Hyper-reflective retinal foci as possible in vivo imaging biomarker of microglia activation in von Hippel-Lindau disease

Abstract

Purpose von Hippel-Lindau (VHL) disease is caused by a mutation of the VHL gene and characterized by the development of retinal hemangioblastomas (RH). Current pathophysiologic mechanisms of RH development and progression are still insufficient to predict RH behavior. VHL gene is involved in the cellular response to hypoxia and in many intracellular signaling pathways expressed both in angiogenesis and inflammation. Optical coherence tomography (OCT) allows to identify hyper-reflective retinal foci (HRF) known as aggregates of activated microglial cells as possible in vivo biomarker of local inflammation. The aim of the present study was to investigate the presence of HRF in patients with genetically confirmed VHL disease. Methods In this cross-sectional study, patients with VHL underwent complete ophthalmological examination and OCT with HRA + OCT Spectralis. HRF were manually identified and calculated in inner (IR), outer (OR) and full retina. Age-matched healthy subjects were enrolled as controls. Results 113 eyes of 63 VHL patients and 56 eyes of 28 healthy subjects were evaluated. HRF number was significantly higher in VHL than in controls in IR (28.06 ± 7.50 vs 25.25 ± 6.64, p = 0.042). No difference was observed in OR and in full retina (OR: 7.73 ± 2.59 vs 7.95 ± 2.51, p = 0.599; full retina: 35.79 ± 8.77 vs 33.20 ± 7.47, p = 0.093). Conclusion The increase of HRF, which mirror retinal microglial activation, characterizes VHL eyes. The role of activated microglia in the retina of VHL eyes needs to be better investigated, mainly considering local VHL disease manifestations.

Photoreceptor loss does not recruit neutrophils despite strong microglial activation

“…A standing question in OCT/confocal AOSLO interpretation is whether microglia contribute or directly produce the hyperreflective phenotype seen in axial B-scans and en-face fundus images 52,53 . With confocal AOSLO, we find that the hyperreflective phenotype is visible as early as 30 minutes and becomes slightly larger and brighter by 90 minutes.…”

New Prospects on Neuroimaging in Von Hippel Lindau Disease—A Narrative Review

“…Another publication on the application of OCT, suggests the potential role of hyper-reflective retinal foci as a possible biomarker for microglial activation due to VHL. In this study, the authors explore the potential pathogenesis for the development of retinal hemangioblastomas through inflammatory processes [18].…”

Hyper‐reflective dots in optical coherence tomography imaging and inflammation markers in diabetic retinopathy

“…Here we provide evidence of the co‐relation between microglia and single dot HRF, reinforced by previous studies in other models (Miller et al, 2019). Clinical reports have proposed that these small dot HRF represent aggregated microglial cells, and small HRF are used in many clinical studies as an in vivo biomarker of local inflammation (Pilotto et al, 2020, 2022; Turgut & Yildirim, 2015; Vujosevic et al, 2013, 2017, 2023).…”