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PURPOSE: To estimate and compare cross-sectional scotopic versus mesopic macular sensitivity losses measured by microperimetry, and to report and compare the longitudinal rates of scotopic and mesopic macular sensitivity losses in ABCA4 gene associated Stargardt Disease (STGD1). DESIGN: Multicenter prospective cohort study. METHODS: PARTICIPANTS: 127 molecular confirmed STGD1 patients enrolled from 6 centers in the USA and Europe and followed every 6 months for up to 2 years. OBSERVATION PROCEDURES: The Nidek MP-1S device was used to measure macular sensitivities of the central 20° under mesopic and scotopic conditions. The mean deviations (MD) from normal for mesopic macular sensitivity for the fovea (within 2° eccentricity) and extrafovea (4°−10° eccentricity), and the MD for scotopic sensitivity for the extrafovea were calculated. Linear mixed effects models were used to estimate mesopic and scotopic changes. MAIN OUTCOME MEASURES: Baseline mesopic mean deviation (mMD) and scotopic MD (sMD) and rates of longitudinal changes in the mMDs and sMD. RESULTS: At baseline, all eyes had larger sMD, and the difference between extrafoveal sMD and mMD was 10.7 dB (p

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.Multicenter, international, prospective cohort study: ProgStar Study.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).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 (β = -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 (β = .09; P = .461).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.

Objective : Stargardt Disease type 1 (STGD1) is the most common macular dystrophy. The assessment of fixation describes an important dimension of visual function but there is limited data on its progression over time. We present longitudinal changes and investigate its usefulness for clinical trials. Design : International, multicenter, prospective cohort study Participants and Main Outcome Measures : A total of 239 individuals with genetically confirmed STGD1 (≥ 1 disease-causing ABCA4 variant). We determined the fixation stability (FS) using the bivariate contour ellipse area (1 SD-BCEA) and fixation location (FL) using the eccentricity of fixation from the fovea during 5 study visits every 6 months. Results : At baseline, 239 patients (105 males, 44 %) and 459 eyes with a median age of 32 years were included. The baseline mean log BCEA was 0.70 ± 1.41 log deg 2 and the mean FL was 6.25 ± 4.40 deg. Although the mean log BCEA did not monotonically increase from visit to visit, the overall yearly increase in log BCEA was 0.124 log deg 2 (95% CI, 0.063-0.185). The rate of change was not different between the two years but increased faster in eyes without flecks outside of the vascular arcades and depended on baseline log BCEA. FL did not change statistically significantly over time. Conclusion and relevance : Fixation parameters are unlikely to be sensitive outcome measures for clinical trials in STGD1 but they may provide useful ancillary information in selected cases to longitudinally describe and understand an eye's visual function.

PURPOSE To report the yearly rate of change in macular function in patients with Stargardt disease type 1 (STGD1) over 24 months and to establish a new volumetric visual function index for use in clinical trials investigating the efficacy on retinal sensitivity. METHODS Design: International, multicenter, prospective cohort study with 5 study visits every 6 months over 24 months. PARTICIPANTS A total of 233 individuals with genetically confirmed STGD1 (≥1 disease-causing ABCA4 variant). MAIN OUTCOME MEASURES The total volume (VTOT) beneath the sensitivity surface of a 3-D model of the hill of vision and mean sensitivity (MS) derived from mesopic microperimetry performed with a white stimulus. Changes of VTOT over time and its correlation with the ABCA4 genotype and baseline features. RESULTS At baseline, 440 eyes (233 patients) with a mean (SD) age of 33.7 (15.0) years, mean (SD) visual acuity of 46.08 (16.03) ETDRS letters were analyzed with an average VTOT of 0.91 decibel-steradian (dB-sr) and an MS of 10.73 dB. The overall mean rate of decrease in sensitivity [95% confidence interval] was 0.077 [0.064, 0.090] dB-sr/y for VTOT and 0.87 [0.72, 1.02] dB/year for MS. The progression rate of VTOT depended on baseline visual function (0.029 dB-sr/year for low and 0.120 dB-sr/year for high baseline VTOT; P < .001) and exhibited a difference in the first vs second year of follow-up (0.065 dB-sr/year vs 0.089 dB-sr/year, respectively; P < .001). The absence of pigmentary abnormalities of the retinal pigment epithelium at baseline was found to be associated with a faster progression rate (P < .001), whereas a significant association with the genotype was not detected (P = .7). CONCLUSION In STGD1, both microperimetric outcomes demonstrate statistically significant and clinically meaningful changes after relatively short follow-up periods. Volumetric modeling may be useful in future interventional clinical trials that aim to improve retinal sensitivity or to slow down its decline and for structure-function correlations.

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 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.

Purpose To investigate the natural history of Stargardt disease (STGD1) using fixation location and fixation stability. Design Multicenter, international, prospective cohort study. Methods Fixation testing was performed using the Nidek MP-1 microperimeter as part of the prospective, multicenter, natural history study on the Prog ression of Star gardt disease (ProgStar). A total of 238 patients with ABCA4-related STGD1 were enrolled at baseline (bilateral enrollment in 86.6%) and underwent repeat testing at months 6 and 12. Results Outcome measures included the distance of the preferred retinal locus from the fovea (PRL) and the bivariate contour ellipse area (BCEA). After 12 months of follow-up, the change in the eccentricity of the PRL from the anatomic fovea was −0.0014 degrees (95% confidence interval [CI], −0.27 degrees, 0.27 degrees; P = .99). The deterioration in the stability of fixation as expressed by a larger BCEA encompassing 1 standard deviation of all fixation points was 1.21 degrees squared (deg2) (95% CI, −1.23 deg2, 3.65 deg2; P = .33). Eyes with increases and decreases in PRL eccentricity and/or BCEA values were observed. Conclusions Our observations point to the complexity of fixation parameters. The association of increasingly eccentric and unstable fixation with longer disease duration that is typically found in cross-sectional studies may be countered within individual patients by poorly understood processes like neuronal adaptation. Nevertheless, fixation parameters may serve as useful secondary outcome parameters in selected cases and for counseling patients to explain changes to their visual functionality.

To study whether fixation patterns changed over time in patients with central scotomas from geographic atrophy from age-related macular degeneration.Prospective cohort study.setting: Institutional. patient or study population: Prospective natural history study of geographic atrophy included 34 eyes of 25 patients with baseline acuity between 20/80 and 20/200 and with subsequent follow-up. observation procedures: Baseline and annual follow-up visits included best-corrected visual acuity, scanning laser ophthalmoscope macular perimetry, reading rate, and clinical evaluation. main outcome measures: Location of eccentric preferred retinal locus for fixation (PRL).At baseline, 77% of study eyes had a PRL. At the final visit (median follow-up, 5.3 years), 91% of study eyes had a PRL, with 81% of the eyes retaining the baseline PRL location. Fixation with the scotoma to the right and fixation with the scotoma superior were the first and second most common fixation patterns, respectively. Reading rates of50 words/min were present in 54% of eyes. Eyes fixating with the scotoma to the left tended to have lower reading rates than eyes fixating with right or superior patterns.Fixation with right pattern remained the most common fixation pattern, both in patients with a PRL at baseline and in patients who had a PRL during follow-up. Eyes with a PRL at baseline generally retained this pattern. The reading rate data suggest an advantage of fixation with right or superior pattern, rather than left. Reading rate declined further during follow-up in most patients.

Purpose To evaluate the effects of subfoveal choroidal neovascularization secondary to age-related macular degeneration on functional parameters obtained by scanning laser ophthalmoscope microperimetry. Design Retrospective observational case series and cross-sectional study. Methods At the Doheny Retina Institute and Wilmer Eye Institute a consecutive series of 179 eyes of 175 patients with subfoveal choroidal neovascularization secondary to age-related macular degeneration was studied. The onset of visual symptoms, best-corrected visual acuity, fluorescein angiography, evaluation of fundus microperimetry and fixation pattern using the Rodenstock scanning laser ophthalmoscope were obtained for each patient. The main outcome measures were central retinal sensitivity and fixation pattern (fixation location and fixation stability) in eyes with subfoveal choroidal neovascularization and their relationship to the length of disease, type and characteristics of choroidal neovascularization, and visual acuity. Results Of 179 eyes, 135 (75%) had central fixation, 27 (15%) had poor central fixation, and 17 (9%) had predominantly eccentric fixation. Seventy-six eyes (42%) had stable fixation, 70 eyes (39%) had relatively unstable fixation, and 33 eyes (18%) had unstable fixation. In 50 eyes (28%) a dense central scotoma was noted. Eighty-nine of 100 eyes (89%) with length of symptoms of less than 3 months had predominantly central fixation and 58 (58%) had stable fixation; 14 of 34 eyes (41%) with length of symptoms of more than 6 months had predominantly central fixation, and 5 eyes (15%) had stable fixation. In 15 eyes of patients who elected not to receive treatment, successive scanning laser ophthalmoscope microperimetry were obtained over time (follow-up of 18 months after onset of symptoms). Three months or less after the onset of symptoms, 13 eyes (87.7%) had predominantly central fixation and 9 eyes (60%) had stable fixation. More than 3 months and 6 months or less after the onset of symptoms, 10 eyes (66.7%) had predominantly central fixation and 7 eyes (46.7%) had stable fixation. This trend was further demonstrated in eyes more than 6 months after the onset of symptoms. Conclusions We conclude that the sequence of events leading to visual function deterioration appears to involve an initial mild decrease in central retinal sensitivity and visual acuity followed by progressive fixation instability and, ultimately, development of an absolute central scotoma with totally eccentric fixation. Increased length of disease is associated with worse fixation pattern and retinal sensitivity deterioration as assessed by scanning laser ophthalmoscope microperimetry. A better understanding of the characteristics of visual loss assessed by fixation pattern evaluation and microperimetry in age-related macular degeneration may help optimize timing, patient selection, and treatment options in eyes with this condition.

PURPOSE: To identify additional mutations in the ABCR gene and describe the clinical features of four affected siblings with autosomal recessive Stargardt disease. METHODS: A cohort of eight siblings was identified for study. Four of these individuals were diagnosed with Stargardt disease based on clinical evaluation and fluorescein angiography. Blood samples were obtained from seven of eight siblings, including all those affected. All 50 exons of the ABCR gene were analyzed by single-stranded confirmation polymorphism analysis, followed by direct sequencing of observed variants, to identify mutations in the ABCR gene. RESULTS: We identified a previously unreported kindred of eight siblings, four of whom had mutations in both of their ABCR alleles. A previously described G-to-C transversion of nucleotide 2588, predicting a Gly863Ala amino acid substitution, and a novel G-to-A transition of nucleotide 161, resulting in a Cys54Tyr substitution, were identified. These mutations co-segregated with the affected members of this family. Three of the siblings demonstrated clinical features characteristic of classic Stargardt disease, with bilateral regions of macular atrophy associated with yellow-white "flavimaculatus" flecks in the posterior pole at the level of the retinal pigment epithelium. The fourth affected sibling showed features of early Stargardt disease, with a beaten-bronze appearance to both maculas, as well as perimacular flecks. In all four affected patients, fluorescein angiography showed a characteristic peripheral dark choroid. CONCLUSIONS: We have identified both a previously described and a novel mutation in the ABCR gene in four patients with autosomal recessive Stargardt disease. In-depth knowledge of the ABCR mutation spectrum in patients with Stargardt disease will provide for more efficient screening and may provide potential therapies for Stargardt disease and other retinal diseases.

Purpose: Submacular surgery is under investigation for the treatment of subfoveal choroidal neovascularization secondary to age-related macular degeneration, ocular histoplasmosis syndrome, and other causes. The aims of this study were to determine whether the macular area from which choroidal neovascularization was removed surgically remained functional and whether there was any qualitative difference between eyes with different disease conditions or between eyes of younger and older patients. Methods: Our study included 19 patients (19 eyes) with choroidal neovascularization, seven cases caused by age-related macular degeneration and 12 caused by ocular histoplasmosis syndrome, pathologic myopia, or idiopathic causes. All tests were performed at least 6 months after surgical removal of choroidal neovascularization. All patients underwent fundus perimetry with the scanning laser ophthalmoscope for evaluation of dense and relative scotomas and fixation site. Results: After submacular surgery in 19 patients, 10 patients (one with age-related macular degeneration and nine with pathologic myopia, ocular histoplasmosis syndrome, or an idiopathic cause of choroidal neovascularization) fixated within an area that ophthalmoscopically and angiographically was an area of retinal pigment epithelial disturbance occupied by choroidal neovascularization preoperatively. Of 12 patients without age-related macular degeneration, seven of eight patients younger than 50 years of age compared with two of four patients 50 years or older fixated within the area of retinal pigment epithelial disturbance. Conclusions: Our data suggest that in patients without age-related macular degeneration who undergo submacular surgery, the surgically disturbed area previously occupied by choroidal neovascularization can remain functional postoperatively. Furthermore, occasionally a patient with age-related macular degeneration undergoing submacular surgery still can fixate in the area from which the choroidal neovascularization was removed.

Purpose To describe the use of red contact lenses to alleviate photophobia in patients with cone disorders. Design Retrospective interventional case series. Methods Twenty-three patients with achromatopsia or an acquired cone disorder with complaints of severe photophobia were fit with absorptive red soft contact lenses to alleviate photophobia and improve their ability to use their remaining vision more effectively Results The contact lenses immediately resolved the aversion to light, with dramatic improvement in visual function in all patients (determined by observation of the patient and by patient report). It allowed eight patients to become eligible to drive. Conclusions Red contact lenses successfully alleviate photophobia in patients with cone disorders.

Purpose We explored the clinical impression that geographic atrophy of the retinal pigment epithelium, a form of advanced age-related macular degeneration, is perceived by the patient as progressing gradually, even when fixation switches from foveal to extrafoveal. Methods We analyzed the responses of 60 patients with geographic atrophy to a questionnaire administered as part of a five-year study of the natural course of geographic atrophy, funded by the National Eye Institute. We performed scanning laser ophthalmoscope perimetry on all patients. We examined two additional patients with geographic atrophy who reported abrupt visual loss. Results No eye with geographic atrophy was reported by any patient to have had sudden visual loss. Although most patients with geographic atrophy show foveal fixation until the fovea is atrophic and then show extrafoveal fixation, scanning laser ophthalmoscope perimetry in three patients with geographic atrophy showed alternation between a foveal and an extrafoveal retinal locus for fixation. Two patients with geographic atrophy who complained of abrupt visual loss were found to have occult choroidal neovascularization, which evolved in one patient to classic choroidal neovascularization. The neovascularization was difficult to detect because of the presence of geographic atrophy and its associated ophthalmoscopic and fluorescein angiographic features. Conclusions Visual loss in geographic atrophy is nearly always perceived by the patient as being gradual, even when considerable decreases in visual acuity occur and when foveal vision and fixation are lost. A possible explanation for this perception is that there is a transitional period during which a patient uses both a foveal and extrafoveal site for fixation. The complaint of abrupt visual loss in a patient with geographic atrophy should raise the suspicion of choroidal neovascularization, which may be occult and difficult to detect.