Dark-adapted Threshold Research Articles

Characteristics of Eyes With CRB1-Associated EOSRD/LCA: Age-Related Changes

PurposeTo evaluate ocular and retinal features of CRB1-associated early onset severe retinal dystrophy/Leber congenital amaurosis (EOSRD/LCA) for age-related changes. DesignRetrospective cohort study. MethodsSixteen pediatric patients with biallelic CRB1 EOSRD/LCA who had been followed for up to 18 years were reviewed. Results of comprehensive ophthalmic examinations—including visual acuity, refractive error, dark-adapted visual threshold, Goldmann perimetry, and macular optical coherence tomography (OCT)—were analyzed for significant age-related changes using mixed-effects models. ResultsVisual acuity dark-adapted visual sensitivity, and area of seeing visual field (all subnormal from the earliest ages recorded) declined with increasing age. Hyperopia was stable through childhood and adolescence. In CRB1 EOSRD/LCA, OCT extrafoveal inner and outer laminar thicknesses exceeded those in controls but varied little with age, and foveal metrics (depth, breadth, thickness at rim) differed significantly from those in controls, but variations in foveal metrics were not associated with declines in acuity. ConclusionsFrom the youngest ages, retinal and visual function is significantly subnormal and becomes progressively compromised. A goal of future therapies should be intervention at young ages, when there is more function to be rescued.

The Development of Retinal Function and Refractive Error in Children With Retinopathy of Prematurity.

The purpose of this study was to test the hypothesis that retinopathy of prematurity (ROP) prolongs development of rod-mediated thresholds for detection of stimuli at 10degrees but not 30degrees eccentricity. In addition, to evaluate the thresholds at each site for an association with visual acuity (VA) and spherical equivalent (SE). We estimated rod-mediated dark-adapted thresholds (DATs) for the detection of 2degree diameter, 50ms, blue (λ < 510nm) flashes at 10degrees and 30degrees eccentric in former preterm subjects (n = 111), stratified by ROP severity: None (n = 32), Mild (n = 66), and Severe (n = 13). We also tested Term-born (n = 28) controls. To determine the age at half-maximal sensitivity (Agehalf) for each group and eccentricity, we fit DATs to logistic growth curves. We obtained VA and SE for Preterm subjects and evaluated the course of threshold development at 10degrees and 30degrees for significant association with VA and SE predicted at age 10 years. DAT development at 10degrees was significantly delayed in ROP (Mild and Severe); ROP did not significantly alter DAT development at 30degrees. At age 10years, among Preterm subjects, both VA and SE were significantly associated with group (None,Mild, and Severe). SE was predicted by the course of DAT development at 30degrees. VA was not associated with the course of DAT development at 10degrees. At 10degrees, ROP-whether mild or severe-is associated with significant delays in DAT development, evidence that the late-maturing central retina is vulnerable to ROP. The association of 30degree threshold and myopia are evidence that more peripheral retina is important to refractive development.

Development and Validation of a Novel Mobility Test for Rod-Cone Dystrophies: From Reality to Virtual Reality

To validate a novel mobility test (MOST, MObility Standardized Test) and performance outcomes in real (RL) and virtual (VR) environments to be used for interventional clinical studies in order to characterize vision impairment in rod-cone dystrophies, also known as retinitis pigmentosa (RP). Prospective, interventional, noninvasive, reliability and validity analysis. We designed MOST to be used in both VR and RL and conducted 3 experimental studies with 89 participants to (1) validate the difficulty of the mobility courses (15 controls), (2) determine the optimal number of light levels and training trials (14 participants with RP), and (3) validate the reproducibility (test-retest), reliability (VR/RL), sensitivity, and construct/content validity of the test (30 participants with RP and 30 controls). A comprehensive ophthalmologic examination was performed in all subjects. Outcomes of interest included MOST performance score, visual acuity, contrast sensitivity, dark adaptation thresholds, visual field parameters, and correlation between the performance score and visual function. The mobility courses exhibited statistically similar difficulty, and 5 trials are sufficient to control for the learning effect. MOST is highly reproducible (test-retest correlations >0.98) and reliable (correlations VR/RL=0.98). MOST achieved a discrimination between participants with RP and controls (accuracy >95%) and between early and late stages of the disease (82.3% accuracy). The performance score is correlated with visual function parameter (0.57-0.94). MOST is a validated mobility test, with the controlled learning effect, excellent reproducibility, and high agreement between RL and VR conditions, as well as sensitivity and specificity to measure disease progression and therapeutic benefit in rod-cone dystrophies.

Retinal gene therapy in RPE-65 gene mediated inherited retinal dystrophy.

Voretigene neparvovec (VN) is a gene therapeutic agent for treatment of retinal dystrophies caused by bi-allelic RPE65 mutations. We illustrate, both the benefits and pitfalls associated with ocular gene therapy in the same patient. Two eyes of one patient with bi-allelic RPE65 mutations have been treated with VN. The clinical examinations included visual acuity (VA, in normal and low luminance), colour vision, contrast sensitivity, International Society for Clinical Electrophysiology of Vision (ISCEV) standard retinal electrophysiology and dark-adapted full-field stimulus threshold (FST), Goldmann VF analysis and imaging studies, including optical coherence tomography (OCT) and autofluorescence. These were performed at baseline, 2-weeks, 3 and 6-months, 1 and 2-years follow-up. The first eye showed improvement in rod photoreceptor function with increased peripheral and low luminance vision (baseline VA: 0.9 logMAR and 2-years post-operative VA: 0.7 logMAR). The second eye, whilst showing increased light sensitivity, suffered a drop in central vision (at 2-weeks) with loss of foveal photoreceptors as shown by the loss of ellipsoid zone on OCT scan (baseline VA: 0.6, 2-year post-operative VA: 1.2). FST improvements were maintained in both eyes indicating a sustained efficacy of VN with little waning of its effect. We present a previously unreported adverse complication of subretinal VN therapy in bi-allelic RPE65, indicating a probable immune response in treatment of the second eye, resulting in loss of foveal photoreceptors. This case-series highlights the potential and pitfalls of retinal gene therapy in the same patient. The immune responses of the body to a 'foreign vector', remains a challenge.

Full-field sensitivity threshold and the relation to the oxygen metabolic retinal function in retinitis pigmentosa.

The aim of our study was to evaluate retinal function with white light dark-adapted full-field sensitivity threshold (FST) and find possible correlations with metabolic function measured with retinal oximetry (RO) in patients with retinitis pigmentosa (RP). In this prospective observational study (BASEC 2020-00,122), FST and RO measurements were performed on 66 RP eyes (33 subjects, 12♀ 21♂) aged between 18 and 80years (mean 43.2years); all eyes were graded for disease severity. Main outcome parameters were white FST thresholds using the Diagnosys Espion system with the ColorDomeTM LED full-field stimulator (Diagnosys LLC, Lowell, MA) as well as the main RO parameters: the mean arterial (A-SO2; %), venular (V-SO2; %) oxygen saturation, their difference (A-V SO2; %), and the corresponding mean diameters of the peripapillary retinal arterioles (D-A; μm) and venules (D-V; μm) recorded with the oxygen saturation tool of the Retinal Vessel Analyser (RVA; IMEDOS Systems UG, Jena, Germany). In addition, semi-automated kinetic perimetry (V4e, III4e, I4e, III3e isopters, Octopus 900®, Haag-Streit AG Bern, Switzerland) was performed and included in the linear mixed-effects models analysis calculated with SPSS®. Neither the oxygen saturation parameters (p > 0.21) nor the D-A and D-V (p > 0.13) showed significant correlations with the FST. However, when compared systematically with the visual field (VF) areas of the different isopters, RO parameters V-SO2 (p = 0.024) and A-V SO2 (p < 0.02) showed significant correlations. Furthermore, both V-SO2 and A-V SO2 showed gradual changes with more pronounced impairment in oxygen metabolic function in advanced stages of RP when analyzed in subgroups of disease severity grades. In contrast to standardized VF parameters, white dark-adapted FST appears not to correlate with retinal oxygen metabolic function measured with RO in patients with RP, suggesting that the two examinations may capture unrelated aspects of the retinal pathological process. However, RO showed a significant association with standardized VF testing parameters and may, therefore, offer an alternative outcome measure for interventional trials.

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

PurposeTo provide a comprehensive analysis of light- and dark-adapted luminance thresholds and their associations with retinal structure in X-linked retinoschisis (XLRS).MethodsNine 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.ResultsFor 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.ConclusionsThreshold 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.

Visual Dysfunction and Structural Correlates in Sorsby Fundus Dystrophy

To elucidate morphological determinants of rod and cone dysfunction in Sorsby fundus dystrophy (SFD), and to systematically compare visual function tests for interventional trials. Prospective cross-sectional study. Patients with SFD (n=16) and controls (n=20) underwent visual function testing (best-corrected visual acuity [BCVA] and low luminance visual acuity [LLVA], contrast sensitivity, mesopic and dark-adapted (DA) fundus-controlled perimetry [FCP], rod-mediated dark adaptation [RMDA]), and multimodal imaging. Vision-related quality of life was evaluated. FCP and RMDA thresholds were analyzed using mixed models and structure-function correlation using machine learning (ML). Longitudinal data of 1 patient with high-dose vitamin A supplementation were available. Although photopic BCVA was normative in SFD, LLVA was impaired (0.30 LogMAR [0.20; 0.45] vs 0.20 LogMAR [0.03; 0.28], P < .05). Scotopic visual function exhibited a delayed rod-intercept time (21 minutes [12.15; 21] vs 4.05 minutes [3.22; 5.36], P < .001), and marked DA cyan mean sensitivity loss (-11.80 dB [-3.47; -19.85]), paralleled by a reduced vision-related quality of life. ML-based structure-function correlation allowed prediction of mesopic, DA cyan, and red sensitivity with high accuracy (cross-validated mean absolute error: 4.36, 7.77, and 5.31 dB, respectively), whereas RMDA could be slowed even in the absence of fundus alterations on multimodal imaging. After high-dose vitamin A supplementation, RMDA and DA thresholds improved markedly. Patients with SFD exhibit severely impaired scotopic visual function even in the absence of funduscopic alterations on multimodal imaging. In contrast to BCVA, scotopic visual function tests are suitable to quantify dysfunction in the early stages. Improvement of scotopic dysfunction after (off-label) high-dose vitamin A intake, as observed in one patient in our study, is compatible with the hypothesized local deficiency of vitamin A secondary to Bruch's membrane alterations.

Correlations Between Dark-Adapted Rod Threshold Elevations and ERG Response Deficits in Duchenne Muscular Dystrophy.

PurposeThe purpose of this study was to characterize changes in the full-field flash electroretinogram (ERG) in association with psychophysical dark-adapted visual thresholds in patients with genetically characterized Duchenne muscular dystrophy (DMD) either lacking Dp427 (Up 30) or at least Dp260 in addition to Dp427 (Down 30).MethodsTwenty-one patients with DMD and 27 age-similar controls participated in this study. Dark-adapted (0.01, 3.0, and 10 cd.s/m² flashes) and light-adapted (3.0 cd.s/m² flash) ERGs were recorded following International Society for Clinical Electrophysiology of Vision (ISCEV) standard protocols. Visual detection thresholds to 625-nm (cone function) and 527-nm (rod function) light-emitting diode (LED) flashes (2 degree diameter) were measured during a dark adaptation period after a 1-minute exposure to a bleaching light (3000 cd/m²). Initially, 8 minutes of interleaved 625-nm and 527-nm thresholds were measured. After an additional 5 minutes of dark-adaptation, a second set of threshold measurements to 527-nm stimuli was performed during the subsequent 6 minutes.ResultsDark-adapted b-wave amplitude was significantly reduced to all strengths of flash and a-wave in response to the strong flash stimulus was delayed (15.6 vs. 14.7 ms, P < 0.05) in patients with Down 30 compared with controls. Dark-adapted cone thresholds did not differ among the groups (−2.0, −1.8, and −1.7 log cd/m² for Down 30, Up 30, and controls, respectively, P = 0.21). In contrast, dark-adapted rod thresholds were elevated (F(2,36) = 8.537, P = 0.001) in patients with Down 30 (mean = −3.2 ± 1.1 log cd/m²) relative to controls (mean = −4.2 ± 0.3 log cd/m²). Dark-adapted b-wave amplitudes were correlated with dark-adapted rod sensitivity in patients with DMD (Spearman Rho = 0.943, P = 0.005). The changes were much smaller or absent in patients with intact Dp260.ConclusionsDp260 is particularly required for normal rod-system function in dark adaptation.

Dark-adapted threshold and electroretinogram for diagnosis of Usher syndrome.

To determine the utility of ophthalmology evaluation, dark-adapted threshold, and full-field electroretinogram for early detection of Usher syndrome in young patients with bilateral sensorineural hearing loss. We identified 39 patients with secure genetic diagnoses of Usher Syndrome. Visual acuity, spherical equivalent, fundus appearance, dark-adapted threshold, and full-field electroretinogram results were summarized and compared to those in a group of healthy controls with normal hearing. In those Usher patients with repeated measures, regression analysis was done to evaluate for change in visual acuity and dark-adapted threshold with age. Spherical equivalent and full-field electroretinogram responses from dark- and light-adapted eyes were evaluated as a function of age. The majority of initial visual acuity and spherical equivalent results were within normal limits for age. Visual acuity and dark-adapted threshold worsened significantly with age in Usher type 1 but not in Usher type 2. At initial test, full-field electroretinogram responses from dark- and light-adapted eyes were abnormal in 53% of patients. Remarkably, nearly half of our patients (17% of Usher type 1 and 30% of Usher type 2) would have been missed by tests of retinal function alone if evaluated before age 10. Although there is an association of abnormal dark-adapted threshold and full-field electroretinogram at young ages in Usher patients, it appears that a small but important proportion of patients would not be detected by tests of retinal function alone. Thus, genetic testing is needed to secure a diagnosis of Usher syndrome.

Spatial and temporal resolution of the photoreceptors rescue dynamics after treatment with voretigene neparvovec

BackgroundVoretigene neparvovec is a gene therapeutic agent for treatment of retinal dystrophies caused by bi-allelic RPE65 mutations. In this study, we report on a novel and objective evaluation of a...

Full-Field Electroretinography, Pupillometry, and Luminance Thresholds in X-Linked Retinoschisis.

PurposeTo evaluate the nature and extent of functional abnormality in X-linked retinoschisis (XLRS) by comparing three dark-adapted, full-field measures: the electroretinogram (ERG), pupillary light reflex (PLR), and luminance threshold.MethodsERGs, PLRs (pupil constriction due to light stimulation), and luminance thresholds were measured from seven XLRS subjects and from 10 normally sighted, age-similar controls. ERGs and PLRs were obtained for a range of flash strengths, and these data were fit with Naka–Rushton functions to derive the maximum saturated b-wave (Vmax) and PLR (Pmax) amplitudes. Additionally, semi-saturation constants were obtained for the b-wave (σ) and PLR (s). Values of 1/σ and 1/s provide sensitivity measures. Full-field, dark-adapted luminance thresholds were measured using 465-nm and 642-nm flash stimuli.Results V max and 1/σ were significantly reduced in XLRS compared to the controls (both t ≥ 5.33, P < 0.001). In comparison, Pmax was normal in the XLRS subjects (t = 1.39, P = 0.19), but 1/s was reduced (t = 7.84, P < 0.001). Luminance thresholds for the control and XLRS groups did not differ significantly (F = 3.57, P = 0.08). Comparisons among measures indicated that pupil sensitivity was correlated with luminance threshold for the long- and short-wavelength stimuli (both, r ≥ 0.77, P ≤ 0.04). Correlations among all other measures were not statistically significant.ConclusionsThe results indicate that the presumed bipolar cell dysfunction in XLRS, indicated by b-wave abnormalities, has complex downstream effects: Dark-adapted luminance threshold and maximum pupil responses are not significantly affected, but pupil sensitivity is reduced.

IMPAIRED DARK ADAPTATION ASSOCIATED WITH A DISEASED BRUCH MEMBRANE IN PSEUDOXANTHOMA ELASTICUM.

To characterize dark adaptation in patients with pseudoxanthoma elasticum, a systemic disease leading to calcification of elastic tissue including the Bruch membrane. In this prospective case-control study, dark adaptation thresholds were measured using a Goldmann-Weekers dark adaptometer. Additional assessments included best-corrected visual acuity testing, contrast sensitivity, low luminance deficit, and vision-related quality of life. Dark adaptation thresholds were significantly higher, and adaptation periods were prolonged in patients with pseudoxanthoma elasticum (n = 35; 33 with 2 ABCC6 mutations) compared with controls (n = 35). The time to adapt 4 log units (20.6 ± 8.6 vs. 8.0 ± 1.3 minutes) and the mean dark adaptation threshold after 15 minutes (3.5 ± 1.1 vs. 1.8 ± 0.2 log units) were significantly different between patients and controls (both P < 0.001). Low luminance deficits (12.3 ± 6.4 vs. 6.1 ± 4.3 ETDRS letters), contrast sensitivity (1.4 ± 0.3 vs. 1.9 ± 0.1), and low luminance-related quality of life (LLQ score: 1,286 ± 355 vs. 2,167 ± 68) were also significantly worse in patients with pseudoxanthoma elasticum (all, P < 0.001). Two patients were treated with high-dose vitamin A which partially reversed impaired dark adaptation. Patients with pseudoxanthoma elasticum often have impaired dark adaptation. Positive effects of vitamin A supplementation may indicate restricted retinal access of vitamin A through the Bruch membrane as one possible underlying pathogenic factor.

Fundus-Controlled Dark Adaptometry in Young Children Without and With Spontaneously Regressed Retinopathy of Prematurity.

PurposeWe correlate dark adaptation course with foveal morphologic alterations in preterm and term-born children using a modified fundus-controlled perimeter and spectral domain–optical coherence tomography (SD-OCT) imaging.MethodsWe performed fundus-controlled chromatic dark adaptometry in premature children aged 6 to 13 years without retinopathy of prematurity (no-ROP; n = 61) and with spontaneously regressed ROP (sr-ROP, n = 29), and in 11 age-matched term-born children. The degree of macular developmental arrest (MDA), defined as a disproportion of the outer nuclear layer to inner retinal layers in the fovea (ONL+/IRL-ratio), was analyzed with the DiOCTA tool in SD-OCT scans.ResultsChildren with MDA showed a flatter dark adaptation course progression with a significant rod-mediated sensitivity recovery delay (0.0113 vs. 0.0253 dB/s; P < 0.001). Preterm-born children with regular foveal morphology reached the final rod-mediated dark-adapted threshold at 12 minutes after bleach at 18.8 dB, compared to after 18.7 minutes at 17.6 dB in children with MDA (no significant difference in final threshold; P = 0.773). The cone-mediated dark adaptation progression showed a significant lower final threshold in children with MDA (6.0 vs. 8.1 dB; P = 0.004).ConclusionsChanges in dark adaptation were seen in the presence of MDA observed in premature children in the no-ROP and sr-ROP groups. MDA in former premature children is associated with functional deficits of cone and rod photoreceptor visual pathways.Translational RelevanceMorphologic alterations in the central retina of premature children, evident in SD-OCT, are associated with long-term functional deficits in the rod and cone pathways, particularly evident in the rod dark adaptation course measured at 12° eccentricity. This indicates a more widespread retinal functional pathology not limited to the fovea, but occurring together with foveal alterations best defined as MDA.

Sildenafil Administration in Dogs Heterozygous for aFunctional Null Mutation in Pde6a: Suppressed Rod-Mediated ERG Responses and Apparent Retinal Outer Nuclear Layer Thinning.

This study was designed to assess risk for retinal toxicity associated with administration of high-dose sildenafil citrate to dogs heterozygous for a functionally null mutation in Pde6a over a 4-month period. Three Pde6a +/- dogs were administered 14.3mg/kg sildenafil per os and two Pde6a +/- dogs placebo once daily for 16weeks. Three Pde6a +/+ dogs were administered sildenafil for 7days. Ophthalmic examination, vision testing, and electroretinography (ERG) were regularly performed. At study termination, dogs were euthanized and globes collected. Retinal layer thickness and photoreceptor nuclei counts were determined from plastic sections. In both Pde6a +/- and Pde6a +/+ sildenafil-treated (ST) dogs, elevation of dark-adapted b-wave threshold and unmasking of the scotopic threshold response (STR) were observed. Sildenafil treated Pde6a +/- dogs had significantly thinner ONL (24.90 +/-1.88μm, p=0.004) and lower photoreceptor nuclei counts (273.6 +/- 29.3 cells/100μm, p=0.008) compared to measurements (35.90 +/- 1.63μm) and counts (391.5 +/-27.0 cells/100μm) from archived untreated Pde6a +/- dogs.

The Tuebingen Scotopic Threshold Test (TSTT).

Measurement of the dark-adaptation threshold plays a key role in the diagnosis and estimation of disease progression of many retinal disorders. Determining the threshold is, however, difficult to perform in young children. We present here a prototype for a dark adaptometer, the Tuebingen Scotopic Threshold Test aimed to ease measurement of photoreceptor thresholds in young subjects. The device consists of two 7cm ×10cm fields with either blue or yellow LEDs, for testing rod or cone sensitivity, respectively. Presentation of homogenous field patterns or a flickering stimulus is also possible. The luminance threshold is measured by the method of ascending limits and the stimulus luminance, data recording and analysis are computer controlled. Preliminary results for six adults and two older children were ascertained and the influence of pupil dilation, binocular presentation, and a flickering stimulus examined. The method provides credible and consistent evaluations of the absolute threshold.

Increment Threshold Functions in Retinopathy of Prematurity.

PurposeTo assess scotopic background adaptation in subjects with a history of preterm birth and retinopathy of prematurity (ROP). Retinopathy of prematurity is known to have long-term effects on rod photoreceptor and rod mediated postreceptor retinal function.MethodsRod-mediated thresholds for detection of 3° diameter, 50 ms stimuli presented 20° from fixation were measured using a spatial forced choice method in 36 subjects (aged 9–17 years) with a history of preterm birth and 11 age similar term-born subjects. Thresholds were measured first in the dark-adapted condition and then in the presence of 6 steady background lights (−2.8 to +2.0 log scot td). A model of the increment threshold function was fit to each subject's thresholds to estimate the dark-adapted threshold (TDA) and the Eigengrau (A0, the background that elevates threshold 0.3 log unit above TDA).ResultsIn subjects with a history of severe ROP, both TDA and A0 were significantly elevated relative to those in former preterms who never had ROP and term-born control subjects. Subjects who had mild ROP had normal TDA but elevated A0. Neither TDA nor A0 differed significantly between former preterms who never had ROP and term-born controls.ConclusionsThe results suggest that in severe ROP, threshold is affected at a preadaptation site, possibly the rod outer segment. In mild ROP, changes in the Eigengrau may reflect increased intrinsic noise in the photoreceptor or postreceptor circuitry or both.

Substituting mouse transcription factor Pou4f2 with a sea urchin orthologue restores retinal ganglion cell development.

Pou domain transcription factor Pou4f2 is essential for the development of retinal ganglion cells (RGCs) in the vertebrate retina. A distant orthologue of Pou4f2 exists in the genome of the sea urchin (class Echinoidea) Strongylocentrotus purpuratus (SpPou4f1/2), yet the photosensory structure of sea urchins is strikingly different from that of the mammalian retina. Sea urchins have no obvious eyes, but have photoreceptors clustered around their tube feet disc. The mechanisms that are associated with the development and function of photoreception in sea urchins are largely unexplored. As an initial approach to better understand the sea urchin photosensory structure and relate it to the mammalian retina, we asked whether SpPou4f1/2 could support RGC development in the absence of Pou4f2. To answer this question, we replaced genomic Pou4f2 with an SpPou4f1/2 cDNA. In Pou4f2-null mice, retinas expressing SpPou4f1/2 were outwardly identical to those of wild-type mice. SpPou4f1/2 retinas exhibited dark-adapted electroretinogram scotopic threshold responses, indicating functionally active RGCs. During retinal development, SpPou4f1/2 activated RGC-specific genes and in S. purpuratus, SpPou4f2 was expressed in photoreceptor cells of tube feet in a pattern distinct from Opsin4 and Pax6. Our results suggest that SpPou4f1/2 and Pou4f2 share conserved components of a gene network for photosensory development and they maintain their conserved intrinsic functions despite vast morphological differences in mouse and sea urchin photosensory structures.

Role of extrinsic noise in the sensitivity of the rod pathway: rapid dark adaptation of nocturnal vision in humans.

Rod-mediated 500 nm test spots were flashed in Maxwellian view at 5 deg eccentricity, both on steady 10.4 deg fields of intensities (I) from 0.00001 to 1.0 scotopic troland (sc td) and from 0.2 s to 1 s after extinguishing the field. On dim fields, thresholds of tiny (5') tests were proportional to √I (Rose-DeVries law), while thresholds after extinction fell within 0.6 s to the fully dark-adapted absolute threshold. Thresholds of large (1.3 deg) tests were proportional to I (Weber law) and extinction thresholds, to √I. rod thresholds are elevated by photon-driven noise from dim fields that disappears at field extinction; large spot thresholds are additionally elevated by neural light adaptation proportional to √I. At night, recovery from dimly lit fields is fast, not slow.

Full-Field Pupillary Light Responses, Luminance Thresholds, and Light Discomfort Thresholds in CEP290 Leber Congenital Amaurosis Patients.

To investigate visual function in patients with CEP290 Leber congenital amaurosis (LCA-CEP290), using three full-field tests that can be performed by patients with poor fixation. Six patients (age range, 9-39 years) with LCA-CEP290 participated in the study. Stimuli for all three tests (full-field stimulus test [FST], pupillometry, and light discomfort threshold [LDT] testing) were generated by the Diagnosys ColorDome ganzfeld, by using achromatic stimuli as well as long- and short-wavelength stimuli to target rod and cone photoreceptors with all three tests and, in the latter two tests, melanopsin photoreceptors. Dark-adapted FST thresholds in LCA-CEP290 patients were cone mediated and elevated between 4.8 and 6.2 log units above the normal achromatic threshold. The FST threshold was not measurable in one patient. The rod-mediated transient pupillary light reflex (PLR) was absent in all but the youngest patient, where unreliable responses precluded PLR quantification. Cone-mediated transient PLRs were subnormal in five patients, and absent in another. Sustained melanopsin-mediated PLRs were measurable in all patients. Full-field LDT thresholds were elevated compared to normal controls, and were lower for short-wavelengh than for long-wavelength stimuli. The FST thresholds and transient PLRs were cone mediated in our cohort LCA-CEP290 patients. Rod-mediated PLRs were undetectable, whereas melanopsin-mediated sustained responses were detected in all patients, suggesting a relative preservation of inner-retina function. The LDT elevations for the patients are somewhat paradoxical, given their subjective perception of photoaversion. Relative aversion to short-wavelength light suggests influence from melanopsin on LDTs in these patients.

Docosahexaenoic Acid Slows Visual Field Progression in X-Linked Retinitis Pigmentosa: Ancillary Outcomes of the DHAX Trial

Docosahexaenoic acid (DHA) was supplemented in a single-site, placebo-controlled, randomized clinical trial designed to slow vision loss associated with X-linked retinitis pigmentosa (XLRP); the DHAX Trial. We previously reported no significant differences between supplemented and placebo groups in intent-to-treat analysis of primary ERG outcomes. Assessed herein are hypothesis-generating measures of ancillary visual function outcomes in participants fully adhering to trial protocol. Male participants with XLRP (range, 7-31 years) received 30 mg DHA/kg/d (n = 29) or placebo (n = 22) for 4 years. Visual outcomes were measured annually and red blood cell (RBC) DHA determined every 6 months. Oral DHA supplementation increased mean RBC-DHA levels by 4-fold (P < 0.0001) over placebo. No group differences in progression were found for visual acuity (P = 0.11), shape discrimination (P = 0.18), or fundus appearance (P = 0.70). Optical coherence tomography (OCT) became available during year 2 of the trial; no group differences were seen in ellipsoid zone constriction (P = 0.87) over 2 years. Yearly rates of progression were reduced for dark-adapted thresholds (P = 0.06) and visual field sensitivity for foveal, macular, peripheral, total, and ellipsoid zone regions by DHA supplementation (P = 0.039, P = 0.031, P < 0.0001, P < 0.0001, and P = 0.033). Rates of visual field sensitivity decline were dependent on RBC-DHA (P = 0.046 to <0.0001). Supplementation of DHA significantly elevated blood DHA levels and reduced the rate of progression in final dark-adapted thresholds and visual field sensitivity. From the relationship between RBC-DHA and the rate of field sensitivity loss, we can extrapolate that an RBC-DHA level of 17% could minimize the decline in field sensitivity. (ClinicalTrials.gov number, NCT00100230.)