In his talk on “Fully Automated Patient-Tailored Microperimetry: A FirstOrbit Study Report” at the American Society of Retina Specialists 2024 annual meeting, Dr. Hendrik Scholl sought to “validate a novel, fully automated microperimetry test paradigm for evaluating perilesional function in Stargardt disease.”
Unmeet Needs in Stargardt Disease
Stargardt disease is a form of hereditary macular degeneration characterized by central vision loss with minimal changes visible on exam. Current experimental treatments are variant-agnostic and target either the visual cycle, lipofuscin accumulation, or retinal pigment epithelium (RPE) cell metabolism. According to Dr. Scholl, variant-specific gene editing is on the horizon,1 and variant-specific natural-history studies are needed to estimate re-test reliability and changes in clinic outcome assessments over time. As a pretreatment natural history study, FirstOrbit aimed to evaluate structural vs functional changes associated with STGD1 to help “facilitate statistically efficient cross-over trial designs.”
Microperimetry has been widely used to study the central macular light sensitivity in inherited retinal dystrophies, but standard microperimetry has several technical challenges such as the large fraction of ‘static test-points’ that are either too far from the junctional zone or within atrophy. Dr. Scholl suggests that fully automated patient-tailored microperimetry is a possible solution to these issues. He describes the evolution of the test used in this study:
- Scotoma-boundary–based analyses are limited to test-points at risk of progression, but do not maximize the number of relevant test-points.
- Patient-tailored microperimetry 1.0 maximizes the number of relevant test points while keeping the overall number in check, but the technician must adjust the grid position in eyes with extrafoveal fixation.
- Fully automated patient-tailored microperimetry (microperimetry 2.0) uses spectral domian (SD)-OCT segmentation, automated grid design and grid placement, runs the test through an external computer (with the MAIA device), and bypasses use of a technician that could be a source of error.
FirstOrbit Study
The prospective, observational FirstOrbit study assesses the progression of photoreceptor inner and outer segment loss in Stargardt disease through the use of a fully automated microperimetry paradigm, tailored to the lesions of patients with atrophic macular diseases.2 The study focuses on ABCA4 G1961E–associated Stargardt Disease (STGD1). ABCA4 retinopathy is the most common genetically distinct inherited retinal disease and can lead to isolate macular dystrophy, generalized cone and cone-and-rod dystrophies, and other retinal disorders.
A total of 20 patients with genetically confirmed STGD1 and a median age of 31 years (all 18 years old or older) were enrolled in FirstOrbit: 19 were tested with microperimetry 2.0 at baseline and again at 2 months (re-test). The ellipsoid zone (EZ) loss on SD-OCT was measured by an artificial intelligence (AI)-based algorithm. Microperimetry test points were placed around the EZ-loss boundary at specific distances. The fully automated perimetry test was presented with the S-MAIA (macular integrity assessment system) interface device with a ZEST protocol for mesopic white-on-white, dark-adapted cyan, and red testing. Mixed models analyzed the sensitivity.
Retest Reliability and Repeatability
Patients had a median BCVA of 0.79 logMAR in the study eye. The results were that both mesopic and dark-adapted cyan sensitivity increased significantly as the distance increased to the EZ-loss boundary. The retinal sensitivity profile was reviewed for a structure–function correlation, and the AI-based segmentation revealed a close association between EZ-loss and light-adapted vision loss (R2 of 0.83) and dark-adapted vision loss (R2 of 0.63). Functional measures (visual acuity and contrast sensitivity) at the preferred retinal locus showed good reproducibility, as did light- and dark-adapted visual field (VF) measurements. The results point to indirect, contrast sensitivity–based acuity measurements providing better repeatability than VA and other measures.
Potential Treatment Target
Dr. Scholl concluded that patients with G1961E-STGD1 exhibited a junctional zone with increasing sensitivity that spans at least 873 µm, “which represents a potential treatment target.” He added that the results of the patient-tailored VF test for STGD1 in this study could be “proof-of-concept for use with common atrophic macular diseases such as geographic atrophy secondary to AMD.”
References
1 Pau M et al. JCI Insight 2022 Jan 25; 7(2)e155373.
2 Scholl H et al. The natural history of G1961E-associated Stargardt disease: Design and baseline characteristics of the FirstOrbit Study. NCT05674058, July 5, 2024.