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.

Fig 1. Hyperreflective retinal foci (HRF) and retinal segmentation.

Hyperreflective retinal foci (HRF) at the OCT linear scan identified in the full retina, from the boundary between nerve fiber layer and ganglion cell layer (RNFL/GCL) to the external limiting membrane (ELM); in Inner Retina (IR), all layers between the boundary between RNFL/GCL and the lower limit of the outer plexiform layer; and in Outer Retina (OR), between the upper limit of the outer nuclear layer and the ELM.

Fig 2. Example of hyperreflective retinal foci (HRF).

Hyperreflective retinal foci (HRF) at the OCT linear scan in one VHL eye (A) and in one healthy control (B). HRF are more numerous in VHL eye than in control, mainly in the Inner Retina.