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Interpreting Hyperreflective Foci in Age-Related Macular Degeneration: A Critical Review of Cell Origins, Evolving
Thomas Desmond1, Hemal Mehta1,2, Weng Sehu1
1Save Sight Institute, The University of Sydney, Sydney, New South Wales, Australia.
Background:
Hyperreflective foci identified on optical coherence tomography are promising biomarkers in age-related macular degeneration. However, their clinical application is limited by inconsistent definitions and ongoing uncertainty regarding their cellular origin. This review critically evaluates the evidence underlying hyperreflective foci definitions, examines competing hypotheses of cellular origin, and assesses their clinical utility.
Methods:
A structured critical review was conducted using a systematic search of MEDLINE and Scopus in July 2025, identifying 164 publications reporting hyperreflective foci in age-related macular degeneration. Eligible studies included clinical imaging, clinicopathological, and histological investigations. Given substantial heterogeneity in study design and outcome measures, findings were synthesised interpretively across three domains: imaging definitions, cellular origin, and clinical associations.
Results:
Clinical OCT definitions for hyperreflective foci were heterogeneous across studies. Histologically, hyperreflective foci correspond to pigment-laden epithelioid cells that consistently express monocyte/macrophage markers (CD68, CD163, IBA1) and lack retinal pigment epithelium markers (RPE65, peropsin). These cells are interpreted as pigment-containing macrophages that have ingested RPE-derived material, or as transdifferentiated RPE cells. Clinically, increasing hyperreflective foci burden is associated with disease severity, progression to geographic atrophy, and localised functional deficits, although associations with neovascular conversion and treatment response are inconsistent.
Conclusions:
The available evidence suggests hyperreflective foci are pigment-containing immune cells, although altered or displaced retinal pigment epithelium cells may also be involved, and independent replication is required. Interpreting hyperreflective foci within this biological context may refine their role in disease monitoring and risk stratification. Establishing consensus imaging criteria, grounded in cellular identity, will be important for clinical translation.
