The Role of the Choroid in Stargardt Disease.

Stargardt disease is the commonest juvenile macular dystrophy. It is caused by genetic mutations in the ABCA4 gene. Diagnosis is not always straightforward, and various phenocopies exist. Late-onset disease can be misdiagnosed with age-related macular disease. A correct diagnosis is particularly critical because of emergent gene therapies. Stargardt disease is known to affect retinal pigment epithelium and photoreceptors. Many studies have also highlighted the importance of the choroid in the diagnosis, pathophysiology, and progression of the disease. The choroid is in an integral relationship with the retinal pigment epithelium and photoreceptors, and its possible involvement during the disease should be considered. The purpose of this review is to analyze the current diagnostic tools for choroidal evaluation and the extrapolation of useful data for ophthalmologists and researchers studying the disease.

Choroidal Caverns in Stargardt Disease.

Purpose: To report choroidal caverns in patients affected by recessive Stargardt disease (STGD1) and to investigate its clinical features. Methods: Retrospective analysis of STGD1 patients recruited at the Regional Reference Center for Hereditary Retinal Degenerations at the Eye Clinic in Florence from 2012 to 2017. Patients included in the study underwent a complete ophthalmic examination including best-corrected visual acuity, color fundus photography, fundus autofluorescence, optical coherence tomography (OCT) and OCT angiography. Results: Eighty-six patients (172 eyes) were included in the study. Twenty-three eyes (13.3%) of 21 patients presented choroidal caverns. The total number of detected choroidal caverns was 63. Choroidal caverns were only present in patients with stage III and IV STGD. Interestingly, patients with choroidal caverns presented larger macular atrophy (20.53 ± 16.9 mm2 vs. 18.11 ± 20.39 mm2), worse visual acuity (1.03 ± 0.29 vs. 0.83 ± 0.26), and a thinner choroidal thickness (245.9 ± 88.7 vs. 266.0 ± 110.5 µm). Conclusions: Choroidal caverns are present only in the advanced stage of STGD1, and a possible degenerative origin of the finding has been hypothesized.

Perifoveal Cone- and Rod-Mediated Temporal Contrast Sensitivities in Stargardt Disease/Fundus Flavimaculatus.

Purpose: The purpose of this study was to compare L-cone-driven, S-cone-driven, and rod-driven temporal contrast sensitivities (tCSs) in patients with Stargardt disease 1/fundus flavimaculatus (STGD1/FF). Methods: Fourteen patients (eight male, six female; mean age, 43.21 ± 13.18 years) with genetically confirmed STGD1/FF participated in this study. A dedicated light-emitting diode stimulator was used to measure perifoveal tCSs in an annular test field (1°-6° of visual eccentricity) at temporal frequencies between 1 and 20 Hz. Photoreceptor classes were isolated with the triple silent substitution technique. To compare functional damage among photoreceptor classes, sensitivity deviations (decibels) were calculated based on age-related normal values and then averaged across those frequencies where perception is mediated by the same post-receptoral pathway (L-cone red-green opponent pathway: 1, 2, 4 Hz; luminance pathway: 12, 16, 20 Hz; S-cone pathway: 1, 2, 4 Hz; fast rod pathway: 8, 10, 12 Hz). Sensitivity deviations were compared with infrared scanning laser ophthalmoscopy (IR-SLO) and standard automated perimetry (SAP). Results: Photoreceptor-driven tCSs were generally lower in patients with STGD1/FF than in normal subjects but were without systematic differences among photoreceptors. Although sensitivity deviations were significantly correlated between each other, only luminance-driven L-cone sensitivity deviations were significantly correlated with the IR-SLO area of hyporeflectance (AoH) and SAP central mean deviation within 6° eccentricity (MD6deg). Conclusions: No systematic differences between photoreceptor classes were detected; however, our data suggest that temporal contrasts detected by the luminance pathway were closely correlated with other clinical parameters (AoH and MD6deg) and might be most useful as functional biomarkers in clinical trials.

Treatment and longitudinal follow-up of CNV associated with pattern dystrophy with novel PRPH2 variant.

BACKGROUND: Peripherin-2 (PRPH2) is a transmembrane glycoprotein crucial for the morphogenesis and stabilization of the photoreceptor outer segments. Variations in PRPH2 gene are associated with vision-threatening diseases. METHODS: Clinical manifestations and multimodal imaging were presented, as well as treatment history and six-year follow-up. In addition, genetic testing was performed to confirm the diagnosis. RESULTS: In this report, we present an extremely rare case of choroidal neovascularization (CNV) secondary to pattern dystrophy simulating fundus flavimaculatus (PDSFF). Multimodal imaging showed typical symmetric yellow flecks in posterior pole and choroidal neovascularization requiring timely treatment. A novel nonsense variant of c.552 C > G; p.Y184X in PRPH2 gene was detected. The patient received intravitreal anti-vascular endothelial growth factor (anti-VEGF) treatment and maintained a good vision after six years. CONCLUSION: We described a novel PRPH2 variant (Y184X) associated with PDSFF, its multimodal imaging, and long-term prognosis. Intravitreal anti-VEGF treatment can offer excellent visual prognosis in patients with PDSFF-associated CNV.

Microvascular and metabolic alterations in retinitis pigmentosa and Stargardt disease.

PURPOSE: The aim of our study was to evaluate retinal microvascular changes recorded with optical coherence tomography angiography (OCTA) and the metabolic function measured with retinal oximetry (RO) in patients with retinitis pigmentosa (RP) and Stargardt disease (STGD). METHODS: In this prospective, noninterventional study, OCTA and RO were performed on 107 eyes (56 subjects): 53 eyes diagnosed with RP without the presence of macular oedema (no-ME-RP), 26 eyes with STGD, and 28 control eyes. Main outcome measures were the mean superficial (FAZ-S; mm2 ) and deep foveal avascular zone (FAZ-D; mm2 ) measured with OCTA as well as 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) determined with RO. RESULTS: Stargardt disease (STGD) patients differed from controls and no-ME-RP by an enlarged FAZ-S and reduced A-SO2 and V-SO2 (p ≤ 0.013). No-ME-RP eyes presented with attenuated vessels (p < 0.001) and increased A-SO2 and V-SO2 (p ≤ 0.012) compared to controls and STGD. The FAZ-D showed significant interactions with A-SO2 (p = 0.003) in no-ME-RP while the FAZ-S correlated with visual acuity in no-ME-RP (p = 0.007) and STGD (p = 0.034). CONCLUSION: Retinitis pigmentosa (RP) and Stargardt disease (STGD) patients suffer from microvascular and metabolic alterations, however, showing a different pattern. A combined microvascular-metabolic model may therefore allow to more precisely characterize RP and STGD as well as presumably other inherited retinal diseases.

Inferred retinal sensitivity in recessive Stargardt disease using machine learning.

Spatially-resolved retinal function can be measured by psychophysical testing like fundus-controlled perimetry (FCP or 'microperimetry'). It may serve as a performance outcome measure in emerging interventional clinical trials for macular diseases as requested by regulatory agencies. As FCP constitute laborious examinations, we have evaluated a machine-learning-based approach to predict spatially-resolved retinal function ('inferred sensitivity') based on microstructural imaging (obtained by spectral domain optical coherence tomography) and patient data in recessive Stargardt disease. Using nested cross-validation, prediction accuracies of (mean absolute error, MAE [95% CI]) 4.74 dB [4.48-4.99] were achieved. After additional inclusion of limited FCP data, the latter reached 3.89 dB [3.67-4.10] comparable to the test-retest MAE estimate of 3.51 dB [3.11-3.91]. Analysis of the permutation importance revealed, that the IS&OS and RPE thickness were the most important features for the prediction of retinal sensitivity. 'Inferred sensitivity', herein, enables to accurately estimate differential effects of retinal microstructure on spatially-resolved function in Stargardt disease, and might be used as quasi-functional surrogate marker for a refined and time-efficient investigation of possible functionally relevant treatment effects or disease progression.

NEGATIVE VESSEL REMODELING IN STARGARDT DISEASE QUANTIFIED WITH VOLUME-RENDERED OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY.

PURPOSE: To quantify retinal vasculature changes in Stargardt disease1 (STGD1) with volume-rendered optical coherence tomography angiography. METHODS: Optical coherence tomography angiography volumes from healthy subjects and two subgroups of patients with STGD1 with the presence/absence of definitely decreased autofluorescence areas were compared. Optical coherence tomography angiography vessel surface area and vessel volume were measured in central zones (Z) of 1-, 2-, and 3-mm diameter. RESULTS: Twenty nine eyes of 15 patients with STGD1 (20/9 eyes with/without definitely decreased autofluorescence) and 30 eyes of 15 controls contributed data. An enlarged foveal avascular zone was found in patients with STGD1 without and even more with definitely decreased autofluorescence associated with a vessel rarefication in central and also paracentral zones with unnoticeable autofluorescence. Vessel surface area and vessel volume were reduced in both STGD1 subgroups for all zones (P < 0.0001). Stargardt disease 1 eyes when compared to without definitely decreased autofluorescence showed reduced vessel surface area and vessel volume in Z2+3 (both P < 0.05). CONCLUSION: Volume rendering of optical coherence tomography angiography in STGD1 shows a reduced retinal flow in the central macula. This is most likely secondary to loss of neurosensory tissue with disease progression and therefore not likely be favorably influenced by gene transfer and retinal pigment epithelial transplantation. Retinal blood flow assessed by 3D volume-rendered optical coherence tomography angiography could serve as surrogate marker for vascular changes of the central retina.

Retinal light sensitivity as outcome measure in recessive Stargardt disease.

BACKGROUND/AIMS: To evaluate the applicability of mesopic light sensitivity measurements obtained by fundus-controlled perimetry (FCP, also termed 'microperimetry') as clinical trial endpoint in Stargardt disease (STGD1). METHODS: In this retrospective, monocentre cohort study, 271 eyes of 136 patients (age, 37.1 years) with STGD1 and 87 eyes of 54 healthy controls (age, 41.0 years) underwent mesopic FCP, using a pattern of 50 stimuli (achromatic, 400-800 nm) centred on the fovea. The concurrent validity of mesopic FCP testing using the MAIA device (CenterVue, Italy), the retest variability and its determinants, and the progression of sensitivity loss over time were investigated using mixed-model analyses. The main outcomes were the average pointwise sensitivity loss in dependence of patients' demographic, functional and imaging characteristics, the intrasession 95% coefficient of repeatability, and the pointwise sensitivity loss over time. RESULTS: Pointwise sensitivity loss was on average (estimate (95% CI)) 13.88 dB (12.55 to 15.21) along the horizontal meridian and was significantly associated with the electrophysiological subgroup, presence/absence of foveal sparing, best-corrected visual acuity and disease duration. The 95% coefficient of repeatability was 12.15 dB (10.78 to 13.38) and varied in dependence of the underlying mean sensitivity and local sensitivity slope. The global progression rate for the sensitivity loss was 0.45 dB/year (0.13 to 0.78) and was higher for the central and inner ETDRS subfields compared with more peripheral regions. CONCLUSIONS: Mesopic light sensitivity measured by FCP is reliable and susceptible for functional changes. It constitutes a potential clinical outcome for both natural history studies as well as future interventional studies in patients with STGD1.

Living with Stargardt disease: insights from patients and their parents.

Background: Stargardt disease (STGD), a rare, inherited macular degeneration most commonly affecting children and young adults, is a rapidly progressive disease leading to severe central vision loss. This research aimed to develop a conceptual disease model describing STGD symptoms and their impact on patients' lives.Material and Methods: Qualitative interviews were conducted with patients (juvenile and adult) and parents of children and adolescents with STGD. Interviewed subjects were enrolled through ophthalmologists from specialized eye centers in the USA and in France. Trained interviewers used semi-structured techniques to elicit concepts relevant to patients and their parents. Thematic analysis of interview transcripts led to the identification of concepts which were organized to generate a disease model.Results: A total of 21 patients (12 in the US; 9 in France) - 14 adults, 7 juveniles - and 7 parents were interviewed. The most cited ocular symptoms were photosensitivity and central vision decline. Interviewees reported limitations on Physical (e.g. difficulty with sports/physical activities), Mental (e.g. frustration and worry, reduced ability to concentrate), Social (e.g. issue with facial recognition and difficulty discussing disease) and Role (e.g. impact on driving and reading, difficulties at school/work) functioning. These impacts were, when possible, mitigated by coping strategies and support (e.g. using electronic devices, setting up routines or accepting the disease).Conclusions: This research provides an overview of symptoms experienced by patients with STGD and highlights the dramatic impact these have on patients' lives, allowing the identification of concepts of importance when evaluating new therapeutic options for STGD.

V1 Projection Zone Signals in Human Macular Degeneration Depend on Task Despite Absence of Visual Stimulus.

Identifying the plastic and stable components of the visual cortex after retinal loss is an important topic in visual neuroscience and neuro-ophthalmology.1-5 Humans with juvenile macular degeneration (JMD) show significant blood-oxygen-level-dependent (BOLD) responses in the primary visual area (V1) lesion projection zone (LPZ),6 despite the absence of the feedforward signals from the degenerated retina. Our previous study7 reported that V1 LPZ responds to full-field visual stimuli during the one-back task (OBT), not during passive viewing, suggesting the involvement of task-related feedback signals. Aiming to clarify whether visual inputs to the intact retina are necessary for the LPZ responses, here, we measured BOLD responses to tactile and auditory stimuli for both JMD patients and control participants with and without OBT. Participants were instructed to close their eyes during the experiment for the purpose of eliminating retinal inputs. Without OBT, no V1 responses were detected in both groups of participants. With OBT, to the contrary, both stimuli caused substantial V1 responses in JMD patients, but not controls. Furthermore, we also found that the task-dependent activity in V1 LPZ became less pronounced when JMD patients opened their eyes, suggesting that task-related feedback signals can be partially suppressed by residual feedforward signals. Modality-independent V1 LPZ responses only in the task condition suggest that V1 LPZ responses reflect task-related feedback signals rather than reorganized feedforward visual inputs.

The Effect of Attention on Fixation Stability During Dynamic Fixation Testing in Stargardt Disease.

PURPOSE: Sensitive, reproducible visual function biomarkers are necessary to evaluate the efficacy of emerging treatments for Stargardt disease type 1 in clinical trials. We previously demonstrated that fixation stability may serve as a secondary outcome parameter for visual function loss. However, the test duration and protocol have an unknown effect on the assessment of fixation stability. Here, we hypothesize that separate fixation testing with a single target is different from combined fixation testing using the same target with simultaneous perimetry testing. DESIGN: International, multicenter, prospective, cross-sectional study. METHODS: Microperimetry data from the international, multicenter, prospective Progression of Atrophy Secondary to Stargardt Disease (ProgStar, NCT01977846) study were analyzed. Patients underwent various types of fixation testing including static testing and dynamic testing, and a duration-corrected dynamic test was generated (30sEpoch). RESULTS: A total of 437 eyes from 235 patients were included (mean age, 33.8 ± 15.1 years; 55.3% female). The mean 1SD-BCEA (bivariate contour ellipse area), which is the smallest ellipse encompassing 1 standard deviation of all fixation events, was smaller for the static fixation test compared to the 30sEpoch (4.5 ± 6.9 deg2 vs 5.3 ± 7.0 deg2; P = .02) and the number of points within both the 2-degree and 4-degree circles was larger (P < .0001). CONCLUSIONS: Our results suggest that differences in static and dynamic assessment of fixation stability are dependent not only on different test durations but also on the testing protocol of a single fixation target vs fixation target plus simultaneous perimetry testing and provide information on the conduct of fixation testing for clinical trials.

Optical Gap Biomarker in Cone-Dominant Retinal Dystrophy.

PURPOSE: To characterize the progression of optical gaps and expand the known etiologies of this phenotype. DESIGN: Retrospective cohort study. METHODS: Thirty-six patients were selected based on the identification of an optical gap on spectral-domain optical coherence tomography (OCT) from a large cohort of patients (N = 746) with confirmed diagnoses of inherited retinal dystrophy. The width and height of the gaps in 70 eyes of 36 patients were measured by 2 independent graders using the caliper tool on Heidelberg Explorer. Measurements of outer and central retinal thickness were also evaluated and correlated with gap dimensions. RESULTS: Longitudinal analysis confirmed the progressive nature of optical gaps in patients with Stargardt disease, achromatopsia, occult macular dystrophy, and cone dystrophies (P < .003). Larger changes in gap width were noted in patients with Stargardt disease (78.1 µm/year) and cone dystrophies (31.9 µm/year) compared with patients with achromatopsia (16.2 µm/year) and occult macular dystrophy (15.4 µm/year). Gap height decreased in patients with Stargardt disease (6.5 µm/year; P = .02) but increased in patients with achromatopsia (3.3 µm/year) and occult macular dystrophy (1.2 µm/year). Gap height correlated with measurements of central retinal thickness at the fovea (r = 0.782, P = .00012). Interocular discordance of the gap was observed in 7 patients. Finally, a review of all currently described etiologies of optical gap was summarized. CONCLUSION: The optical gap is a progressive phenotype seen in an increasing number of etiologies. This progressive nature suggests a use as a biomarker in the understanding of disease progression. Interocular discordance of the phenotype may be a feature of Stargardt disease and cone dystrophies.

Faster Sensitivity Loss around Dense Scotomas than for Overall Macular Sensitivity in Stargardt Disease: ProgStar Report No. 14.

PURPOSE: Mean sensitivity (MS) derived from a standard test grid using microperimetry is a sensitive outcome measure in clinical trials investigating new treatments for degenerative retinal diseases. This study hypothesizes that the functional decline is faster at the edge of the dense scotoma (eMS) than by using the overall MS. DESIGN: Multicenter, international, prospective cohort study: ProgStar Study. METHODS: Stargardt disease type 1 patients (carrying at least 1 mutation in the ABCA4 gene) were followed over 12 months using microperimetry with a Humphrey 10-2 test grid. Customized software was developed to automatically define and selectively follow the test points directly adjacent to the dense scotoma points and to calculate their mean sensitivity (eMS). RESULTS: Among 361 eyes (185 patients), the mean age was 32.9 ± 15.1 years old. At baseline, MS was 10.4 ± 5.2 dB (n = 361), and the eMS was 9.3 ± 3.3 dB (n = 335). The yearly progression rate of MS (1.5 ± 2.1 dB/year) was significantly lower (ß = -1.33; P < .001) than that for eMS (2.9 ± 2.9 dB/year). There were no differences between progression rates using automated grading and those using manual grading (ß = .09; P = .461). CONCLUSIONS: In Stargardt disease type 1, macular sensitivity declines significantly faster at the edge of the dense scotoma than in the overall test grid. An automated, time-efficient approach for extracting and grading eMS is possible and appears valid. Thus, eMS offers a valuable tool and sensitive outcome parameter with which to follow Stargardt patients in clinical trials, allowing clinical trial designs with shorter duration and/or smaller cohorts.

Exploration of the functional consequences of fixational eye movements in the absence of a fovea.

A recent theory posits that ocular drifts of fixational eye movements serve to reformat the visual input of natural images, so that the power of the input image is equalized across a range of spatial frequencies. This "spectral whitening" effect is postulated to improve the processing of high-spatial-frequency information and requires normal fixational eye movements. Given that people with macular disease exhibit abnormal fixational eye movements, do they also exhibit spectral whitening? To answer this question, we computed the power spectral density of movies of natural images translated in space and time according to the fixational eye movements (thus simulating the retinal input) of a group of observers with long-standing bilateral macular disease. Just as for people with normal vision, the power of the retinal input at low spatial frequencies was lower than that based on the 1/f2 relationship, demonstrating spectral whitening. However, the amount of whitening was much less for observers with macular disease when compared with age-matched controls with normal vision. A mediation analysis showed that the eccentricity of the preferred retinal locus adopted by these observers and the characteristics of ocular drifts are important factors limiting the amount of whitening. Finally, we did not find a normal aging effect on spectral whitening. Although these findings alone cannot form a causal link between macular disease and spectral properties of eye movements, they suggest novel potential means of modifying the characteristics of fixational eye movements, which may in turn improve functional vision for people with macular disease.

Prospective Cohort Study of Childhood-Onset Stargardt Disease: Fundus Autofluorescence Imaging, Progression, Comparison with Adult-Onset Disease, and Disease Symmetry.

PURPOSE: To determine the reliability and repeatability of quantitative evaluation of areas of decreased autofluorescence (DAF) from fundus autofluorescence (FAF) images and track disease progression in children with Stargardt disease (STGD1), and to investigate clinical and genotype correlations, disease symmetry, and intrafamilial variability. DESIGN: Prospective cohort study. METHODS: Children and adults with molecularly confirmed STGD1 (n = 90) underwent longitudinal FAF imaging with subsequent semiautomated measurement of the area of DAF and calculation of the annual rate of progression. The age of disease onset was recorded for all subjects, as well as the electroretinography (ERG) group at baseline (n = 86). Patients were grouped for analysis based on the age at baseline and age of onset, into children (n = 56), adults with childhood-onset STGD1 (n = 15), and adults with adult-onset (n = 19). Fifty FAF images were selected randomly and analyzed by 2 observers to evaluate repeatability and reproducibility. Differences between groups, interocular symmetry, genotype-phenotype correlations, and intrafamilial variability were also investigated both for baseline measurements as well as progression rates. We measured visual acuity, molecular genetics, ERG group, FAF metrics, and their correlations. RESULTS: The mean age of onset ± SD was 9.6 ± 3.4 years for childhood-onset (n = 71) and 28.3 ± 7.8 years for adult-onset STGD1 (n = 19). The intra- and interobserver reliability of DAF quantification was excellent (intraclass correlation coefficients 0.995 and 0.987, respectively). DAF area was symmetric between eyes and the mean rate of progression (SD) was 0.69 (0.72), 0.78 (0.48), and 0.40 (0.36) mm2/year for children, adults with childhood-onset, and adults with adult-onset disease, respectively. Patients belonging to a group 3 ERG phenotype (generalized cone and rod dysfunction) had a significantly greater progression rate. Limited intrafamilial variability was observed. CONCLUSIONS: This is the first large prospective study of FAF in a cohort of molecularly confirmed children with STGD1. DAF area quantification was highly reliable and may thereby serve as a robust structural endpoint. A high rate of progression was observed in childhood-onset disease, making this subtype of STGD1 ideally suited to be considered for prioritization in clinical trials.

Choroidal hyper-reflective foci and vascularity in retinal dystrophy.

Purpose: To investigate choroidal hyper-reflective foci (HRF) in subjects with retinal dystrophy [Stargardt's disease (SGD) and retinitis pigmentosa (RP)] and their association with demographics, visual acuity, choroidal thickness (CT), and choroidal vascularity index (CVI). Methods: Single center retrospective study of subjects with previously diagnosed SGD or RP. Swept-source optical coherence tomography images were analyzed for the presence of choroidal HRFs and CVI using previously validated automated algorithm. A Spearman's rank correlation coefficient was used to evaluate the correlation between the number of HRF and various baseline parameters including age, visual acuity, intraocular pressure, and other optical coherence tomography (OCT) parameters (CT, choroidal area, and CVI) were evaluated in these subjects. Results: This study included 46 eyes (23 subjects) and 55 eyes (28 subjects) with previously diagnosed RP and SGD, respectively. In the RP group, the mean number of HRFs was 247.9 ± 57.1 and mean CVI was 0.56 ± 0.04. In SGD group, mean HRF was 192.5 ± 44.3 and mean CVI was 0.41 ± 0.04. Mean HRF was significantly greater in the RP group (0.02), however, the mean CVI was not statistically different. In RP, mean HRF were correlated only with CVI (r = 0.49; P = 0.001), however, in SGD, it correlated with only choroidal area (r = 0.27; P = 0.04). Conclusion: Choroidal HRF were present in both RP and SGD subjects with more HRFs in those with RP. These HRFs were associated with alteration in choroidal vascularity, which further adds into the pathogenesis of these diseases.

Multimodal evaluation of central and peripheral alterations in Stargardt disease: a pilot study.

BACKGROUND: The clinical phenotype of Stargardt disease (STGD) can be extremely heterogeneous, with variable macular and peripheral retinal involvement. The study aim was to correlate peripheral ultrawide field (UWF) involvement with macular alterations, as assessed by structural optical coherence tomography (OCT) and OCT angiography (OCTA), in order to identify potentially different phenotypes. METHODS: The study involved patients with STGD and healthy controls. We performed a complete ophthalmologic assessment and multimodal imaging, including OCT, OCTA, fundus autofluorescence and UWF imaging. Patients with STGD were subdivided according to the peripheral involvement. OCT and OCTA quantitative parameters were analysed. The main outcome of the study was the classification of UWF subtypes and the correlation between UWF subtypes and macular involvement. RESULTS: Seventy STGD eyes (19 male; mean age 41.3±13.2 years) and 70 healthy eyes (35 male; 50%; mean age 41.2±9.8 years) were included in the analyses. Mean best-corrected visual acuity was 0.60±0.45 LogMAR for the STGD group and 0.0±0.0 LogMAR for controls (p<0.01). All clinical and imaging findings proved to be statistically worse in patients with STGD than in the control subjects (p<0.01). UWF types were distributed as follows: type I (49%), type II (34%), type III (17%). Type III patients proved to be significantly worse in terms of visual function and OCT and OCTA imaging parameters. CONCLUSIONS: The UWF autofluorescence performed in the present study suggests that there exist three different STGD phenotypes. Each phenotype is associated with variable OCT and OCTA impairment. Further studies providing a better assessment of the peripheral retinal involvement in STGD are warranted.

Motion perception in central field loss.

Motion information is essential in daily life because it provides cues to depth, timing, object identification, and self-motion, as well as input to the oculomotor system. As the peripheral visual field is exquisitely sensitive to motion, we investigated the periphery of individuals with central visual field loss (CFL) to determine whether speed and direction discrimination are intact in this population. We compared CFL participants' (N = 8), older (N = 6), and young controls' (N = 6) ability to discriminate motion speed and direction in a two-spatial-alternative forced-choice design. Participants viewed moving dots on the left and right of a fixation marker and judged which side had the faster speed or more clockwise direction. For the young control group, we repeated the experiment with the stimulus limited to thin strips of fixed width at eccentricities of 5°, 10°, and 15°. There was no significant difference in mean speed or direction discrimination thresholds of CFL participants and older controls for either velocity. Young controls had significantly lower thresholds than the CFL group for both tasks. We did not find an effect of visual acuity, viewing eccentricity, or scotoma location on individuals' ability to discriminate speed or direction. Our results indicate that for high-visibility stimuli moving at 5°-10°/s, speed and direction discrimination are intact in the periphery of individuals with CFL.

Peripapillary Sparing With Near Infrared Autofluorescence Correlates With Electroretinographic Findings in Patients With Stargardt Disease.

Purpose: To evaluate the correlation between the quantification of peripapillary sparing and electroretinogram (ERG) outcomes in autosomal recessive Stargardt disease (STGD1). Methods: Near infrared fundus autofluorescence (NIR-FAF) images of 101 eyes of 101 patients were retrospectively reviewed. Peripapillary sparing was assessed both qualitatively and quantitatively. The area of spared tissue (AST) was calculated in a 1-mm-wide ring around the optic disc after binarization of the 55° NIR-FAF. These measurements were correlated with the presence of normal ERG (group I), abnormal photopic responses (group II), or abnormal photopic and scotopic responses (group III). Results: AST showed significant correlations with ERG groups (R = -0.802, P < 0.001). While qualitative assessment of peripapillary sparing (i.e., present or not) also showed a significant correlation with ERG groups (R = -0.435, P < 0.001), it was weaker than by AST quantification. The ordinal regression analysis showed that the increase in AST was associated with a decrease in the odds of belonging to ERG groups II and III, with an odds ratio of 0.82 (95% confidence interval [CI] 0.78-0.87), P < 0.001. Conclusions: The AST around the optic disc in eyes with STGD1 correlates with the impairment of photoreceptors as shown in the ERG. If replicated in future longitudinal studies, the quantification of peripapillary sparing may prove to be a useful parameter for evaluating the visual prognosis of these eyes.

Perceptual learning in patients with Stargardt disease.

OBJECTIVE: To evaluate the efficacy of Perceptual Learning in improving the peripheral reading performance of patients with Stargardt disease (STGD). DESIGN: Prospective observational randomized study. PARTICIPANTS: Fourteen consecutive patients (7 females, 7 males; median age of 50.4 ± 12.8 years) with STGD were analyzed and divided into two groups: Group A received "Win-flash" as Perceptual Learning training and Group B was used as control. METHODS: Subjects underwent an ophthalmic evaluation at baseline, after perceptual learning training and at 6 months of follow-up. Outcomes measured included reading speed, contrast sensitivity and fixation stability. RESULTS: Reading speed improved of 51,7% after training in group A. Visual acuity, contrast sensitivity and fixation stability enhanced in group A after training from 0.89 (±0.09) LogMAR to 0.75 (±0.2) LogMAR (t(6)= 3.6, p= 0.001), from 0.8 (±0.3) LogC (0.6 - 0.9) to 1.3 (±0.3) LogC (t(13)=3.17, p= 0.003) and from 59.3 % (± 24.3) to 71.5 % (± 20.4) (t(13)=1.8 p= 0.04), respectively. No changes were found in group B. At 6-monts of follow-up, visual acuity and contrast sensitivity decreased in group A. CONCLUSIONS: STGD patients receiving "Win-flash training", as PL technique, showed an improvement of reading performance on a real-world task. Early follow-up for perceptual learning re-intervention should be considered.