGs were generally normal. Full-field luminance thresholds were normal under dark-adapted conditions and were elevated, but measurable, under light-adapted conditions. The CNNM4 subjects had large PLRs under dark-adapted conditions and responses near the lower limit of normal, or slightly subnormal, under light-adapted conditions. CONCLUSION: CNNM4 variants can result in Jalili syndrome with cone dystrophy and generally preserved rod function. The PLR may be a useful measure for evaluating cone function in these individuals, as robust cone-mediated PLRs were recordable despite non-detectable light-adapted ERGs.

Clinical electroretinography in diabetic retinopathy: a review.

The electroretinogram (ERG) is a noninvasive, objective technique to evaluate retinal function that has become increasingly important in the study of diabetic retinopathy. We summarize the principles and rationale of the ERG, present findings from recent clinical studies that have used the full-field ERG, multifocal ERG, and pattern ERG to evaluate neural dysfunction in patients with diabetes, and weigh the strengths and limitations of the technique as it applies to clinical studies and management of patients with diabetic retinopathy. Taken together, ERG studies have provided convincing evidence for dysfunction of the neural retina in patients with diabetes, including those who have no clinically-apparent retinal vascular abnormalities. Recent full-field ERG findings have pointed to the intriguing possibility that photoreceptor function is abnormal in early-stage disease. Pattern ERG data, in conjunction with recently developed photopic negative response analyses, indicate inner retina dysfunction. In addition, multifocal ERG studies have shown spatially localized neural abnormalities that can predict the location of future microaneurysms. Given the insights provided by the ERG, it is likely to play a growing role in understanding the natural history of neural dysfunction in diabetes, as well as providing an attractive outcome measure for future clinical trials that target neural preservation in diabetic retinopathy.

Effect of Pharmacological Pupil Dilation on Dark-Adapted Perimetric Sensitivity in Healthy Subjects Using an Octopus 900 Perimeter.

Purpose: To determine whether dilation status has a clinically meaningful effect on sensitivity in normal subjects undergoing two-color dark-adapted perimetry, which can be useful to assess rod function. Methods: A perimeter measured naturally and pharmacologically dilated scotopic sensitivities using a test grid consisting of 16 points across the horizontal meridian ranging from 60° temporal to 45° nasal using cyan (500 nm wavelength) or red (650 nm wavelength) stimuli. The primary outcome was average overall sensitivity based on dilation status, which was compared using a linear mixed effect model for each color stimuli. A difference of 2 dB or more was considered clinically significant. Results: Twenty-nine eyes from 15 subjects (nine female) ages 23 to 63 with no known retinal pathology were included. Pharmacologically dilated eyes were 0.54 dB (95% confidence interval [CI], 0.05 dB to 1.03 dB; P = 0.032) more sensitive to a red stimulus than naturally dilated eyes, but this was not statistically significant after correction for multiple comparisons. Pharmacologically dilated eyes were 0.03 dB (95% CI, -0.20 dB to 0.14 dB; P = 0.734) less sensitive to a cyan stimulus compared to naturally dilated eyes. Conclusions: These findings show no clinically significant differences in sensitivity of scotopic perimetry in eyes without retinal pathology based on dilation status for both cyan and red stimuli. Translational Relevance: In this study, pharmacological dilation did not have a clinically meaningful effect on sensitivity, suggesting that this is not necessary when using two-color dark-adapted perimetry to assess for rod function.

Luminance Thresholds and Their Correlation With Retinal Structure in X-Linked Retinoschisis.

Purpose: To provide a comprehensive analysis of light- and dark-adapted luminance thresholds and their associations with retinal structure in X-linked retinoschisis (XLRS). Methods: Nine subjects with XLRS and 10 visually-normal individuals participated. Threshold was measured at 15 locations along the horizontal meridian of the visual field at several adaptation levels (5 × 10-5 to 50 cd/m2) after dark-adaptation. The relationship between threshold and adaptation level across the field was described using a standard "threshold-versus-illuminance" model. Optical coherence tomography images were obtained and segmented to quantify outer nuclear layer (ONL+) and outer segment (OS+) thickness. A linear structure-function model was used to describe the relationship between threshold and the product of ONL+ and OS+ thickness. Results: For peripheral field measurements, thresholds were generally normal for most subjects with XLRS. All subjects had perifoveal and parafoveal threshold elevations under dark-adapted and high illuminance conditions, with thresholds at moderate illuminances being closer to normal. For foveal measurements, seven of nine subjects with XLRS had normal dark-adapted thresholds, and all had abnormally elevated high illuminance thresholds. Threshold-versus-illuminance curves in the fovea, parafovea, and perifovea were abnormally steep for subjects with XLRS, appearing similar to the normal peripheral field shape. Under both dark- and light-adapted conditions, threshold was predicted by ONL+ × OS+ thickness at nearly all field locations. Conclusions: Threshold elevation in XLRS is complex, depending on both the adaptation level and the visual field location. The pattern of threshold-versus-illuminance suggests that macular function in XLRS is similar to the periphery of controls.

Rod pathway and cone pathway retinal dysfunction in the 5xFAD mouse model of Alzheimer's disease.

To characterize rod- and cone-pathway function in the 5xFAD mouse model of Alzheimer's disease (AD) using the full-field electroretinogram (ERG). Dark-adapted (DA; rod-pathway) and light-adapted (LA; cone-pathway) ERGs were recorded from three-month-old 5xFAD and wild type (WT) mice. ERGs were elicited by achromatic flashes (0.01-25 cd-s-m-2). Amplitude and implicit time (IT) of the a-wave, b-wave, and oscillatory potentials (OPs) were calculated according to convention. In addition, the amplitude and IT of the photopic negative response (PhNR) were measured from the LA recordings. Amplitude and IT differences between the 5xFAD and WT groups were evaluated using quantile regression models. Under DA conditions, there were significant differences between the 5xFAD and WT groups in post-receptor function, whereas photoreceptor function did not differ significantly. Specifically, the DA a-wave amplitude did not differ between groups (p = 0.87), whereas the b-wave amplitude was reduced in the 5xFAD mice (p = 0.003). There were significant OP (p < 0.001) and a-wave (p = 0.04) delays, but the a-wave delay may be attributable to a post-receptor abnormality. Under LA conditions, the only 5xFAD abnormalities were in the PhNR, which was reduced (p = 0.009) and delayed (p = 0.04). The full-field ERG can be abnormal in the 5xFAD model of AD, with the greatest effects on post-receptor rod pathway function. These results indicate that retinal electrophysiology may be a useful tool for evaluating neural dysfunction in AD.

Electrophysiological and Pupillometric Abnormalities in PROM1 Cone-Rod Dystrophy.

Purpose: To compare electrophysiological and pupillometric responses in subjects with cone-rod dystrophy due to autosomal recessive (AR) PROM1 mutations. Methods: Four subjects with AR PROM1 dystrophy and 10 visually normal, age-similar controls participated in this study. Full-field, light- and dark-adapted electroretinograms (ERGs) were obtained using conventional techniques. Full-field, light- and dark-adapted measures of the pupillary light reflex (PLR; pupil constriction elicited by a flash of light) were obtained across a range of stimulus luminance using long- and short-wavelength light. Pupil size as a function of stimulus luminance was described using Naka-Rushton functions to derive Pmax (maximum response) and s (pupil response sensitivity). Results: Light-adapted ERGs were non-detectable in all four PROM1 subjects, whereas dark-adapted ERGs were non-detectable in three subjects and markedly attenuated in the fourth. By contrast, each PROM1 subject had light- and dark-adapted PLRs. Pmax ranged from normal to slightly attenuated under all conditions. Light-adapted s was generally normal, with the exception of two subjects who had abnormal s for the long-wavelength stimulus. Dark adapted s was abnormal for each PROM1 subject for the long-wavelength stimulus and ranged from the upper limit of normal to substantially abnormal for the short-wavelength stimulus. Conclusions: ERG and PLR comparison showed an unanticipated dichotomy: ERGs were generally non-detectable, whereas PLRs were normal for all PROM1 subjects under select conditions. Differences between the measures may be attributed to distinct spatiotemporal summation/gain characteristics. Translational Relevance: These data highlight the potential usefulness of pupillometry in cases where the ERG is non-detectable.