Progression of Stargardt Disease as Determined by Fundus Autofluorescence Over a 12-Month Period

Abstract

IMPORTANCESensitive outcome measures for disease progression are needed for treatment trials of Stargardt disease.OBJECTIVE To estimate the progression rate of atrophic lesions in the prospective Natural History of the Progression of Atrophy Secondary to Stargardt Disease (ProgStar) study over a 12-month period. DESIGN, SETTING, AND PARTICIPANTSThis multicenter prospective cohort study was conducted in an international selection of tertiary referral centers from October 21, 2013, to February 15, 2017. Patients who were affected by Stargardt disease, aged 6 years and older at baseline, and harboring disease-causing variants of the ABCA4 gene were enrolled at 9 centers in the United States, United Kingdom, and continental Europe. Data analysis occurred from November 2016 to January 2017.EXPOSURES Autofluorescence images obtained with a standard protocol were sent to a central reading center, and areas of definitely decreased autofluorescence, questionably decreased autofluorescence, and the total combined area of decreased autofluorescence were outlined and quantified. Progression rates were estimated from linear mixed models with time as the independent variable. MAIN OUTCOMES AND MEASURESYearly rate of progression, using the growth of atrophic lesions measured by autofluorescence imaging.RESULTS A total of 259 study participants (488 eyes; 230 individuals [88.8%] were examined in both eyes) were enrolled (mean [SD] age at first visit, 33.3 [15.1] years; 118 [54.4%] female). Gradable images were available for evaluation for 480 eyes at baseline and 454 eyes after 12 months. At baseline, definitely decreased autofluorescence was present in 306 eyes, and the mean (SD) lesion size was 3.93 (4.37) mm 2 . The mean total area of decreased autofluorescence at baseline was 4.07 (4.04) mm 2 . The estimated progression of definitely decreased autofluorescence was 0.76 (95% CI, 0.54-0.97) mm 2 per year (P < .001), and the total area of both questionably and definitely decreased autofluorescence was 0.64 (95% CI, 0.50-0.78) mm 2 per year (P < .001). Both progression rates depended on initial lesion size. CONCLUSIONS AND RELEVANCEIn Stargardt disease, autofluorescence imaging may serve as a monitoring tool and definitely decreased autofluorescence and total area as outcome measures for interventional clinical trials that aim to slow disease progression. Rates of progression depended mainly on initial lesion size.

Factors Influencing Retinal Pigment Epithelium-Atrophy Progression Rate in Stargardt Disease

“…The association between the RPE atrophy size at baseline and rate of its enlargement over the follow-up is in agreement with the results of both the retrospective and prospective cohorts of the ProgStar study. 30,31 In accordance with previous studies, 30,31 patients with multifocal disease had faster RPE-atrophy enlarging rates. Similarly, SW-FAF pattern 3, characterized by extensive changes within and beyond the vascular arcades and a heterogeneous background FAF, was a predictor of faster disease progression.…”

“…This value was higher than the one reported by the retrospective analysis of Natural History of the Progression of Atrophy Secondary to Stargardt Disease (ProgStar) study, which estimated a mean progression of definitely decreased SW-FAF signal of 0.51 mm 2 /year, 30 but it was only slightly slower than the rate found in the prospective analysis of the ProgStar study (0.76 mm 2 /year). 31 Müller et al 4 have reported a mean rate of RPE-atrophy enlargement of 0.89 ± 0.13 mm 2 /year in ABCAArelated retinopathy eyes. Whereas both the ProgStar and Müller et al 4 used the mean as a measure of central tendency, it might be not appropriate in our series as the distribution of progression rates was highly rightskewed ( Supplementary Fig.…”

“…Factors with a P value < 0.20 at the univariable analysis and those previously associated with SW-FAF enlargement rate regardless of their P value were included in the multivariable model. 30,31 A second model was carried out in which the squareroot-transformed RPE atrophy enlargement rate was the dependent variable. 4 Because baseline SW-FAF and NIR-FAF hypoautofluorescent areas strongly correlated with each other, only the former was included in multivariable models to avoid collinearity.…”

Macular dystrophies: clinical and imaging features, molecular genetics and therapeutic options

“…Autofluorescence imaging may serve as a monitoring tool, and decreased autofluorescence area measurements can be used as a structural outcome for interventional clinical trials that aim to slow disease progression. 17 Ultrawide field FAF has now allowed for the classification of the posterior pole and peripheral fundus FAF findings in STGD. [18][19][20][21] OCT is an invaluable modality in all macular diseases, which in STGD identifies and sensitively quantifies the degree and extent of outer retinal loss (photoreceptor layers) and RPE atrophy (figure 1C,D).…”

Analysis of retinal sublayer thicknesses and rates of change in ABCA4-associated Stargardt disease

“…Although the clinical features of STGD1 are well-described, debate remains regarding the exact sequence of tissue loss in this disease (e.g., whether RPE loss precedes photoreceptor loss, or vice versa). Most imagingbased studies of progression in STGD1 have assessed the area of RPE loss, which is readily measured using en face fundus autofluorescence (FAF) imaging 9,[11][12][13][14][15] . However, recent studies using optical coherence tomography (OCT) have suggested that photoreceptor loss may actually precede RPE loss 16,17 .…”