Longitudinal Changes of Fixation Stability and Location Within 24 Months in Stargardt Disease: ProgStar Report No. 16


Stargardt disease type 1 (STGD1) is the most common macular dystrophy. The assessment of fixation describes an important dimension of visual function, but data on its progression over time are limited. We present longitudinal changes and investigate its usefulness for clinical trials.


International, multicenter, prospective cohort study.


Included were 239 individuals with genetically confirmed STGD1 (one or more disease-causing ATP binding cassette subfamily A member 4 [ ABCA4 ] variant). We determined the fixation stability (FS) using 1 SD of the bivariate contour ellipse area (1 SD-BCEA) and fixation location (FL) using the eccentricity of fixation from the fovea during five study visits every 6 months.


At baseline, 239 patients (105 males [44%]) and 459 eyes, with a median age of 32 years, were included. The baseline mean logBCEA was 0.70 ± 1.41 log deg and the mean FL was 6.25° ± 4.40°. Although the mean logBCEA did not monotonically increase from visit to visit, the overall yearly increase in the logBCEA was 0.124 log deg (95% CI, 0.063-0.185 log deg ). The rate of change was not different between the 2 years but increased faster in eyes without flecks outside of the vascular arcades and depended on baseline logBCEA. FL did not change statistically significantly over time.


Fixation parameters are unlikely to be sensitive outcome measures for clinical trials in STGD1 but may provide useful ancillary information in selected cases to longitudinally describe and understand an eye’s visual function.

A utosomal-recessive Stargardt disease type 1 (STGD1; OMIM: 248200) is the most common macular dystrophy. , It is commonly characterized by funduscopically visible atrophy of the retinal pigment epithelium (RPE), RPE pigmentary abnormalities, and flecks within or outside of the major vascular arcades. The age of disease onset is highly variable, and symptoms are often first noticed when reduced best-corrected visual acuity develops. With progressive RPE atrophy in STGD1, most affected eyes develop slowly progressive worsening of BCVA, while a subset of eyes show small improvements over time on the visual acuity chart. Because a number of novel therapeutic approaches, such as pharmacotherapy, gene therapy, and stem cell therapy, are currently in clinical trials, structural and functional outcomes for STGD1 are needed to investigate the efficacy of the new treatments.

The Progression of Atrophy Secondary to Star gardt disease (ProgStar; NCT01977846) study group reported the yearly progression of the area of definitely decreased autofluorescence signal as 0.76 mm 2 (95% CI, 0.54-0.97 mm 2 ) per year. However, structural changes in clinical trials should ideally be associated with functional changes to obtain United States Food and Drug Administration approval.

BCVA is not a useful functional end point due to its slow progression: neither the retrospective nor prospective ProgStar cohorts showed a statistically significant change after 12 months and only a borderline statistically significant change of 0.55 letters/y ( P = .004) in the analysis of the 2-year data. , The ProgStar study provided detailed information on the progression of functional decline using microperimetry and described an automated approach to selectively measure progression at the scotoma edge. In addition to quantifying the sensitivity of the macula, microperimetry devices allow a thorough characterization of an eye’s fixation behavior. Fixation stability is associated with reading speed and visual search ability.

We previously observed a small but statistically significant improvement in BCVA among eyes with severe visual impairment at baseline (defined as BCVA worse than 20/200) , and suggested changes in fixation behavior as a possible explanation. While these parameters seem to have a complex relationship with visual acuity, literature on the progression of the location of fixation and its stability over time is scarce. , The present research aims to report the longitudinal changes of fixation parameters in a well-defined cohort of genetically confirmed cases. We further investigate associations with demographic features, clinical examination characteristics, and results from genetic testing.


This study was conducted as a prospective natural history study. The ProgStar study follows International Conference on Harmonisation Good Clinical Practice Guidelines, the applicable regulatory requirements, and the current Declaration of Helsinki. It is in compliance with Health Insurance Portability and Accountability Act and was approved by the Western Institutional Review Board, the local Institutional Review Boards, and the Human Research Protection Office of the United States Army Medical Research & Materiel Command. ProgStar is registered as NCT01977846 at www.clinicaltrials.gov. Written informed consent was obtained.

Patient Eligibility and Exclusion Criteria

All inclusion and exclusion criteria are detailed in ProgStar Report No. 1. The most relevant inclusion criteria for this analysis include a minimum age of ≥6 years and the presence of two or more pathogenic mutations in the ATP binding cassette subfamily A member 4 ( ABCA4 ) gene or one pathogenic mutation with a typical STGD1 phenotype. The primary end point of ProgStar is the progression of atrophic lesions as measured on fundus autofluorescence (FAF) imaging, and therefore, a well-demarcated area of atrophy on FAF imaging with a minimum lesion diameter of 300 µm was required. At the same time, the summed area of FAF atrophy had to be ≤12 mm 2 (equivalent to no more than five disc areas) in the primary study eye. A minimum BCVA of 20 Early Treatment Diabetic Retinopathy Study (ETDRS) letters (20/400 Snellen equivalent) was also required for inclusion.

Data Collection and Management

Clinical information, including visual acuity, demographics, and dilated fundus examination findings, were entered into Research Electronic Data Capture (REDCap; Institute of Translational Health Sciences) by the clinical sites and Doheny Imaging Reading Center (DIRC), the central reading center. The presence or absence of flecks outside the arcades was determined by clinical examination. The data coordinating center (Dana Center for Preventive Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, and Johns Hopkins Bloomberg School of Public Health) then verified completeness and consistency of the collected data.

All microperimetry testing was performed with the Nidek MP-1 (Nidek Technologies Srl), and all machines were certified by the DIRC. The DIRC also checked the submitted examinations for quality and completeness and notified the sites if data were missing or had poor quality. Two certified graders graded all examinations, and if discordant, a DIRC investigator made a final assessment.

Genetic Categorization

All patients underwent genetic screening between 2000 and 2014. As part of the ProgStar study, detected variants were confirmed in 2016. The predicted severity of dysfunction of the ABCA4 gene product was used to categorize all patients into three groups. The classification was presented in detail previously, and was updated as new experimental/clinical evidence became available. In brief, patients with two or more severe/null variants were included in group A, those with one severe/null variant and at least one missense or in-frame insertion/deletion in group B, and those with two or more missense or in-frame insertion/deletion variants in group C.


All patients underwent microperimetry testing using the Nidek MP-1, as described previously, , with 6-month follow-up visits for a total of 24 months. All testing was performed monocularly with the contralateral eye patched. Static fixation data were recorded during a fixation task that preceded the microperimetric sensitivity test. During this task, the patients were asked to fixate as steadily as possible on the center of a single red cross (2° in extension and 1° in thickness) on a white background. The testing lasted approximately 30 seconds after the target was located. During the test, real-time fundus images were acquired at a frequency of 25 Hz, and the locations of fixation events ( x, y coordinates) were registered for each image. A training examination was available to novice patients to minimize the effects of learning.

Description of the Preferred Retinal Locus

The cloud of recorded fixation events was then further analyzed, and the distance between their barycenter and the foveal center was measured. This distance in degrees defines the preferred retinal locus (PRL) eccentricity. The Nidek NAVIS software (1.7.0 or higher) can automatically center a concentric grid on this barycenter of all fixation events, and two graders manually determined the distance to the fovea by reading the grid. Optical coherence tomography imaging was used as an auxiliary technology for difficult cases with foveal atrophy, whereas the point of maximal inner retinal layer convergence of the adjoining B scans immediately superior and inferior to the approximate foveal center were viewed to determine the foveal location as closely as possible.

We previously performed a subgroup analysis of 45 randomly selected eyes. The PRL distance from the fovea for dynamic testing (based on the full macular sensitivity test) and for the separate fixation examination were not significantly different (ρ PRL = 0.87; P < .001; n = 45). Because more data from the dynamic test were available and the results did not appear different from the static test, we used PRL eccentricity measurements from dynamic testing for all PRL analyses.

Description of the 1-SD Bivariate Contour Ellipse Area

The 1-SD Bivariate Contour Ellipse Area (1 SD-BCEA) is the smallest elliptical area that encompasses 1 SD (68.3%) of all recorded fixation events ( Figure 1 ). It is commonly calculated with the following formula:

<SPAN role=presentation tabIndex=0 id=MathJax-Element-1-Frame class=MathJax style="POSITION: relative" data-mathml='BCEA=2kπσHσV(1−ρ2)12′>𝐵𝐶𝐸𝐴=2𝑘𝜋𝜎𝐻𝜎𝑉(1𝜌2)12BCEA=2kπσHσV(1−ρ2)12
where σ H and σ V are the SDs of the horizontal and vertical eye movements, ρ is the Pearson product-moment correlation coefficient of eye movements in the horizontal and vertical meridian, and k is dependent on the chosen probability area but for 1 SD (68.3%), k must be approximately 1.15:
<SPAN role=presentation tabIndex=0 id=MathJax-Element-2-Frame class=MathJax style="POSITION: relative" data-mathml='P=1−e−k’>𝑃=1𝑒𝑘P=1−e−k
and e is the base of the natural logarithm.


Grading of the 1-SD bivariate contour ellipse area (1 SD-BCEA). The 1 SD-BCEA is the smallest possible ellipse that encompasses 1 SD of all fixation events (blue dots) in two perpendicular axes. A. The dark blue innermost ellipse represents the 1 SD-BCEA. The eccentricity of the preferred retinal locus (PRL) was determined in degrees from the anatomical fovea by overlying a grid centered on the barycenter of all fixation events (not shown). In A compared with B, fixation is more unstable, with a larger 1 SD-BCEA of 2.57 log deg (vs 0.59 log deg in B) and PRL eccentricity of 5° (vs 0° in B). C. The spaghetti plot shows the change of all study eyes over the five study visits. Each eye was assigned a color in the plot depending on its baseline 1 SD-BCEA. Those eyes with a baseline logBCEA in the 33rd percentile or below are indicated in red, those between the 33rd and 67th percentile in green, and those in the 67th percentile or above in blue. The black lines connect the means of the logBCEAs in the three groups between the visits over time. D. The plot visualizes the corresponding information for the eccentricity of the preferred retinal locus in degrees from the anatomical fovea, also described as fixation location (FL).

We calculated a global 1 SD-BCEA using the raw data of all recorded fixation events and their x and y coordinates. For this analysis and as in most of the available literature on fixation stability, we used data from the static fixation test to calculate the 1 SD-BCEA after export of raw data from the Nidek MP-1 in the “.mfd” format. All calculations were performed in Excel software (Microsoft).

Statistical Analyses

The two main outcome variables in this analysis are the eccentricity of the PRL from the anatomical fovea in degrees and the logarithm of the 1 SD-BCEA in log deg . All logarithmic calculations are based on the 1 SD-BCEA. The logBCEA was chosen because the distribution of the 1 SD-BCEA is strongly positively skewed, whereas its natural logarithm has a relatively normal distribution. Linear mixed-effects models were used for statistical analysis to estimate the yearly change for each outcome.


This analysis included 239 patients and 459 eyes. Information on the location of the PRL was missing in 42 eyes (9.2%) and on the 1 SD-BCEA in 17 eyes (3.8%). The results on visual acuity, the 1 SD-BCEA, the logBCEA, and the PRL are reported as averages over the patients’ eyes.

The demographic features of the cohort are detailed in Table 1 . STGD1 had been confirmed molecularly for all patients in the study, 134 patients (55.9%) were female, the mean age at baseline was 33.8 ± 15.2 years, and 207 patients (86.8%) were of Caucasian ethnicity. The mean age at the time of diagnosis of STGD1 was 22.57 ± 12.84 years, with a mean duration of 11.85 ± 9.47 years since diagnosis. Macular disease was found in 94 patients (39.5%) before age 18 and was diagnosed in 127 patients (53.4 %) at age 18 or older. Two participants (0.8%) were diagnosed with STGD1 without symptoms, and 15 patients (6.3%) did not remember the age when they first noticed symptoms. BCVA at baseline was 45.72 ± 16.56 ETDRS letters, with the lower limit of 20 ETDRS letters related to the inclusion criteria of ProgStar.


Baseline Characteristics of Eligible Patients and Eyes by Inclusion in the Analysis

Variable Patient and Eye Data
Patient level a (N = 239)
Age, mean (SD), y b 33.75 (15.20)
Female sex, No. (%) 133 (55.9)
Race/ethnicity, No. (%) c
Asian/South Asian 11 (4.7)
African American 20 (8.5)
White 203 (86.8)
Other, unknown 0 (0.0)
Age of onset, mean (SD), y d 22.57 (12.84)
Age of onset categorized, No. (%) d
<18 y 94 (39.5)
≥18 y 127 (53.4)
Unknown 15 (6.3)
Asymptomatic, No. (%) 2 (0.8)
Duration of Disease, mean (SD), y d 11.77 (9.47)
Duration of disease categorized, No. (%) d
≤2 y 22 (10.0)
3-6 y 57 (25.8)
7-11 y 53 (24.0)
≥12 y 89 (40.3)
Genotype group, No. (%) e , f
A 7 (4.0)
B 82 (46.3)
C 88 (49.7)
Eye level (N = 459 eyes)
Best-corrected visual acuity in ETDRS letters, mean (SD) g 45.72 (16.56)
Visual impairment, No. (%)
Severe 108 (23.8)
Moderate 245 (54.1)
Mild 71 (15.7)
None 24 (5.3)
Retinal pigment epithelium abnormalities, No. (%) 314 (70.2)
Flecks outside the arcades, No. (%) 210 (47.1)
BCEA, mean (SD), deg 2 h 4.85 (9.34)
logBCEA, mean (SD), deg 2 h 0.70 (1.41)
Preferred retinal locus, mean (SD), deg i 6.25 (4.40)

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Jan 3, 2022 | Posted by in OPHTHALMOLOGY | Comments Off on Longitudinal Changes of Fixation Stability and Location Within 24 Months in Stargardt Disease: ProgStar Report No. 16

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