Tomographic Predictors of Foveal Versus Extrafoveal Atrophy Onset in Intermediate Age-Related Macular Degeneration: Clinical Implications and Biomarker Insights

Highlights

• Baseline tomographic lesions at the fovea, including soft drusen, subretinal drusenoid deposits, drusenoid pigment epithelial detachment (dPED), acquired vitelliform lesions (AVL), and incomplete retinal pigment epithelium and outer retinal atrophy (iRORA), differentially predict foveal-first versus extrafoveal-first onset of complete retinal pigment epithelial and outer retinal atrophy (cRORA) in intermediate AMD (iAMD).
• Subretinal drusenoid deposits (SDD) and soft drusen predominantly associate with extrafoveal-first atrophic onset, whereas AVL, iRORA, and dPED are more linked with foveal-first onset, suggesting distinct spatial progression patterns based on lesion subtype.
• Once extrafoveal cRORA has developed, the time interval to foveal involvement is similar across lesion types, underscoring a common atrophic progression phase irrespective of initial lesion characteristics.
• Presence of foveal hyperreflective foci (HRF) independently predicts a faster progression to foveal atrophy, indicating its utility as a potent biomarker for risk stratification and monitoring.

Background

Age-related macular degeneration (AMD) remains a leading cause of irreversible central vision loss worldwide, particularly affecting the elderly population. Intermediate AMD (iAMD) represents a critical disease stage characterized by large drusen and other subclinical changes predisposing to advanced atrophic or neovascular phenotypes. Complete retinal pigment epithelial and outer retinal atrophy (cRORA) denotes a late-stage atrophic lesion corresponding to clinically significant geographic atrophy (GA), contributing substantially to visual disability. Delineating early biomarkers predictive of the anatomical onset and spatial pattern of cRORA is vital for timely intervention and personalized care, especially with burgeoning dry AMD therapeutics targeting atrophic progression. Recent advances in spectral-domain optical coherence tomography (SD-OCT) enable detailed visualization of the retinal microstructure, identifying subtle tomographic lesions and hyperreflective foci (HRF) that precede atrophy development.

Key Content

Evidence from the Gagliardi et al. 2026 Retrospective Cohort Study

This landmark study evaluated 129 eyes of 89 iAMD patients progressing to cRORA, utilizing longitudinal SD-OCT back-tracking over a mean follow-up of 10.4 years. The study operationally defined the foveal region as the 1-mm central subfield per Early Treatment Diabetic Retinopathy Study (ETDRS) metrics and examined baseline foveal lesions including soft drusen, subretinal drusenoid deposits (SDD), drusenoid pigment epithelial detachment (dPED), acquired vitelliform lesions (AVL), and incomplete retinal pigment epithelial and outer retinal atrophy (iRORA). HRF presence was also documented.

Their principal findings showed that cRORA onset was evenly split between foveal-first (46.5%) and extrafoveal-first (53.5%) patterns. Statistically significant associations emerged: SDD and soft drusen corresponded with extrafoveal-first onset (91% and 63%, respectively), while AVL, iRORA, and dPED favored foveal-first onset (70%, 70%, and 59%, respectively). This suggests lesion-specific spatial propensities in atrophic evolution. Moreover, among eyes exhibiting extrafoveal-first onset, the median time to foveal involvement ranged similarly between 1.5-1.8 years irrespective of lesion type, indicating a convergent atrophic expansion once extrafoveal cRORA is established.

Critically, time to foveal cRORA was significantly shorter for eyes with baseline iRORA, dPED, and AVL compared to soft drusen (time ratios 0.12, 0.40, and 0.50 respectively), denoting a more aggressive atrophic trajectory. Foveal HRF independently predicted faster progression (time ratio 0.66), underscoring its role as a biomarker for accelerated atrophy.

Supporting Evidence from Complementary OCT Studies and Cohorts

Additional studies corroborate these findings by characterizing OCT-defined iAMD features such as pigmentary abnormalities, reticular pseudodrusen (RPD, synonymous with SDD), and HRF distribution and their spatial prevalence. The MACUSTAR study (2023) highlighted the topographic segregation of RPD preferentially in superior and temporal macular subfields, whereas HRF and large drusen frequently involve the foveal center, confirming lesion-specific spatial distribution relevant to atrophy onset patterns.

Retrospective work by Nassisi et al. (2021) on the natural history of iRORA demonstrated that iRORA lesions predominantly convert to cRORA within 24 months, with extrafoveal location and intraretinal HRF predicting rapid progression, paralleling the risk factors identified by Gagliardi et al.

Moreover, the study by Sun et al. (2013) described that vision loss correlated with foveal drusen accompanied by other foveal pathologies and overlying focal hyperreflectivity, reinforcing the clinical relevance of tomographic lesions seen on SD-OCT for functional prognosis.

Functional and Morphological Correlations

Quantitative OCT parameters such as subretinal pigment epithelium illumination (SRI) and focal electroretinogram (fERG) amplitude correlate with morphological abnormalities in RORA and visual acuity, as demonstrated by Midena et al. (2022). These measures may provide functional prognostic biomarkers that complement structural lesion assessment and improve personalized disease monitoring in iAMD.

Expert Commentary

The differentiation of tomographic lesion types at baseline in iAMD provides crucial insight into mechanisms underlying spatial patterns of atrophy onset. The preferential extrafoveal-first onset associated with SDD and soft drusen may reflect the known histopathological predilections of these lesions and their relationship to choroidal and retinal pigment epithelium dysfunction. Conversely, lesions like AVL, iRORA, and dPED that predict foveal-first atrophy suggest localized retinal pigment epithelial destabilization with more direct impact on the foveal center.

The independent predictive value of HRF for faster progression aligns with evidence implicating these hyperreflective elements as aggregates of activated retinal pigment epithelial cells, microglia, or macrophages involved in inflammatory and degenerative cascades. Their presence in the fovea, therefore, signals an active atrophic process.

From a clinical standpoint, these insights advocate for enhanced SD-OCT phenotyping in iAMD patients to stratify risk and tailor monitoring intervals. Lesion-specific prognostication can refine patient selection for emerging therapeutic agents aimed at slowing atrophic progression, such as complement pathway inhibitors or neuroprotective strategies.

Limitations include the retrospective design and potential referral bias inherent to tertiary center cohorts. Prospective validation in larger, diverse populations is warranted. Furthermore, integration with functional metrics and multimodal imaging could enhance predictive algorithms.

Conclusion

Current evidence establishes that distinct baseline foveal tomographic lesions in iAMD differentially associate with foveal-first versus extrafoveal-first cRORA onset. HRF presence further stratifies risk by predicting accelerated progression. These findings underscore the utility of detailed SD-OCT imaging for lesion-specific risk stratification, thereby informing clinical surveillance and guiding future therapeutic developments in dry AMD.

References

• Gagliardi OM, Sahoo NK, Hasan N, et al. Tomographic predictors of foveal versus extrafoveal atrophy onset in intermediate age-related macular degeneration. Am J Ophthalmol. 2026 Jul 11;S0002-9394(26)00378-8. doi: 10.1016/j.ajo.2026.07.010. PMID: 42435833.
• Schmitz-Valckenberg S, Fleckenstein M, Steinberg JS, et al. MACUSTAR Study Group. Characteristics and Spatial Distribution of Structural Features in Age-Related Macular Degeneration: A MACUSTAR Study Report. Ophthalmol Retina. 2023 May;7(5):420-430. doi:10.1016/j.oret.2022.12.007. PMID: 36563964.
• Nassisi M, Singh RP, Dolz-Marco R, et al. Natural history of incomplete retinal pigment epithelial and outer retinal atrophy in age-related macular degeneration. Can J Ophthalmol. 2021 Oct;56(5):325-334. doi:10.1016/j.jcjo.2021.01.005. PMID: 33539821.
• Midena E, Pilotto E, Blarzino MC, et al. Subretinal Pigment Epithelium Illumination Combined With Focal Electroretinogram and Visual Acuity for Early Diagnosis and Prognosis of Non-Exudative Age-Related Macular Degeneration: New Insights for Personalized Medicine. Transl Vis Sci Technol. 2022 Jan 3;11(1):35. doi:10.1167/tvst.11.1.35. PMID: 35077530.
• Sunness JS, Rubin GS, Applegate CA, et al. Spectral-domain optical coherence tomography characteristics of intermediate age-related macular degeneration. Ophthalmology. 2013 Jan;120(1):140-50. doi:10.1016/j.ophtha.2012.07.004. PMID: 22968145.