Topographic associations of hyperreflective materials in diabetic retinopathy: a multimodal correlation with microvascular pathology, structural remodeling and systemic metabolic dysregulation

Abstract

Background: Hyperreflective materials (HRMs), enigmatic biomarkers observed in diabetic retinopathy (DR), exhibit poorly characterized pathophysiological origins and clinical implications.

Methods: This retrospective cross-sectional study investigates the spatial distribution patterns of HRMs subtypes and their integrative relationships with retinal microvascular architecture, structural remodeling, and systemic metabolic parameters in 205 DR eyes. HRMs were systematically classified via multimodal optical coherence tomography angiography (OCTA) analysis, incorporating topographic localization (inner vs. outer retinal), reflectivity profiles, morphometric dimensions, posterior shadowing artifacts, and decorrelation signal. Quantitative correlations were established between HRMs subtypes and OCTA-derived vascular parameters (intraretinal microvascular abnormalities [IRMA], non-perfusion [NP] areas, microaneurysms), diabetic macular edema (DME) status, and systemic metabolic indices (glycemic control, lipid profiles, renal function, inflammatory markers).

Results: Six distinct HRMs phenotypes were identified: inner retinal hyperreflective spots (IRHFs), outer retinal hyperreflective spots (ORHFs), intraretinal hard exudates (IRHE), outer retinal hard exudates (ORHE), decorrelation-positive HRMs, and cotton-wool spots. Spatial mapping revealed predominant HRMs colocalization with IRMA territories (75.4% IRHFs, 89.5% ORHFs, 90.8% IRHE, 94% ORHE), while 19% of IRHFs and 8.7% of ORHFs overlapped NP zones. Decorrelation-positive HRMs demonstrated dual associations with IRMA (77.6%) and microaneurysms (21.0%). DME eyes exhibited significantly elevated HRMs density within IRMA and NP regions (P < 0.001). Multivariate analysis identified dyslipidemia as a strong predictor of HRMs burden.

Conclusions: These findings establish HRMs as spatially resolved biomarkers of diabetic retinal pathophysiology, reflecting compartment specific interactions between microvascular incompetence (IRMA-associated barrier failure), ischemic remodeling (NP zones), and systemic metabolic dysregulation. The colocalization of HRMs subtypes with IRMA walls and leakage-prone microaneurysms supports their putative role as optical signatures of lipoprotein extravasation and inflammatory lipidotoxicity in DR progression.

Keywords: diabetic macular edema; diabetic retinopathy; hyperreflective materials; lipid metabolism; optical coherence tomography angiography.

Figure 1

Category of hyperreflective materials based on characters including location, reflectivity, size and presence or absence of back shadowing, decorrelation signal on B-scan and structural en face images (6 × 6 mm scanning area) using OCTA. The scanning position of each image is identified by horizontal (lake blue) or vertical navigation (purple) line. IR is defined as layers between the inner limiting membrane and the OPL; OR is defined as the Henle NFL and outer nuclear layer. (A) Inner retinal hyperreflective spots (IRHFs) and outer retinal hyperreflective spots (ORHFs), invisible on structural en-face images, are observed on B-scan OCTA images characterized by size small than 30 μm, reflectivity similar to NFL, not forming any back shadowing and without decorrelation signal. Green arrows indicating IRHFs and white arrows indicating ORHFs. (B) Inner retinal hard exudates (IRHE, yellow arrows) are characterized by dimension >30 mm, reflectivity similar to RPE with back shadowing, obviously seen on en face images (yellow circle). (C) Outer retinal hard exudates (ORHE, yellow arrows) located in the outer retina, share the similar character as IRHE but invisible on superficial en face images. (D) Decorrelation-positive HRMs (blue arrows) are visible on B-scan OCTA images with apparent flow signal (in red), dimension >30 mm, reflectivity similar to NFL with back shadowing. Detailed structure can be seen on OCT B scan. (E) Cotton-wool spots, marked with red circles on en face and red arrows on B scan OCTA images, are located on NFL with large size, medium reflectivity and no back shadowing.

Figure 2

Association of hyperreflective materials distribution with vascular abnormalities including no perfusion area, neovascular membrane and microneurysm. (A–C) No perfusion is observed on superficial vascular plexuses en face OCTA images (A), where cotton-wool spots (B, red circles; C, red arrows), hard exudates (B, yellow arrows), IRHFs (C, green arrows) and ORHFs (C, white arrows) are visible. (D–F) IRHFs (F, green arrows) and decorrelation-positive hyperreflective materials (F, blue arrows) are distributed in the neovascular area detected by superficial vascular plexuses en face OCTA images (D). (G–I) IRHFs (I, green arrows) and decorrelation-positive hyperreflective materials (I, blue arrows) were located in the area of microneurysm (G, blue rectangle).

Figure 3

Distribution of hyperreflective materials in the area of intra-retinal microvascular abnormalities (IRMA) detected by OCTA. The scanning position of each image is identified by horizontal (lake blue) or vertical navigation (purple) line. (A1–A3) OCTA images from a DME patients show the association of inner retinal hyperreflective spots (IRHFs) and decorrelation-positive hyperreflective materials distribution with the IRMA. Red rectangle showing IRMA in superficial vascular plexuses en face OCTA images (A1), IRHFs (A3, green arrows) and decorrelation-positive hyperreflective materials (A3, blue arrows) are visible in the corresponding area of OCTA B-scan and invisible in the superficial OCT en face image (A2). (B1–B3) Example of outer retinal hyperreflective spots (ORHFs) distributing in the area of IRMA. IRMA is showed in deep vascular plexuses en face OCTA images (B1, black arrow heads), ORHFs (B3, white arrows) are detected on B scan images and invisible in the deep OCT en face image (B2). (C1–C3) OCTA images of a DR patient with inner retinal hard exudates (IRHE) demonstrate IRHE are mostly located on IRMA. IRHE are visible on superficial OCT en face (C2, yellow circle) and B scan images (C3, yellow arrows), where IRMA are apparently detected by superficial vascular plexuses en face OCTA images (C1, red rectangle). (D1–D3) OCTA images of a DR patient with outer retinal hard exudates (ORHE). ORHE are observed on deep structural en face (invisible on superficial, D2, yellow circle) and B scan images (D3, yellow arrows), where IRMA also are detected by deep vascular plexuses en face OCTA images (D1, black arrow heads).