José‐Alain Sahel, Kate Grieve, Chloé Pagot, Colas Authié, Saddek Mohand‐Saïd, Michel Pâques, Isabelle Audo, Karine Thaís Becker, Anne-Elisabeth Chaumet-Riffaud, Line Azoulay, Emmanuel Gutman, Thierry Léveillard, Christina Zeitz, Serge Picaud, Deniz Dalkara, Katia Marazova
6 min
Inherited retinal dystrophies (IRDs) such as rod-cone dystrophy (RCD) cause progressive photoreceptor degeneration and significant vision loss. As new therapies like gene replacement, neuroprotection, and retinal prostheses emerge, clinicians need reliable methods to stage disease severity and measure real-life functional improvements. This study explores the integration of phenotype and genotype data, advanced in vivo imaging, and naturalistic functional vision assessments to better track disease progression and evaluate therapeutic outcomes.
To evaluate how structural retinal changes relate to functional vision loss, the researchers conducted cross-sectional and retrospective longitudinal studies in a large cohort of RCD patients. Standard evaluations included visual acuity (VA), macular sensitivity, static perimetry (visual field [VF]), fundus autofluorescence (FAF), and optical coherence tomography (OCT). The findings demonstrated that standard visual acuity and macular sensitivity were only weakly correlated with structural variables. However, functional impairment assessed via visual field tests strongly correlated with reductions in anatomical markers of photoreceptor structure and an increasing width of the hyper-autofluorescent ring. Furthermore, flood-illumination adaptive optics (FIAO) revealed complex phenotypic variations in photoreceptor alignment and orientation, emphasizing the influence of directional illumination on photoreceptor visibility.
Because traditional clinical charts often fail to capture the severe visual limitations of patients undergoing emerging treatments, the study utilized a specialized indoor platform called Streetlab. This controlled environment simulates urban settings with adjustable lighting and motion-capture technology. Mobility assessments under varying illumination levels showed that visual field measurements were primary predictors of mobility performance under high and low light, while contrast sensitivity best explained the number of collisions. In patients treated with gene therapy (Luxturna) for RPE65-related Leber congenital amaurosis, evaluations at Streetlab confirmed marked real-life benefits, including increased travel speeds and fewer collisions, especially under low-luminance conditions.
Integrating quantitative structural imaging with naturalistic functional assessments provides a comprehensive framework for patient-centered management of retinal dystrophies. These tools enable clinicians to select appropriate candidates for mutation-specific or mutation-independent therapies and objectively measure treatment efficacy in daily life conditions.
Purpose To describe the value of integrating phenotype/genotype data, disease staging, and evaluation of functional vision in patient-centered management of retinal dystrophies. Methods (1) Cross-sectional structure-function and retrospective longitudinal studies to assess the correlations between standard fundus autofluorescence (FAF), optical coherence tomography, visual acuity (VA), and perimetry (visual field [VF]) examinations to evaluate photoreceptor functional loss in a cohort of patients with rod-cone dystrophy (RCD); (2) flood-illumination adaptive optics (FIAO) imaging focusing on photoreceptor misalignment and orientation of outer segments; and (3) evaluation of the impact of visual impairment in daily life activities, based on functional (visual and mobility) vision assessment in a naturalistic environment in visually impaired subjects with RCD and subjects treated with Luxturna Ⓡ for RPE65 -related Leber congenital amaurosis before and after therapy. Results The results of the cross-sectional transversal study showed that (1) VA and macular sensitivity were weakly correlated with the structural variables; and (2) functional impairment (VF) was correlated with reduction of anatomical markers of photoreceptor structure and increased width of autofluorescent ring. The dimensions of the ring of increased FAF evolved faster. Other criteria that differed among groups were the lengths of the ellipsoid zone, the external limiting membrane, and the foveal thickness. FIAO revealed a variety of phenotypes: paradoxical visibility of foveal cones; heterogeneous brightness of cones; dim, inner segment–like, and RPE-like mosaic. Directional illumination by varying orientation of incident light (Stiles-Crawford effect) and the amount of side illumination (gaze-dependent imaging) affected photoreceptor visibility. Mobility assessment under different lighting conditions showed correlation with VF, VA, contrast sensitivity (CS), and dark adaptation, with different predictive values depending on mobility study paradigms and illumination level. At high illumination level (235 lux), VF was a predictor for all mobility performance models. Under low illumination (1 and 2 lux), VF was the most significant predictor of mobility performance variables, while CS best explained the number of collisions and segments. In subjects treated with Luxturna Ⓡ , a very favorable impact on travel speed and reduction in the number of collisions, especially at low luminance, was observable 6 months following injection, in both children and adults. Conclusions Our results suggest the benefit of development and implementation of quantitative and reproducible tools to evaluate the status of photoreceptors and the impact of both visual impairment and novel therapies in real-life conditions. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.
Sam: It's a subtle but important point. Cone cells—the ones responsible for color and detail—are most efficient when light enters them straight on, through the center of the pupil. If a cone tilts even slightly out of alignment, it becomes far less sensitive. So imaging that captures orientation, not just whether a cell is present, gives a much more accurate picture of how well that part of the retina is actually functioning.
Alex: And then there's the mobility testing side of things.
Sam: Yes, and this is where the paper becomes particularly interesting. The researchers use a platform called StreetLab—essentially a controlled indoor environment designed to mimic real navigating challenges. Patients walk through it under different lighting conditions while sensors track their path, their speed, and how close they come to obstacles. Performance on this kind of test correlates far better with how patients actually function in daily life than any letter chart does.
Alex: What did they find when they put those two approaches together?
Sam: The clearest finding is that dark adaptation and the size of a patient's visual field are much stronger predictors of real-world navigation ability than standard visual acuity. In other words, how well someone adapts to dim light, and how wide their usable field of view is, tells you far more about their daily struggles than how sharply they can read a letter on a wall.
Alex: Did they test this in patients who had received treatment?
Sam: They did. In patients treated with gene therapy for a specific inherited condition called Leber congenital amaurosis—a severe form that can cause near-total blindness from birth—the results were notable. Before treatment, some patients had a usable visual field so narrow it was like looking at the world through a cardboard tube. After treatment, that field expanded substantially, allowing patients to navigate in near-total darkness with far fewer near-collisions. The mobility test captured that change clearly; a standard eye chart largely would not have.
Alex: That's a meaningful difference in how we'd understand whether a treatment is actually working.
Sam: Exactly. And that's the broader argument the paper is making. When you're evaluating whether a gene therapy, a retinal prosthetic, or any other intervention is genuinely improving someone's life, you need metrics that reflect daily life. Walking down a dimly lit street without bumping into things is a far more relevant measure than reading the bottom line of a chart in a brightly lit clinic.
Alex: Though the paper is careful about its limitations here?
Sam: It is. The gene therapy case studies involve small groups of patients and relatively short follow-up periods, so we can't draw sweeping conclusions yet. There's also a real methodological concern: if a patient takes the same mobility test multiple times, they may simply get better at the test course itself—learning where the obstacles are—rather than showing genuine therapeutic improvement. Separating real recovery from learned familiarity is an ongoing challenge.
Alex: And individual variation plays a role too.
Sam: Significantly. People develop different coping strategies over time. Age, psychological adaptation, prior experience with low vision—all of these introduce variability that's hard to control for. The paper calls for future work that incorporates patient-reported feedback alongside the objective measurements, and that tests across a wider range of lighting conditions to better isolate true treatment effects.
Alex: So the takeaway is really about building a more complete picture.
Sam: That's it. No single test tells the whole story. The retina is a complex, layered structure, and the way its failure affects a person's life is equally complex. Combining microscopic imaging of individual cells with real-world mobility assessments gives clinicians and researchers a far more honest account of where a patient is and whether a treatment is genuinely helping. That's the framework this paper is advocating for.
Alex: A more honest account—that seems like the right goal for any medical measurement. Thanks for listening to ResearchPod.