Xiangrong Kong

Macular sensitivity measured with microperimetry in stargardt disease in the progression of atrophy secondary to stargardt disease (ProgStar) study report No. 7

Importance New outcome measures for treatment trials for Stargardt disease type 1 (STGD1) and other macular diseases are needed. Microperimetry allows mapping of light sensitivity of the macula and provides topographic information on visual function beyond visual acuity. Objective To measure and analyze retinal light sensitivity of the macula in STGD1 using fundus-controlled perimetry (microperimetry). Design, Setting, and Participants This was a multicenter prospective cohort study. A total of 199 patients and 326 eyes with molecularly confirmed (ABCA4) STGD1 underwent testing with the Nidek MP-1 microperimeter as part of the multicenter, prospective Natural History of the Progression of Atrophy Secondary to Stargardt Disease (ProgStar) study. Sensitivity of 68 retinal loci was tested, and the mean sensitivity (MS) was determined; each point was categorized as “normal,” “relative,” or “deep” scotoma. Main Outcomes and Measures Mean sensitivity and the number of points with normal sensitivity, relative, or deep scotomas. Results Mean (SD) patient age was 34.2 (14.7) years, mean (SD) best-corrected visual acuity of all eyes was 47.8 (16.9) Early Treatment Diabetic Retinopathy Study letter score (approximately 20/100 Snellen equivalent), and mean MS of all eyes of all 68 points was 11.0 (5.0) dB. The median number of normal points per eye was 49 (mean [SD], 41.3 [20.8]; range, 0-68); abnormal sensitivity and deep scotomas were more prevalent in the central macula. Mean sensitivity was lower in the fovea (mean [SD], 2.7 [4.4] dB) than in the inner (mean [SD], 6.8 [5.8] dB) and outer ring (mean [SD], 12.7 [5.3] dB). Overall MS per eye was 0.086 dB lower per year of additional age (95% CI, −0.13 to −0.041; Pu2009<u2009.001) and 0.21 dB lower per additional year of duration of STGD1 (95% CI, −0.28 to −0.14; Pu2009<u2009.001). Longer duration of STGD1 was associated with worse MS (&bgr; = −0.18; Pu2009<u2009.001), with a lower number of normal test points (&bgr; = −0.71; Pu2009<u2009.001), and with a higher number of deep scotoma points (&bgr; = −0.70; Pu2009<u2009.001). We found 11 eyes with low MS (<6 dB) but very good best-corrected visual acuity of at least 72 Early Treatment Diabetic Retinopathy Study letter score (20/40 Snellen equivalent). Conclusions and Relevance We provide an extensive analysis of macular sensitivity parameters in STGD1 and demonstrate their association with demographic characteristics and vision. These data suggest microperimetry testing provides a more comprehensive assessment of retinal function and will be an important outcome measure in future clinical trials.

Visual Acuity Change over 12 Months in the Prospective Progression of Atrophy Secondary to Stargardt Disease (ProgStar) Study: ProgStar Report Number 6

PURPOSEnTo estimate the yearly rate of change of best-corrected visual acuity (BCVA) and the risk of loss 1 line or more over 1 year and to identify risk factors for BCVA loss in patients with Stargardt disease (STGD1).nnnDESIGNnMulticenter, prospective cohort study.nnnPARTICIPANTSnTwo hundred fifty-nine patients (489 eyes) with molecularly confirmed STGD1 enrolled at 9 centers in the United States and Europe.nnnMETHODSnParticipants were followed up every 6 months, and data at the baseline and 6- and 12-month visits were analyzed. Best-corrected visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Standardized reporting forms were used to collect participants characteristics and clinical observations. Linear mixed effects models were used to estimate the rate of BCVA loss. Linear models with generalized estimating equations were used to identify risk factors for BCVA loss of 1 line or more over 1 year.nnnMAIN OUTCOME MEASURESnChange in BCVA over 1 year.nnnRESULTSnCross-sectional analysis at baseline showed that earlier symptom onset and longer duration since onset was associated with worse BCVA. Longitudinal analysis showed no overall significant change of BCVA within 12 months, but the rate of BCVA change was significantly different by baseline BCVA (P < 0.001). The BCVA of eyes with baseline BCVA of 20/25 or better declined at a rate of 2.8 ETDRS letters per year (Pxa0= 0.10), eyes with baseline BCVA between 20/25 and 20/70 declined at a rate of 2.3 ETDRS letters per year (Pxa0= 0.002), eyes with baseline BCVA between 20/70 and 20/200 declined at a rate of 0.8 ETDRS letters per year (Pxa0= 0.08), and eyes with baseline BCVA worse than 20/200 showed a significant improvement of 2.3 ETDRS letters per year (P < 0.001). Overall, 12.9% of eyes lost 1 line or more, and the risk of such BCVA loss was different by baseline BCVA level (Pxa0= 0.016). Smoking and vitamin A use was not associated significantly with baseline BCVA, nor with rate of BCVA loss over 1 year.nnnCONCLUSIONSnChange in BCVA in STGD1 patients over a 12-month period was small, but varied depending on baseline BCVA. Given the slow change during 1 year, BCVA is unlikely to be a sensitive outcome measure for STGD1 treatment trials with 1 years duration.

Fixation Location and Stability Using the MP-1 Microperimeter in Stargardt Disease

PURPOSEnTo determine fixation location and fixation stability in Stargardt disease (STGD1) and their association with best-corrected visual acuity (BCVA).nnnDESIGNnCross-sectional analysis within the multicenter, prospective ProgStar study.nnnPARTICIPANTSnA total of 238 patients and 440 eyes with ABCA4-related STGD1.nnnMETHODSnPatients underwent testing with the Nidek MP-1 microperimeter (Nidek Technologies Inc., Gamagōri, Japan). Fixation location was expressed as the eccentricity of the preferred retinal locus (PRL) from the anatomic fovea, fixation stability was expressed as the bivariate contour ellipse area (BCEA), and BCVA was expressed as Early Treatment Diabetic Retinopathy Study (ETDRS) letters. Linear models with generalized estimating equations were used for statistical analysis while accounting for between-eye correlations.nnnMAIN OUTCOME MEASURESnFixation location and fixation stability.nnnRESULTSnMedian PRL eccentricity from the fovea was 6° (mean, 6.3°; range, 0°-25°) and median BCEA was 6.31°2 (mean, 12.31°2; range, 0.03°2-365.63°2). Each year of later onset of symptoms of STGD1 was associated with 0.14° more central fixation location (P < 0.0001), but not with fixation stability (Pxa0= 0.53). A single linear model best described the relationship between fixation location and BCVA: 1° farther PRL eccentricity was associated with a 2.3-letter loss of BCVA (P < 0.0001). A piecewise linear model best described the relationship between fixation stability and BCVA: for a BCEA less than 2.8°2, an increase in BCEA by 1°2 was associated with a 10.5-letter (ETDRS) lower BCVA (P < 0.0001). For a BCEA 2.8°2 or more, an increase in BCEA by 1°2 was associated with a 0.036-letter (ETDRS) lower BCVA (Pxa0= 0.0234). Pearson correlation coefficients between patients right and left eyes were 0.89 (P < 0.0001) for fixation location and 0.25 (Pxa0= 0.0006) for fixation stability. After 10 years of disease duration, 82% of patients had eccentric PRLs in both eyes.nnnCONCLUSIONSnWe provide the first extensive database of continuous fixation parameters in STGD1 and demonstrate their association with vision. These measures allow for a more comprehensive assessment of retinal function and may serve as potential secondary outcome measures for future treatment trials for STGD1 and other macular diseases.

Visual Acuity Change Over 24 Months and its Association With Foveal Phenotype and Genotype in Individuals With Stargardt Disease: ProgStar Study Report No. 10

Importance Limited data from prospective studies are available to understand the natural history of ABCA4-related Stargardt disease (STGD1). Such data are important for determining appropriate outcome measures for future STGD1 trials. Objective To estimate the rate of loss of best-corrected visual acuity (BCVA) during 2 years and to estimate the associations of BCVA loss with foveal phenotype and genotype in patients with STGD1. Design, Setting, and Participants This multicenter prospective cohort study included 259 participants (489 study eyes) with molecularly confirmed STGD1 who were 6 years or older. The participants were enrolled at 9 centers in the United States and Europe and were followed up every 6 months for 2 years. Exposures Baseline BCVA and presence and type of foveal lesion (determined via fundus autofluorescence images) and genotype (classified into 4 groups based on the number and pathogenicity of ABCA4 mutations). Main Outcomes and Measures Rate of BCVA change per year. Results The mean (SD) age was 33 (15) years. Of 259 the participants, 141 (54%) were female, and 222 (85%) were white. The overall rate of BCVA loss was 0.55 (95% CI, 0.20-0.90) letters per year during the 2 years. Eyes with baseline BCVA worse than 20/200 showed an improvement of 0.65 (95% CI, 0.1-1.2) letters per year. At baseline, the mean BCVA for eyes without foveal lesion was 20/32, and their BCVA change rate over time was 0.1 (95% CI, −1.2 to 1.35) letters per year (Pu2009=u2009.89). Eyes with a foveal lesion but having BCVA of 20/70 or better at baseline lost BCVA at a rate of 3 (95% CI, 1.5-4.4) letters per year (Pu2009<u2009.001). Genotype was neither associated with baseline BCVA nor with the rate of BCVA change during the follow-up. Conclusions and Relevance A clinically small BCVA loss was observed during 2 years, and the change rate varied depending on baseline BCVA. Eyes without lesion in the fovea had better BCVA at baseline and showed minimal change of BCVA throughout 2 years. Eyes with no or modest acuity impairment but with a foveal lesion at baseline had the fastest loss rate. For trials of STGD1 with 2 years of duration, it may be difficult to show efficacy using BCVA as an end point owing to its slow rate of change over this time.

Predicting Visual Disability in Glaucoma With Combinations of Vision Measures

Purpose We characterized vision in glaucoma using seven visual measures, with the goals of determining the dimensionality of vision, and how many and which visual measures best model activity limitation. Methods We analyzed cross-sectional data from 150 older adults with glaucoma, collecting seven visual measures: integrated visual field (VF) sensitivity, visual acuity, contrast sensitivity (CS), area under the log CS function, color vision, stereoacuity, and visual acuity with noise. Principal component analysis was used to examine the dimensionality of vision. Multivariable regression models using one, two, or three vision tests (and nonvisual predictors) were compared to determine which was best associated with Rasch-analyzed Glaucoma Quality of Life-15 (GQL-15) person measure scores. Results The participants had a mean age of 70.2 and IVF sensitivity of 26.6 dB, suggesting mild-to-moderate glaucoma. All seven vision measures loaded similarly onto the first principal component (eigenvectors, 0.220–0.442), which explained 56.9% of the variance in vision scores. In models for GQL scores, the maximum adjusted-R2 values obtained were 0.263, 0.296, and 0.301 when using one, two, and three vision tests in the models, respectively, though several models in each category had similar adjusted-R2 values. All three of the best-performing models contained CS. Conclusions Vision in glaucoma is a multidimensional construct that can be described by several variably-correlated vision measures. Measuring more than two vision tests does not substantially improve models for activity limitation. Translational Relevance A sufficient description of disability in glaucoma can be obtained using one to two vision tests, especially VF and CS.