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A pathognomonic macular ripple sign has been reported with scanning laser ophthalmoscopy images in patients with foveal hypoplasia, though the optical basis of this sign is presently unknown. Here we present a case series of seven individuals with foveal hypoplasia (based on spectral domain optical coherence tomography). Each patient underwent infrared scanning laser ophthalmoscopy retinal imaging in both eyes, acquired with and without a polarization filter and assessment for a ripple-like effect in the fovea. On imaging, macular ripples were present in all eyes with foveal hypoplasia when using a polarization filter, but not when imaged without the filter. We conclude that the macular ripple sign is an imaging artifact attributable to the unique pattern of phase retardation of the Henle fiber layer in the setting of foveal hypoplasia. By utilizing a polarization filter with retinal photography, this feature can be exploited to promptly identify foveal hypoplasia in settings where OCT is not possible due to nystagmus.

To evaluate spatial and temporal integration across the visual field in individuals with juvenile X-linked retinoschisis (XLRS).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.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.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.

Retinitis pigmentosa (RP) is an inherited pigmentary retinal dystrophy where patients experience poor peripheral, night, and eventually central vision. There are statements in the literature which suggest visual acuity loss can progress to total blindness in these patients. This study sought to examine these statements by performing a retrospective analysis of the visual acuity measured in a large cohort of RP patients.The charts of 1,095 RP patients were reviewed in this retrospective cross-sectional analysis. They included all of the RP patients examined by one of the authors (G.A.F.). Patients with sector RP or a delimited form of this disease were not included. The review was focused on the analysis of patients with 20/200 or worse vision in the better-seeing eye (N = 215).We determined that 0.46% of the enrolled patients progressed to no light perception in each eye. Ninety-two percent of the 1,095 patients examined were able to read a visual acuity chart. There were 6.8% who saw only hand motion, count fingers, or light perception.No light perception was measured in only 0.46% of patients. Thus, only a very small number of the RP patients in our cohort progressed to total blindness.

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).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.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.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.Internal noise measurements can provide insight into a source of CS loss in some individuals with XLRS.

Over 1,500 variants in the ABCA4 locus cause phenotypes ranging from severe, early-onset retinal degeneration to very late-onset maculopathies. The resulting ABCA4/Stargardt disease is the most prevalent Mendelian eye disorder, although its underlying clinical heterogeneity, including penetrance of many alleles, are not well-understood. We hypothesized that a share of this complexity is explained by trans-modifiers, i.e., variants in unlinked loci, which are currently unknown. We sought to identify these by performing exome sequencing in a large cohort for a rare disease of 622 cases and compared variation in seven genes known to clinically phenocopy ABCA4 disease to cohorts of ethnically matched controls. We identified a significant enrichment of variants in 2 out of the 7 genes. Moderately rare, likely functional, variants, at the minor allele frequency (MAF) 25, were enriched in ROM1, where 1.3% of 622 patients harbored a ROM1 variant compared to 0.3% of 10,865 controls (p = 2.41E04; OR 3.81 95% CI [1.77; 8.22]). More importantly, analysis of common variants (MAF>0.1) identified a frequent haplotype in PRPH2, tagged by the p.Asp338 variant with MAF = 0.21 in the matched general population that was significantly increased in the patient cohort, MAF 0.25, p = 0.0014. Significant differences were also observed between ABCA4 disease subgroups. In the late-onset subgroup, defined by the hypomorphic p.Asn1868Ile variant and including c.4253+43G>A, the allele frequency for the PRPH2 p.Asp338 variant was 0.15 vs 0.27 in the remaining cohort, p = 0.00057. Known functional data allowed suggesting a mechanism by which the PRPH2 haplotype influences the ABCA4 disease penetrance. These associations were replicated in an independent cohort of 408 patients. The association was highly statistically significant in the combined cohorts of 1,030 cases, p = 4.00E-05 for all patients and p = 0.00014 for the hypomorph subgroup, suggesting a substantial trans-modifying role in ABCA4 disease for both rare and common variants in two unlinked loci.

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.

PURPOSE: To investigate the Stargardt disease phenotype associated with an unusually common and “extremely hypomorphic” ABCA4 variant, p.N1868I. METHODS: The charts of 27 patients with p.N1868I on one allele and a severe/deleterious mutation on the other allele were reviewed. Subjective age of onset, best-corrected visual acuity, and stage of disease were recorded for all 27 patients, 18 of whom had multiple visits. When available, fundus photography, spectral domain optical coherence tomography, fundus autofluorescence, full-field electroretinograms, Goldmann visual fields, and fluorescein angiography were included. Five families with multiple affected members were analyzed. RESULTS: The median age at symptom onset was 41.5 years, and 3 p.N1868I patients had not developed visual symptoms as of the most recent eye examination. Median best-corrected visual acuity in the better-seeing eye at baseline was 20/25(−2), and the median duration from symptom onset to legal blindness was 25 years. The five families described in this study demonstrated clinically significant intrafamilial variability, and affected family members who did not share the p.N1868I variant had relatively more severe phenotypes. CONCLUSION: This study demonstrates the consistency of foveal sparing, the variation in age at onset, the intrafamilial variability, and the prognosis with regard to visual acuity in p.N1868I-associated Stargardt disease.

PURPOSE: To investigate receptor and post-receptor function in KCNV2 retinopathy (cone dystrophy with supernormal rod ERG), using the pupillary light reflex (PLR) and the electroretinogram (ERG). METHODS: Two unrelated patients (1 male, 1 female) with molecularly confirmed KCNV2 retinopathy underwent full-field two-color pupillometry testing in one eye, with monitoring of the stimulated eye by an infrared digital camera. Pupillometry stimuli consisted of 1-sec duration, short-wavelength (465-nm, blue) and long-wavelength (642-nm, red) stimuli. Pupillometry intensity series were performed under both a dark-adapted condition and a light-adapted condition (on a 0.76-log cd-m(−2) blue background). The transient PLR, defined as the maximum constriction following flash onset, was measured under all conditions. The melanopsin-mediated sustained constriction was measured 5 to 7 sec following flash offset for the highest flash luminance presented in the dark. Both patients were also tested in one eye with the full-field ERG, including a dark-adapted intensity series and ISCEV-standard stimuli. RESULTS: Dark-adapted PLRs were markedly attenuated or extinguished for low luminance stimuli, but the responses to higher luminance blue stimuli were within normal limits. Light-adapted PLRs to blue stimuli were generally within normal limits, exceeding the responses to photopically matched red stimuli. Thus, light-adapted responses were consistent with either rod- or S-cone mediation of the PLR. Melanopsin-mediated sustained PLRs were within normal limits. ERG showed the characteristic findings previously reported in this condition. Cone-mediated ERG responses were markedly decreased in amplitude. Rod-mediated ERG responses were absent for low luminance stimuli (−3 log cd-s-m(−2)), but had normal amplitude for stimuli of −2 log cd-s-m(−2) and above (although none were “supernormal”). The b-wave for dark-adapted ISCEV standard 0.01 stimulus was markedly delayed, whereas the b-wave timing was generally normal for higher flash luminances. CONCLUSIONS: The abnormalities measured by pupillometry have a similar pattern to the outer-retinal abnormalities measured by ERG in KCNV2 retinopathy. These findings, as well as the normal sustained PLR suggests that inner-retinal function may be preserved in KCNV2 retinopathy and highlights the potential for therapies designed to restore outer-retinal function in these individuals.

The Usher syndrome phenotype is comprised of ocular and audiologic anomalies. Patients characteristically experience congenital hearing loss, nyctalopia, reduced visual fields, and ultimately decreased visual acuity. However, diagnosis may initially be more difficult in cases with limited ocular findings. Here, we present a case in which an adult patient had neither subjective visual complaints nor ocular findings at the time of diagnosis aside from a moderate reduction in rod and cone function on electroretinogram testing. Nevertheless, 43 years after his initial examination, he showed severe degenerative changes in the retina. A 63-year-old man with Usher syndrome type 2 underwent ophthalmic examination that included visual acuity, optical coherence tomography (OCT), electroretinogram (ERG), fundus photography, and Goldmann visual field testing. The patient also had genetic testing performed. We additionally reviewed the ocular findings on two of his siblings also afflicted with Usher syndrome type 2. Our findings documented the long-term progression of Usher syndrome in this patient. They showed that the patient was asymptomatic with only a moderate reduction on ERG testing at the time of diagnosis, but subsequently progressed to an advanced stage of retinal disease with severe visual loss. The patient demonstrated that the absence of visual symptoms and favorable findings on functional testing on initial presentation might yet belie a future for austere visual loss. Caution is thus warranted when predicting a visual prognosis in such a patient. Further, the value in electroretinographic testing for diagnosis is demonstrated.

Purpose Adaptive optics scanning light ophthalmoscopy (AOSLO) imaging in patients with achromatopsia (ACHM) and albinism is not always successful. Here, we tested whether optical coherence tomography (OCT) measures of foveal structure differed between patients for whom AOSLO images were either quantifiable or unquantifiable. Methods The study included 166 subjects (84 with ACHM; 82 with albinism) with previously acquired OCT scans, AOSLO images, and best-corrected visual acuity (BCVA, if available). Foveal OCT scans were assessed for outer retinal structure, outer nuclear layer thickness, and hypoplasia. AOSLO images were graded as quantifiable if a peak cone density could be measured and/or usable if the location of peak density could be identified and the parafoveal mosaic was quantifiable. Results Forty-nine percent of subjects with ACHM and 57% of subjects with albinism had quantifiable AOSLO images. Older age and better BCVA were found in subjects with quantifiable AOSLO images for both ACHM (P = 0.0214 and P = 0.0276, respectively) and albinism (P = 0.0073 and P < 0.0004, respectively). There was a significant trend between ellipsoid zone appearance and ability to quantify AOSLO (P = 0.0028). In albinism, OCT metrics of cone structure did not differ between groups. Conclusions Previously reported AOSLO-based cone density measures in ACHM may not necessarily reflect the degree of remnant cone structure in these patients. Translational Relevance Until AOSLO is successful in all patients with ACHM and albinism, the possibility of the reported data from a particular cohort not being representative of the entire population remains an important issue to consider when interpreting results from AOSLO studies.

Purpose: To determine whether artifacts in optical coherence tomography (OCT) images are associated with the success or failure of adaptive optics scanning light ophthalmoscopy (AOSLO) imaging in subjects with achromatopsia (ACHM). / Methods: Previously acquired OCT and non-confocal, split-detector AOSLO images from one eye of 66 subjects with genetically confirmed achromatopsia (15 CNGA3 and 51 CNGB3) were reviewed along with best-corrected visual acuity (BCVA) and axial length. OCT artifacts in interpolated vertical volumes from CIRRUS macular cubes were divided into four categories: (1) none or minimal, (2) clear and low frequency, (3) low amplitude and high frequency, and (4) high amplitude and high frequency. Each vertical volume was assessed once by two observers. AOSLO success was defined as sufficient image quality in split-detector images at the fovea to assess cone quantity. / Results: There was excellent agreement between the two observers for assessing OCT artifact severity category (weighted kappa = 0.88). Overall, AOSLO success was 47%. For subjects with OCT artifact severity category 1, AOSLO success was 65%; for category 2, 47%; for category 3, 11%; and for category 4, 0%. There was a significant association between OCT artifact severity category and AOSLO success (P = 0.0002). Neither BCVA nor axial length was associated with AOSLO success (P = 0.07 and P = 0.75, respectively). / Conclusions: Artifacts in OCT volumes are associated with AOSLO success in ACHM. Subjects with less severe OCT artifacts are more likely to be good candidates for AOSLO imaging, whereas AOSLO was successful in only 7% of subjects with category 3 or 4 OCT artifacts. These results may be useful in guiding patient selection for AOSLO imaging. / Translational Relevance: Using OCT to prescreen patients could be a valuable tool for clinical trials that utilize AOSLO to reduce costs and decrease patient testing burden.

Over 1200 variants in the ABCA4 gene cause a wide variety of retinal disease phenotypes, the best known of which is autosomal recessive Stargardt disease (STGD1). Disease-causing variation encompasses all mutation categories, from large copy number variants to very mild, hypomorphic missense variants. The most prevalent disease-causing ABCA4 variant, present in ~ 20% of cases of European descent, c.5882G > A p.(Gly1961Glu), has been a subject of controversy since its minor allele frequency (MAF) is as high as ~ 0.1 in certain populations, questioning its pathogenicity, especially in homozygous individuals. We sequenced the entire ~140Kb ABCA4 genomic locus in an extensive cohort of 644 bi-allelic, i.e. genetically confirmed, patients with ABCA4 disease and analyzed all variants in 140 compound heterozygous and 10 homozygous cases for the p.(Gly1961Glu) variant. A total of 23 patients in this cohort additionally harbored the deep intronic c.769-784C > T variant on the p.(Gly1961Glu) allele, which appears on a specific haplotype in ~ 15% of p.(Gly1961Glu) alleles. This haplotype was present in 5/7 of homozygous cases, where the p.(Gly1961Glu) was the only known pathogenic variant. Three cases had an exonic variant on the same allele with the p.(Gly1961Glu). Patients with the c.[769-784C > T;5882G > A] complex allele exhibit a more severe clinical phenotype, as seen in compound heterozygotes with some more frequent ABCA4 mutations, e.g. p.(Pro1380Leu). Our findings indicate that the c.769-784C > T variant is major cis-acting modifier of the p.(Gly1961Glu) allele. The absence of such additional allelic variation on most p.(Gly1961Glu) alleles largely explains the observed paucity of affected homozygotes in the population.

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.

PURPOSE: To determine interocular symmetry of foveal cone topography in achromatopsia (ACHM) using non-confocal split-detection adaptive optics scanning light ophthalmoscopy (AOSLO). METHODS: Split-detector AOSLO images of the foveal cone mosaic were acquired from both eyes of 26 subjects (mean age 24.3 years; range 8 – 44 years, 14 females) with genetically confirmed CNGA3- or CNGB3-associated ACHM. Cones were identified within a manually delineated rod-free zone. Peak cone density (PCD) was determined using an 80 × 80 μm sampling window within the rod-free zone. The mean and standard deviation (SD) of intercell distance (ICD) were calculated to derive the coefficient of variation (CV). Cone density difference maps were generated to compare cone topography between eyes. RESULTS: PCD (mean ± SD) was 17,530 ± 9,614 cones/mm(2) and 17,638 ± 9,753 cones/mm(2) for right and left eyes, respectively (p = 0.677, Wilcoxon test). The mean (± SD) for ICD was 9.05 ± 2.55 μm and 9.24 ± 2.55 μm for right and left eyes, respectively (p = 0.410, paired t test). The mean (± SD) for CV of ICD was 0.16 ± 0.03 μm and 0.16 ± 0.04 μm for right and left eyes, respectively (p = 0.562, paired t test). Cone density maps demonstrated that cone topography of the ACHM fovea is non-uniform with local variations in cone density between eyes. CONCLUSIONS: These results demonstrate interocular symmetry of the foveal cone mosaic (both density and packing) in ACHM. As cone topography can differ between eyes of a subject, PCD does not completely describe the foveal cone mosaic in ACHM. Nonetheless, these findings are of value in longitudinal monitoring of patients during treatment trials and further suggest that both eyes of a given subject may have similar therapeutic potential and non-study eye can be used as a control.

High-resolution in vivo imaging has provided evidence of residual cone structure in congenital achromatopsia, although the progressive nature of the disease remains unclear. In this study, the authors use optical coherence tomography and adaptive optics scanning light ophthalmoscopy to investigate longitudinal changes in cone structure in achromatopsia., Purpose: Congenital achromatopsia is an autosomal recessive disease causing substantial reduction or complete absence of cone function. Although believed to be a relatively stationary disorder, questions remain regarding the stability of cone structure over time. In this study, the authors sought to assess the repeatability of and examine longitudinal changes in measurements of central cone structure in patients with achromatopsia. Methods: Forty-one subjects with CNGB3-associated achromatopsia were imaged over a period of between 6 and 26 months using optical coherence tomography and adaptive optics scanning light ophthalmoscopy. Outer nuclear layer (ONL) thickness, ellipsoid zone (EZ) disruption, and peak foveal cone density were assessed. Results: ONL thickness increased slightly compared with baseline (0.184 μm/month, P = 0.02). The EZ grade remained unchanged for 34/41 subjects. Peak foveal cone density did not significantly change over time (mean change 1% per 6 months, P = 0.126). Conclusion: Foveal cone structure showed little or no change in this group of subjects with CNGB3-associated achromatopsia. Over the time scales investigated (6–26 months), achromatopsia seems to be a structurally stable condition, although longer-term follow-up is needed. These data will be useful in assessing foveal cone structure after therapeutic intervention.

Purpose To determine outcome measures for a clinical trial of Leber congenital amaurosis (LCA) associated with mutations in the GUCY2D gene. Design Retrospective observational case series. Methods Twenty-eight patients with GUCY2D -LCA (aged 2-59 years) were studied clinically and with chromatic full-field sensitivity testing (FST), optical coherence tomography (OCT), pupillometry, and the NEI Visual Function Questionnaire (VFQ). Results FST permitted quantitation of cone and rod sensitivity in these patients with severe visual impairment. For most patients, the degree of rod and cone sensitivity losses showed a relationship, thereby providing an opportunity to divide patients into cohorts by severity of rod and cone dysfunction. OCT analyses indicated that retinal structure could be used not only as an objective safety measure but also as an exploratory efficacy outcome. A foveal bulge was not present in 67% of patients. The intensity of inner segment/outer segment (ellipsoid zone line) reflectivity was reduced significantly at the fovea and in the rod-dense superior retina. Based on OCT and FST parameters, most patients had dissociation of structure and function. Abnormal pupillometry sensitivity in the majority of GUCY2D -LCA patients provided another objective efficacy outcome. NEI VFQ scores showed a similar range of findings to those of other severe retinal diseases. Conclusion Conventional outcome measures, such as visual acuity and the NEI VFQ, will need to be complemented by methods more specific to this GUCY2D -LCA population. Any therapeutic strategy should determine if there is an effect on rod as well as cone function and structure. FST provides a photoreceptor-based subjective outcome; and OCT in 2 retinal regions, fovea and superior retina, can assess photoreceptor structure. A change in the relationship of structure and function away from baseline becomes evidence of efficacy.

Purpose To define characteristic ocular features in a group of patients with autosomal recessive (AR) PROM1 cone-rod dystrophy (CRD). Methods Three males and one female from three unrelated families were first seen at the ages of 15 to 22 years and diagnosed with CRD. Clinical testing available for review included full-field electroretinogram (ERG) in three patients, as well as near-infrared autofluorescence (NIR-AF), spectral-domain optical coherence tomography (SD-OCT), and color fundus photography in all four patients. Whole exome sequencing (WES) was performed on all cases, and whole genome sequencing (WGS) was performed in two families. Results WES found compound heterozygous PROM1 variants in one isolated male, plus heterozygous variants in the remaining patients. WGS uncovered deleterious PROM1 variants in these two families. ERG showed markedly reduced cone-isolated amplitudes and variably reduced rod-isolated amplitudes. The dark-adapted combined rod and cone responses demonstrated notably reduced a-wave amplitudes and moderately reduced b-waves, and the resultant waveform resembled the normal rod-isolated response. On fundus examination, oval-shaped macular lesions were observed, as were several small, circular hypoautofluorescent lesions within the posterior pole on NIR-AF. Three patients showed extramacular circular atrophic lesions. Conclusions The autofluorescence changes, peripheral retinal abnormalities, and ERG findings have not been emphasized in previous reports of AR PROM1, but they became a recognizable phenotype in this cohort of patients. A similar constellation of findings may be observed in CRD due to CDHR1, a functionally related gene. The pattern of abnormalities reported herein may help to focus genetic screening in patients with these findings.

To evaluate rod-isolated, cone-isolated, and combined rod and cone flicker electroretinograms (ERGs) as a possible means to identify electrophysiological abnormalities in carriers of X-linked retinoschisis (XLRS). Full-field ERGs were recorded from six carriers of XLRS (aged 34–66 years) and eight normally sighted subjects (aged 27–59 years) under rod-isolated (ERGR), cone-isolated (ERGC), and combined rod and cone (ERGR+C) conditions. ERGs were obtained using a four-primary LED-based ganzfeld photostimulator and standard recording techniques. The four primaries were modulated sinusoidally in phase to achieve combined rod and cone activation (ERGR+C) or in different phases to achieve ERGR and ERGC by means of triple silent substitution. After 30 min of dark adaptation, 8- and 15-Hz ERGR, ERGC, and ERGR+C responses were obtained at a mean luminance level of 24 scot. cd/m2. Standard ISCEV ERGs were also obtained from each subject. The ISCEV and 15-Hz flicker ERGs were generally within the normal range for the carriers. The 8-Hz ERGR, ERGC, and ERGR+C amplitudes were also generally normal. In contrast, the carriers had ERGR, ERGC, and ERGR+C timing abnormalities, with phase advances beyond the range of normal for the ERGR (four carriers), ERGC (four carriers), and ERGR+C (three carriers). Only one carrier had normal 8-Hz responses under all conditions. The 8-Hz ERG timing abnormalities in five of six carriers indicate that retinal function is not necessarily normal in carriers of XLRS. The 8-Hz flicker ERG may be useful for studying retinal function in these individuals.

PurposeTo identify specific mutations causing North Carolina macular dystrophy (NCMD).DesignWhole-genome sequencing coupled with reverse transcription polymerase chain reaction (RT-PCR) analysis of gene expression in human retinal cells.ParticipantsA total of 141 members of 12 families with NCMD and 261 unrelated control individuals.MethodsGenome sequencing was performed on 8 affected individuals from 3 families affected with chromosome 6–linked NCMD (MCDR1) and 2 individuals affected with chromosome 5–linked NCMD (MCDR3). Variants observed in the MCDR1 locus with frequencies

Purpose To 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. Methods ERGs, 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. Conclusions The 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.

To evaluate rod and cone contributions to the dark-adapted 15-Hz flicker electroretinogram (ERG) across a broad range of stimulus luminances by comparing rod-isolating (ERGR), cone-isolating (ERGC), and non-receptor-specific (ERGR+C) responses.Dark-adapted, full-field 15-Hz ERGs were obtained from four normally sighted subjects (ages 29-36 years) using a four-primary LED-based stimulating system. The primaries were either modulated sinusoidally in phase (ERGR+C) or were modulated in counter-phase to achieve rod isolation (ERGR) or cone isolation (ERGC) by means of triple silent substitution. Measurements were made for a broad range of luminances (-2.5 to 1.8 log scot. cd/m(2) in 0.2 log unit steps). Fourier analysis was used to obtain the amplitude and phase of the fundamental response component at each stimulus luminance.Stimulus luminance had different effects on response amplitudes and phases under the three paradigms. Specifically, ERGC amplitude and phase increased monotonically as luminance increased. The effects on ERGR+C and ERGR were complex: ERGR+C and ERGR amplitude was small and the phase decreased for low luminances, whereas amplitude and phase increased sharply at moderate luminances. For high luminances, ERGR+C amplitude and phase increased, whereas ERGR amplitude decreased and phase was approximately constant.At low luminances, the ERGR+C and ERGR functions can be attributed to interactions between two rod pathways. At high luminances, the functions can be accounted for by interactions between rod and cone pathways (ERGR+C) or rod insensitivity (ERGR). The ERGR paradigm minimizes cone intrusion, permitting assessment of rod function over a large range of luminance levels.

Purpose To better define visual acuity loss in patients with Stargardt disease later in life. Methods The most recent best-corrected visual acuities in the better-seeing eye of 221 patients with Stargardt disease over 40 years of age were recorded. Also included were the age at subjective onset for symptoms and duration of symptoms. Juvenile onset was defined as onset before age 21; adult onset was defined as onset between 21 and 40 years; and late onset was defined as onset at age 41 or later. Results The median age of the patients with Stargardt disease was 53.1 years. Twenty-four patients (10.9%) had worse than 20/400 best-corrected visual acuity, and none had either light perception or no light perception vision. Whereas 17 of the 52 juvenile onset patients had best-corrected visual acuity worse than 20/400, only 4 of 80 adult-onset patients and 1 of 70 late-onset patients reached this level of acuity loss. Conclusion Although many patients with Stargardt disease lose visual acuity to the 20/200 to 20/400 range, and some lose visual acuity beyond 20/400, none of these patients reached either light perception or no light perception. The numbers found in this study will be valuable in counseling patients with Stargardt disease and could have value in planning treatment trials.

Purpose To determine efficacy outcome measures for clinical trials of Leber congenital amaurosis (LCA) associated with a common intronic mutation in the CEP290 gene. Methods CEP290-LCA patients (ages 5-48) with the intronic mutation (c.2991+1655A>G) were studied as a retrospective observational case series using clinical methods and with full-field sensitivity testing (FST), optical coherence tomography (OCT), autofluorescence imaging (NIR-RAFI), transient pupillary light reflex (TPLR), oculomotor control and instability (OCI), a mobility course, and a questionnaire (NEI-VFQ). Patients were investigated cross-sectionally but a subset was able to be followed longitudinally. Results With FST, there was no rod function; cone sensitivities had a wide range from not detectable to near normal. OCT analyses indicated retained central photoreceptors with abnormal distal laminae. Based on OCT and FST, most patients had dissociation of structure and function. TPLR was nondetectable in the majority of patients, with responders demonstrating severe losses in light sensitivity. OCI was abnormal in most patients. NEI-VFQ scores had a similar range to those of other severe retinopathies. Mobility scores were consistent with FST sensitivities. In patients examined with FST, OCT, and NIR-RAFI over long-term intervals (7-10 years), there was limited but detectable disease progression. Conclusions Efficacy would be a quantitative change in foveal cone function and possibly distal laminar structure. FST provides a subjective photoreceptor-based outcome; OCT and NIR-RAFI can assess photoreceptor and RPE structure. TPLR and OCI can provide objective measures of postretinal transmission. Minimal change over a decade indicates that there is no practical value in natural history studies.

BackgroundVariation in theABCA4gene is causal for, or associated with, a wide range of phenotypes from early onset Mendelian retinal dystrophies to late-onset complex disorders such as age-related macular degeneration (AMD). Despite substantial progress in determining the causal genetic variation, even complete sequencing of the entire open reading frame and splice sites ofABCA4identifies biallelic mutations in only 60%–70% of cases; 20%–25% remain with one mutation and no mutations are found in 10%–15% of cases with clinically confirmed ABCA4 disease. This study was designed to identify missing causal variants specifically in monoallelic cases of ABCA4 disease.MethodsDirect sequencing and analysis were performed in a large familial ABCA4 disease cohort of predominately European descent (n=643). Patient phenotypes were assessed from clinical and retinal imaging data.ResultsWe determined that a hypomorphicABCA4variant c.5603A>T (p.Asn1868Ile), previously considered benign due to high minor allele frequency (MAF) (~7%) in the general population, accounts for 10% of the disease, >50% of the missing causal alleles in monoallelic cases, ~80% of late-onset cases and distinguishes ABCA4 disease from AMD. It results in a distinct clinical phenotype characterised by late-onset of symptoms (4th decade) and foveal sparing (85%). Intragenic modifying effects involving this variant and another, c.2588G>C (p.Gly863Ala) allele, were also identified.ConclusionsThese findings substantiate the causality of frequent missense variants and their phenotypic outcomes as a significant contribution to ABCA4 disease, particularly the late-onset phenotype, and its clinical variation. They also suggest a significant revision of diagnostic screening and assessment ofABCA4variation in aetiology of retinal diseases.

Autosomal recessive Stargardt disease (STGD1) is caused by hundreds of mutations in the ABCA4 gene, which are often specific to racial and ethnic groups. Here, we investigated the ABCA4 variation and their phenotypic expression in a cohort of 44 patients of African American descent, a previously under-characterized racial group. Patients were screened for mutations in ABCA4 by next-generation sequencing and array-comparative genomic hybridization (aCGH), followed by analyses for pathogenicity by in silico programs. Thorough ophthalmic examination was performed on all patients. At least two (expected) disease-causing alleles in the ABCA4 gene were identified in 27 (61.4%) patients, one allele in 11 (25%) patients, and no ABCA4 mutations were found in six (13.6%) patients. Altogether, 39 different disease-causing ABCA4 variants, including seven new, were identified on 65 (74%) chromosomes, most of which were unique for this racial group. The most frequent ABCA4 mutation in this cohort was c.6320G>A (p.(R2107H)), representing 19.3% of all disease-associated alleles. No large copy number variants were identified in any patient. Most patients reported later onset of symptoms. In summary, the ABCA4 mutation spectrum in patients of West African descent differs significantly from that in patients of European descent, resulting in a later onset and “milder” disease.

To investigate psychophysical thresholds in Stargardt disease with the full-field stimulus test (FST).Visual acuity, spectral domain optical coherence tomography, full-field electroretinogram, and FST measurements were made in 1 eye of 24 patients with Stargardt disease. Dark-adapted rod FST thresholds were measured with short-wavelength stimuli, and cone FST thresholds were obtained from the cone plateau phase of dark adaptation using long-wavelength stimuli. Correlation coefficients were calculated for FST thresholds versus macular thickness, visual acuity, and electroretinogram amplitudes.The Stargardt disease patients' FST cone thresholds correlated significantly with visual acuity, macular thickness, and electroretinogram cone response amplitudes (all P0.01). The patients' FST rod thresholds correlated with electroretinogram rod response amplitudes (P0.01) but not macular thickness (P = 0.05). All patients with Stargardt disease with flecks confined to the macula, and most of the patients with flecks extending outside of the macula had normal FST thresholds. All patients with extramacular atrophic changes had elevated FST cone thresholds and most had elevated FST rod thresholds.Full-field stimulus test rod and cone threshold elevation in patients with Stargardt disease correlated well with measures of structure and function, as well as ophthalmoscopic retinal appearance. The Full-field stimulus test appears to be a useful tool for assessing rod and cone function in Stargardt disease.

Stargardt disease is a recessively inherited form of macular dystrophy that predominantly causes loss of central vision in approximately 1 in 8,000 to 1 in 10,000 people in the United States.1 Although it is commonly associated with a juvenile onset, patients may present into adulthood. Described by Karl Stargardt in 1909, the characteristic findings of Stargardt disease include the presence of yellow flecks in the macula or throughout the posterior pole of the fundus.2,3 Patients with Stargardt disease may present with or without an atrophic-appearing macular lesion depending on the level of severity of the disease and can be classified according to the distribution and stage of their fundus flecks.3 Other classification systems exist, including one involving the degree of functional loss using electrophysiologic testing.4 With the emergence of Stargardt treatment trials, it has become of paramount importance to identify sensitive measurements of retinal structure and function that can be used as effective clinical outcome measures. In Stargardt disease, noninvasive retinal imaging, with infrared scanning laser ophthalmoscopy (SLO) and short-wavelength autofluorescence (SW-AF) technology, has allowed for improved visualization of disease-related fundus changes that may be otherwise difficult to see funduscopically. The development of spectral-domain optical coherence tomography (SD-OCT) coupled with infrared-SLO imaging offers confocal and cross-sectional analyses of the retina, allowing an improved clinical assessment of patients with Stargardt disease.5 Additionally, functional testing, made possible with microperimetry (MP), facilitates a comparison with structural retinal abnormalities. In this study, patients with Stargardt disease were evaluated using infrared-SLO imaging, SD-OCT, SW-AF, macular MP, fundus photography, and full-field electroretinograms (ERG). We compared the structural abnormalities seen on infrared-SLO with those observed with SW-AF and SD-OCT, identifying any possible redundancy in the use of these imaging modalities or potentially different information provided by each test. Associations of each test were also made with functional measurements obtained by macular MP.

Neurodegenerative diseases affecting the macula constitute a major cause of incurable vision loss and exhibit considerable clinical and genetic heterogeneity, from early-onset monogenic disease to multifactorial late-onset age-related macular degeneration (AMD). As part of our continued efforts to define genetic causes of macular degeneration, we performed whole exome sequencing in four individuals of a two-generation family with autosomal dominant maculopathy and identified a rare variant p.Glu1144Lys in Fibrillin 2 (FBN2), a glycoprotein of the elastin-rich extracellular matrix (ECM). Sanger sequencing validated the segregation of this variant in the complete pedigree, including two additional affected and one unaffected individual. Sequencing of 192 maculopathy patients revealed additional rare variants, predicted to disrupt FBN2 function. We then undertook additional studies to explore the relationship of FBN2 to macular disease. We show that FBN2 localizes to Bruch's membrane and its expression appears to be reduced in aging and AMD eyes, prompting us to examine its relationship with AMD. We detect suggestive association of a common FBN2 non-synonymous variant, rs154001 (p.Val965Ile) with AMD in 10 337 cases and 11 174 controls (OR = 1.10; P-value = 3.79 × 10(-5)). Thus, it appears that rare and common variants in a single gene--FBN2--can contribute to Mendelian and complex forms of macular degeneration. Our studies provide genetic evidence for a key role of elastin microfibers and Bruch's membrane in maintaining blood-retina homeostasis and establish the importance of studying orphan diseases for understanding more common clinical phenotypes.

PURPOSE To evaluate dark-adapted retinal sensitivity in patients with Stargardt disease (STGD1) using a modified MP-1 microperimeter and to compare the sensitivity loss with structural changes observed using spectral domain optical coherence tomography and confocal scanning laser ophthalmoscope infrared imaging. METHODS Twelve STGD1 patients and 10 normally sighted controls participated. Dark-adapted mean sensitivity (MS) was obtained using a MP-1 microperimeter. Additionally, MS percent difference between the patients and the controls was obtained. Sensitivity results were superimposed on confocal scanning laser ophthalmoscope infrared images and compared with corresponding spectral domain optical coherence tomography scans. RESULTS Dark-adapted MS ± standard deviation was 8.34 ± 1.54 dB for the controls and 3.68 ± 1.74 dB for STGD1 patients (P < 0.001). There was a significant reduction in MS of 24.0% in these patients. Sensitivity reductions were observed in areas that showed changes on confocal scanning laser ophthalmoscope infrared images and on spectral domain optical coherence tomography, including disorganizational loss of the retinal pigment epithelium, and abnormal photoreceptor inner segment ellipsoid and external limiting membrane reflectance bands. CONCLUSION With topographical accuracy, dark-adapted MS measurements can be made in STGD1 patients and controls using the MP-1 microperimeter. Sensitivity loss is associated with structural changes. This finding can be useful for the determination of optimal areas for potential improvement of retinal function in patients with Stargardt disease.

Retinitis pigmentosa (RP) is a form of inherited night blindness. Over decades, various dubious treatment strategies that lacked sufficient theoretically sound underpinnings were explored. Initially they were enthusiastically promoted and subsequently discredited. It is apparent that many were predicated on the erroneous assumption that the primary cause of RP was related to impairment of the retinal circulation. Herein, several of these strategies are reviewed and critiqued. Reasons why clinicians may have been deceived into overzealous interpretations of their treatment methods are explored. The examples disclosed should serve as a note of caution for current investigators to guard against self-deception when exploring newly developed treatment strategies.

Cystic macular lesions frequently contribute to impaired visual acuity in hereditary retinal dystrophies. Their pathogenesis varies and is not entirely understood. Carbonic anhydrase inhibitors have proven to be potentially efficacious, although not in all cases. We discuss the various factors and mechanisms implicated in the etiology of cystic macular lesions (anatomical abnormalities, impairment of the blood-retinal barrier, tangential vitreous traction, and mutations in retinoschin, etc.) and the various treatments that have been proposed.

Mutations in ABCA4 cause Stargardt disease and other blinding autosomal recessive retinal disorders. However, sequencing of the complete coding sequence in patients with clinical features of Stargardt disease sometimes fails to detect one or both mutations. For example, among 208 individuals with clear clinical evidence of ABCA4 disease ascertained at a single institution, 28 had only one disease-causing allele identified in the exons and splice junctions of the primary retinal transcript of the gene. Haplotype analysis of these 28 probands revealed 3 haplotypes shared among ten families, suggesting that 18 of the 28 missing alleles were rare enough to be present only once in the cohort. We hypothesized that mutations near rare alternate splice junctions in ABCA4 might cause disease by increasing the probability of mis-splicing at these sites. Next-generation sequencing of RNA extracted from human donor eyes revealed more than a dozen alternate exons that are occasionally incorporated into the ABCA4 transcript in normal human retina. We sequenced the genomic DNA containing 15 of these minor exons in the 28 one-allele subjects and observed five instances of two different variations in the splice signals of exon 36.1 that were not present in normal individuals (P < 10−6). Analysis of RNA obtained from the keratinocytes of patients with these mutations revealed the predicted alternate transcript. This study illustrates the utility of RNA sequence analysis of human donor tissue and patient-derived cell lines to identify mutations that would be undetectable by exome sequencing.

To determine the prevalence of macular cysts in patients with clinical cone-rod dystrophy (CORD) using spectral-domain optical coherence tomography (SD-OCT). If macular cysts could be demonstrated in such patients, they might benefit from treatment with a carbonic anhydrase inhibitor that has been shown to be effective for treating macular cysts in various night-blinding disorders.Thirty-six CORD patients underwent a complete ophthalmic examination and an SD-OCT examination using two different systems. The presence of hypo-reflective lacunae was used to determine the presence of macular cysts.The patients' mean age was 42.9 ± 19.5 years (range 6-71 years). Mean BCVA was 1.09 ± 0.64 logMAR (range no light perception to 20/25 + 2 in the better-seeing eye). All the 72 eyes studied showed a variable degree of retinal thinning, disruption of what has been referred to as the inner segment ellipsoid and outer nuclear layer (ONL) thinning of the macula. None showed evidence of macular cysts on OCT testing.Although macular cysts are a common feature of various hereditary night-blinding retinal dystrophies, these were not identified in our cohort of CORD patients.

To document a novel NYX gene mutation in a patient with X-linked complete congenital stationary night blindness and to describe this patient's electroretinogram (ERG) characteristics.ERGs were recorded from a 17-year-old male with a previously unreported NYX mutation (819GA) that results in a missense codon change (Trp237Ter). ERGs were recorded in response to brief-flash stimuli, 6.33-Hz sawtooth flicker, and sinusoidal flicker ranging from 6.33-100 Hz. The omitted stimulus response (OSR) of the flicker ERG, which is thought to be generated within the ON-pathway, was also assessed.The patient's single-flash responses were consistent with previously documented NYX ERG characteristics, including a high-luminance flash response that was electronegative under dark-adapted conditions and a square-like a-wave followed by an abnormally shaped positive potential under light-adapted conditions, both of which are consistent with an ON-pathway deficit. Further evidence for an ON-pathway deficit included: (1) ERGs to rapid-on sawtooth flicker in which b-wave amplitude was reduced more than a-wave amplitude, and (2) responses to sinusoidal flicker that lacked the normal amplitude minimum and phase inflection near 12 Hz, ERG characteristics that are like those of patients with other NYX mutations. Novel findings included a pronounced amplitude attenuation for sinusoidal flicker at frequencies above approximately 50 Hz and an absent OSR, suggesting ON-pathway dysfunction at high frequencies.The substantial loss of ERG amplitude and apparent ON-pathway dysfunction at high temporal frequencies distinguish this patient with a Trp237Ter NYX mutation from those with other previously reported NYX mutations.

Purpose Choroideremia is a progressive X-linked recessive dystrophy, characterized by degeneration of the retinal pigment epithelium (RPE), choroid, choriocapillaris, and photoreceptors. We examined photoreceptor structure in a series of subjects with choroideremia with particular attention to areas bordering atrophic lesions. Methods Twelve males with clinically-diagnosed choroideremia and confirmed hemizygous mutations in the CHM gene were examined. High-resolution images of the retina were obtained using spectral domain optical coherence tomography (SD-OCT) and both confocal and non-confocal split-detector adaptive optics scanning light ophthalmoscope (AOSLO) techniques. Results Eleven CHM gene mutations (3 novel) were identified; three subjects had the same mutation and one subject had two mutations. SD-OCT findings included interdigitation zone (IZ) attenuation or loss in 10/12 subjects, often in areas with intact ellipsoid zones; RPE thinning in all subjects; interlaminar bridges in the imaged areas of 10/12 subjects; and outer retinal tubulations (ORTs) in 10/12 subjects. Only split-detector AOSLO could reliably resolve cones near lesion borders, and such cones were abnormally heterogeneous in morphology, diameter and density. On split-detector imaging, the cone mosaic terminated sharply at lesion borders in 5/5 cases examined. Split-detector imaging detected remnant cone inner segments within ORTs, which were generally contiguous with a central patch of preserved retina. Conclusions Early IZ dropout and RPE thinning on SD-OCT are consistent with previously published results. Evidence of remnant cone inner segments within ORTs and the continuity of the ORTs with preserved retina suggests that these may represent an intermediate state of retinal degeneration prior to complete atrophy. Taken together, these results supports a model of choroideremia in which the RPE degenerates before photoreceptors.

Variants in the ABCA4 gene are the most common cause of juvenile-onset blindness affecting close to 1 in 10 000 people worldwide. Disease severity varies largely according to genotype, which can be specific to ethnic and racial groups. Here we investigate the spectrum of ABCA4 variation and its phenotypic expression in 38 patients of South Asian descent, notably from India, Pakistan, Bangladesh and Sri Lanka. Sequencing of all exons and flanking intronic sequences of ABCA4 revealed disease-causing variants in all patients: 3 in 2.6%, 2 in 81.6% and 1 in 15.8%. Altogether, 36 distinct variants were identified, including 9 previously not described. The most frequent variant c.5882G>A, p.(G1961E) was found in half the patients, the highest ever reported in a single study cohort. The South Asian founder variant c.859-9T>C was identified along with other founder variants ascribed to Danish, Chinese, Mexican and African patients. Patients carrying c.5882G>A, p.(G1961E) exhibited a consistently confined disease phenotype, normal quantitative autofluorescence (qAF) levels and preserved full-field ERG (ffERG) while c.859-9T>C resulted in widespread disease, significantly elevated qAF and reduced to non-detectable ffERG. South Asian patients present with a relatively unique ABCA4 profile comprised of various ethnic founder variants resulting in two or three major retinal phenotypes.

The purpose of this study was to evaluate pupillary light reflexes (PLRs) mediated by rod, cone, and intrinsically photosensitive retinal ganglion cell pathways as indices of outer- and inner-retinal function in patients who have enhanced S-cone syndrome (ESCS) due to NR2E3 mutations. Four patients with ESCS (ages 16–23 years) participated in the study. Subjects were tested with long- and short-wavelength single-flash full-field ERG stimuli under light-adapted conditions. They were also tested with an established pupillometry protocol involving 1-s duration, long- and short-wavelength stimuli under dark- and light-adapted conditions. The PLR was measured as a function of stimulus luminance. Transient PLRs were measured under all conditions, and sustained PLRs were measured under the highest luminance dark-adapted condition. Two-color light-adapted full-field ERGs demonstrated larger amplitude responses for short-wavelength stimuli relative to long-wavelength stimuli of the same photopic luminance, with three of four ESCS patients having super-normal a-wave amplitudes to the short-wavelength stimulus. b/a wave ratios were reduced in all four cases. Transient PLRs elicited by low-luminance stimuli under dark-adapted conditions (rod-mediated) were unrecordable, whereas the sustained PLRs elicited by high-luminance stimuli (melanopsin-mediated) were normal. Cone-mediated PLRs were recordable for all four patients, but generally lower than normal in amplitude. However, the cone-mediated PLR was larger for the short-wavelength stimulus compared to the photopically matched long-wavelength stimulus at high luminances, a pattern that was not observed for control subjects. None of the PLR conditions demonstrated “super-normal” responses. ESCS patients appear to have generally well-preserved cone- and melanopsin-mediated PLRs, indicating intact inner-retinal function. Two-color pupillometry demonstrates greater sensitivity to short-wavelength light under higher-luminance conditions and could complement the ERG as a tool for evaluating retinal function in ESCS.

Best disease (BD) is an inherited degenerative disease of the human macula that results in progressive and irreversible central vision loss. It is caused by mutations in the retinal pigment epithelium (RPE) gene BESTROPHIN1 (BEST1), which, through mechanism(s) that remain unclear, lead to the accumulation of subretinal fluid and autofluorescent waste products from shed photoreceptor outer segments (POSs). We employed human iPS cell (hiPSC) technology to generate RPE from BD patients and unaffected siblings in order to examine the cellular and molecular processes underlying this disease. Consistent with the clinical phenotype of BD, RPE from mutant hiPSCs displayed disrupted fluid flux and increased accrual of autofluorescent material after long-term POS feeding when compared with hiPSC-RPE from unaffected siblings. On a molecular level, RHODOPSIN degradation after POS feeding was delayed in BD hiPSC-RPE relative to unaffected sibling hiPSC-RPE, directly implicating impaired POS handling in the pathophysiology of the disease. In addition, stimulated calcium responses differed between BD and normal sibling hiPSC-RPE, as did oxidative stress levels after chronic POS feeding. Subcellular localization, fractionation and co-immunoprecipitation experiments in hiPSC-RPE and human prenatal RPE further linked BEST1 to the regulation and release of endoplasmic reticulum calcium stores. Since calcium signaling and oxidative stress are critical regulators of fluid flow and protein degradation, these findings likely contribute to the clinical picture of BD. In a larger context, this report demonstrates the potential to use patient-specific hiPSCs to model and study maculopathies, an important class of blinding disorders in humans.

PURPOSE To measure the peripapillary retinal nerve fiber layer (RNFL) thickness using spectral-domain optical coherence tomography in patients with retinitis pigmentosa. METHODS Fifty eyes of 30 patients with retinitis pigmentosa underwent a complete ocular examination, including best-corrected visual acuity using a Snellen chart, slit-lamp biomicroscopic examination, and Goldmann applanation intraocular pressure measurement. Dilated fundus examination was performed using both direct and indirect ophthalmoscopy. In addition, all patients underwent peripapillary RNFL thickness measurements using an OPKO spectral-domain optical coherence tomography (OPKO Instrumentations, Miami, FL). RESULTS The mean (± SD) age of the study cohort was 45.8 (± 16.3) years. Of the 50 eyes, 18 (36%) showed a thinning of the peripapillary RNFL in 1 or more quadrants and 21 (42%) showed a thickening of the peripapillary RNFL in 1 or more quadrants. Four eyes (8%) showed both thinning and thickening of the peripapillary RNFL thickness. The overall circumferential RNFL thickness of the 14 eyes that showed only thinning in at least 1 quadrant was 78.78 μm. For the 17 eyes that showed only thickening in at least 1 quadrant, the RNFL thickness was 119.69 μm. The values of the eyes with thinning and the eyes with thickening were significantly different from normal (t = 6.31 and P < 0.01 for thickening; t = 3.62 and P < 0.01 for thinning). CONCLUSION Using spectral-domain optical coherence tomography testing, we demonstrated in the current study that the peripapillary RNFL thickness in patients with RP can be decreased, increased, or maintained within normal limits. Assessment of the RNFL thickness seems prudent in these patients, particularly for identifying notable degrees of RNFL thinning in those being considered for future therapeutic trials.

To evaluate the presence of peripapillary retinal nerve fiber layer (RNFL) defects in patients with choroideremia by using spectral-domain optical coherence tomography (SD-OCT).Twenty-nine eyes of 16 patients with choroideremia underwent peripapillary RNFL thickness measurements by using SD-OCT.The mean (±SD) age of the study population was 44.0 ± 16.0 years (range, 13-63 years). Thirteen eyes (45%) showed a thinning of the peripapillary RNFL in at least 1 quadrant in either 1 or both eyes. Thinning was most commonly found in the superior (13 eyes) and inferior (10 eyes) quadrants. Twenty-one eyes (72%) showed a thickening of the peripapillary RNFL in at least 1 quadrant in either 1 or both eyes. Of these 21 eyes, all had thickening in the temporal quadrant. Additionally, 2 eyes in each of the other 3 quadrants were found to be abnormally thick.Our study demonstrated the presence of defects in the peripapillary RNFL thickness in patients with choroideremia by using SD-OCT. It would be clinically prudent that choroideremia patients considered for various treatment options be considered for RNFL thickness measurements.

Purpose: The purpose of this study was to identify the functional and structural characteristics in three female obligate carriers of X-linked retinitis pigmentosa from the same family by using spectral domain optical coherence tomography, fundus autofluorescence, and microperimetry. Methods: Three female obligate carriers with a tapetal-like reflex, 21, 49, and 57 years of age, from a single family of X-linked retinitis pigmentosa that was seen in the ophthalmology department at the University of Illinois at Chicago, were enrolled in the study. All carriers underwent a complete ophthalmic examination. Spectral domain optical coherence tomography measurements, a macular microperimetry examination, and fundus autofluorescence testing were performed. Results: The spectral domain optical coherence tomography examination in all three carriers showed a normal retinal microstructure and thickness. Microperimeter testing showed subnormal retinal sensitivity in the areas of the tapetal-like reflex. Fundus autofluorescence examination showed the presence of speckled areas of enhanced autofluorescence. Conclusion: Our study demonstrates that the carriers of X-linked retinitis pigmentosa with a tapetal-like reflex can show an enhanced reflectance on infrared images, abnormal autofluorescence properties, elevated retinal thresholds, and a normal retinal morphology within the posterior pole on spectral domain optical coherence tomography testing.

To establish normative values for macular light sensitivity and to determine the intrasession fluctuation of perimetric responses using the OPKO/OTI microperimeter. A total of 32 visually normal subjects participated in the study. A standardized grid pattern was used for testing, which consisted of 28 points arranged concentrically in three circles that occupied an area of 11° (in diameter) within the central macula. Each subject participated in at least two tests. Parameters evaluated included: overall mean macular sensitivity for test 1 and 2, overall difference in mean macular sensitivity between tests, and the mean sensitivity for each circle. The relationship between sensitivity and age was also examined. The overall median sensitivity for test 1 was 16.8 decibels (dB) and for test 2 was 16.9 dB. The median sensitivities for test 1 and test 2 were not significantly different (P=0.72). The mean intrasession sensitivity difference was 0.13 dB. The variability of the sensitivity difference between tests decreased as mean sensitivity increased. The sensitivity values averaged across the two tests for inner, middle, and outer circles ranged from 14.3 to 18.8 dB (median value of 16.9 dB), 13.8–18.3 dB (median value of 17.2 dB), and 11.3–18.3 dB (median value of 16.6 dB), respectively. Linear regression analysis showed a 0.5 dB sensitivity loss for each decade of life. We documented a narrow range of intrasession fluctuation using the OPKO/OTI microperimeter. The establishment of normative sensitivity values will facilitate monitoring the loss of macular visual function in patients with retinal disease.

Aims To evaluate the presence of peripapillary retinal nerve fibre layer (RNFL) defects in patients with Stargardt disease by using spectral-domain optical coherence tomography (SD-OCT). Methods Fifty-two eyes of 27 patients with Stargardt disease underwent peripapillary RNFL thickness measurements using SD-OCT. Results Twenty-seven patients with Stargardt disease were enrolled. Their mean (±SD) age was 38.3 (14.7) years. Fourteen patients (51.9%) showed a thinning of the peripapillary RNFL in one or more quadrants in at least one eye, and four patients (14.8%) in both eyes. Five patients (18.5%) showed a thickening of the peripapillary RNFL in at least one eye, and four patients (14.8%) in both eyes. Conclusion This study demonstrated the presence of defects in the peripapillary RNFL thickness in patients with Stargardt disease by using SD-OCT. It would be clinically prudent that Stargardt patients considered for various treatment options be considered for RNFL thickness measurements.

The purpose of this study was to evaluate the efficacy of topical dorzolamide 2% eye drops on macular function and thickness in a case of enhanced S-cone syndrome (ESCS). A 24-year-old Asian man with enhanced S-cone syndrome treated with topical dorzolamide in the left eye participated in the study. Examinations performed before and during treatment included: visual acuity (VA), contrast sensitivity measured with briefly presented grating targets (grating CS) and the Pelli-Robson chart (P-R CS), microperimetry (MP), and spectral-domain optical coherence tomography (SD-OCT). Following four months of treatment, the mean thickness of the central 1-mm foveal subfield of the left eye, as measured by SD-OCT, decreased from 551 μm to 242 μm. Mean MP sensitivity within the central 12 degrees (28 points) increased from 9.4 dB at baseline to 11.2 dB. Although, Pelli-Robson contrast sensivity improved only minimally in the left eye, grating contrast sensivity improved by more than a factor of two. Mean log MAR VA was 0.22 OD and 1.00 OS (at baseline), which improved to 0.10 OD and 0.66 OS after four months of treatment. The results indicate that in our patient with enhanced S-cone syndrome, treatment with topical dorzolamide was effective in improving macular thickness, VA, microperimetry sensitivity, and grating contrast sensivity. These measures of retinal structure and function are sensitive tools for evaluating the effects of treatment in enhanced S-cone syndrome patients with cystoid macular edema. Further investigation is warranted to assess the relationships among visual performance for daily activities, visual sensitivity, and macular thickness.

The historical evolution in the understanding of Stargardt macular dystrophy (fundus flavimaculatus) from the initial description by Karl Stargardt, identification of mutations in the ABCA4 gene, to the development of a mouse model for the human disease, is described. Highlighted are the studies by several investigators whose contributions illuminated the path to our current understanding of Stargardt disease and helped to advance progress toward future therapeutic trials for the unfortunate group of patients afflicted with this disease.

Purpose To correlate visual acuity of patients with Leber's congenital amaurosis (LCA) and early childhood-onset retinitis pigmentosa (RP) with mutations in underlying LCA genes. Design Multicentered retrospective observational study. Participants After exclusion of 28 subjects, 169 patients with the diagnosis of LCA and 27 patients with early childhood-onset RP were included in the study because the underlying mutations in AIPL1, GUCY2D, RDH12, RPE65, CRX, CRB1, RPGRIP1, CEP290, LCA5 , and TULP1 genes could be identified in this cohort of patients. Methods We collected data on best-corrected visual acuity as recorded at the time of the patient's most recent visit to one of the participating ophthalmology departments. The median and range of visual acuities for each genetic subtype were calculated separately for the LCA and early childhood-onset RP groups. Main Outcome Measures The range and median best-corrected visual acuities for each genetic subtype and age-related mean visual acuities for each genetic subtype. Results A wide variation in visual acuity was observed in patients with LCA and RPE65, RDH12 , and CRB1 mutations, whereas AIPL1, GUCY2D, CRX , and RPGRIP1 gene mutations were associated with severely decreased visual acuities beginning within the first year of life. It was also noted that patients with either an RPE65 or CRB1 mutation have progressive visual loss with advancing age. Onset of visual symptoms after infancy was associated with a relatively better visual prognosis. Conclusions The data obtained from this study will help clinicians provide counseling on visual prognosis to patients with known mutations in LCA genes and be of value in future studies aimed at the treatment of LCA and early childhood-onset RP. Financial Disclosure(s) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Purpose: Fundus albipunctatus is a form of congenital stationary night blindness characterized by an early onset and nonprogressive impairment of night vision and the presence of numerous dull-white punctate lesions scattered throughout the fundus, while retinitis punctata albescens patients often show similar fundus changes but manifest a severe and progressive hereditary retinal dystrophy.Conclusions: In this study, we report the optical coherence tomography and fundus autofluorescence measurements in patients with these hereditary night blinding diseases.

To report a successfully treated case of acquired night blindness associated with fundus white spots secondary to vitamin A deficiency. An ocular examination, electrophysiologic testing, as well as visual field and OCT examinations were obtained on a 61-year-old man with vitamin A deficiency who had previously undergone gastric bypass surgery. The patient had a re-evaluation after treatment with high doses of oral vitamin A. The patient was observed to have numerous white spots in the retina of each eye. Best-corrected visual acuity was initially 20/80 in each eye, which improved to 20/40-1 OU after oral vitamin A therapy for 2 months. Full field electroretinogram (ERG) testing, showed non-detectable rod function and a 34 and 41% reduction for 32-Hz flicker and single flash cone responses, respectively, below the lower limits of normal. Both rod and cone functions markedly improved after initiation of vitamin A therapy. Vitamin A deficiency needs to be considered in a patient with white spots of the retina in the presence of poor night vision.

To evaluate peripapillary retinal nerve fibre layer (RNFL) thickness and macular inner and outer retinal thickness using spectral domain optical coherence tomography (Sd-OCT) in patients with chronic exposure to hydroxychloroquine or chloroquine.Subjects were divided into three groups: Group I, four patients with hydroxychloroquine or chloroquine toxicity with abnormal fundus; Group II, eight patients with chronic exposure without fundus changes; and Group III, eight visually normal controls. Peripapillary RNFL thinning for an individual quadrant was based on measurements of less than the 5th percentile from at least two out of four segments in the quadrant. Macular scans on Groups I and II were carried out to compare the thickness of the inner, outer, and full-thickness retina to that of Group III.The mean ages in Groups I, II, and III were 57.6+/-8.0, 54.9+/-11.0 and 53.7+/-10.5 years, respectively (P=0.83). Median (range) duration of exposure was 7.5 (5-12) years in Group I, and was 10 (6-35) years in Group II. Seven (88%) of eight eyes in Group I showed peripapillary RNFL thinning in at least one quadrant, whereas none of Groups II and III did so. Using macular scans, Group I showed significant thinning of the inner, outer, and full-thickness retina compared to Group III (P0.001). Group II had significant thinning only of the inner retina compared to Group III (P0.001).OCT is useful to detect peripapillary RNFL thinning in clinically evident retinopathy, and selective thinning of the macular inner retina can be detected in the absence of clinically apparent fundus changes.

Stargardt macular dystrophy is the most common form of juvenile onset macular degeneration. This article reviews the four stages through which this dystrophy may progress. Also, reviewed here are the variations that may be observed in the visual acuity of patients with Stargardt disease.