The Impact of Inflammatory Hyperreflective Spots and Hard Exudates on Retinal Function in Diabetic Retinal Disease

Purpose: To characterize the topography of hyperreflective spots (HRSs) and hard exudates (HEs) and to analyze their association with localized retinal sensitivity in diabetic retinal disease (DRD). Methods: In this prospective cross-sectional study, diabetic patients (type I/II) underwent increased axial resolution optical coherence tomography (OCT) and mesopic microperimetry. HRSs (<30 µm, without back shadowing) and HEs (>30 µm, with back shadowing) were annotated in OCT scans and spatially matched to microperimetry test points across Early Treatment Diabetic Retinopathy Study (ETDRS) subfields. Eyes with confounding OCT biomarkers (disorganization of the retinal inner layers, ellipsoid zone/external limiting membrane disruption, vitreomacular traction) were excluded. Linear mixed-effects models were used to evaluate the associations between lesion types and localized retinal sensitivity. Results: Fifty-one eyes of 51 patients were included (mean age, 55.9 ± 14.8 years; diabetic retinopathy severity scale, 3.3 ± 1.6; hemoglobin A1c, 7.6% ± 2.0%). HRSs (n = 2308) were present in all study eyes, while HEs (n = 1222) were present in 21 eyes. Normalized to ETDRS subfield area, both HRSs (229.2 /mm2) and HEs (82.8 /mm2) showed the highest densities in the central subfield. Higher HRS load was independently associated with reduced retinal sensitivity (β = -0.06, P = 0.011), whereas no significant association was observed for HEs (P = 0.461); this finding should be interpreted with caution given the limited number of eyes with HEs. Conclusions: HRSs and HEs demonstrate distinct spatial distributions and functional associations in DRD, with HRSs independently linked to localized sensitivity loss. Translational Relevance: HRSs may serve as an accessible biomarker of early neuroretinal impairment and could improve patient stratification and treatment evaluation in clinical trials.