Using adaptive optics to assess hyporeflective clump speed and size in age-related macular degeneration in the PINNACLE Study. (PINNACLE Study Report 6)

Abstract

Background/objectives: Hyporeflective clumps (HRC) are a common finding in adaptive optics ophthalmoscopy (AOO) of age-related macular degeneration (AMD). They appear on optical coherence tomography (OCT) as hyperreflective foci (HRF) or abutting the retinal pigment epithelium (RPE) layer as RPE thickening. The cellular origin of HRF is debated between migrated RPE cells and mononuclear phagocytes (MP). Microglial cells are MP known to migrate at 0.02 µm/s, but RPE migration speed is unknown. Phenotyping HRCs by migration speed and size may improve our understanding of HRFs.

Methods: Patients with non-neovascular AMD were imaged with the RTX1 retinal camera (Imagine Eyes, Orsey, France). Pairs of AOO images taken 1-3 h apart were centred on areas with multiple HRCs and compared to identify mobile HRCs. Macular OCT scans were performed immediately after initial AOO.

Results: A total of 21 pairs of images from 14 eyes of 12 patients were of adequate quality to assess HRCs. There were 411 measurable HRCs, with a mean diameter of 15.9 ± 6.0 µm. The HRCs were larger in images of atrophy (p < 0.001). Within the timeframe assessed, most HRCs remained static, but mobile HRCs were not uncommon and migrated up to 0.015 µm/s. HRFs on OCT corresponding to mobile HRCs on AOO appeared adjacent to the RPE or in the interdigitation zone.

Conclusion: AOO can detect HRC movement in AMD in images captured a mean of 105.5 min apart. HRC size and movement speed are consistent with microglial cells, but may also represent RPE cells. HRCs appear larger in images of atrophy.

Fig. 1. Selection of hyporeflective clump (HRC) containing lesions, and comparison with optical coherence tomography (OCT) B scans to identify corresponding hyperreflective foci (HRF).

Near infra-red scanning laser ophthalmoscopy image a of a patient with late non-neovascular age-related macular degeneration, displaying the area assessed with 5 overlapping adaptive optics ophthalmoscopy (AOO) images. AOO images b were assessed to identify HRC containing lesions where the HRC margins were clear and well defined (e.g., empty white triangle). Further AOO images centred on the area of interest (white square, c) were captured (d). After a mobile HRC was identified (white arrow), the closest B scan slice (white line, c), was reviewed with inverted colours (e) and magnified f to identify the corresponding HRF. Also visible in d are multiple small (2.3–10 µm diameter), medium (10–25 µm diameter), and large (>25 µm diameter) HRCs.

Fig. 2. Descriptive plots of hyporeflective clump size distribution.

The histogram/density plot a of HRC size shows a normal distribution. Grouping HRC size by type of lesion imaged b showed significantly larger HRCs over complete retinal pigment epithelium and outer retina atrophy (cRORA) compared to drusen (p < 0.001), and similarly, grouping HRC size by whether the cone mosaic was mostly intact c, showed that a mostly intact cone mosaic on the AOO image was associated with smaller HRCs (p < 0.001). The ○ represents mean, the □ median, and the bars the 95% confidence interval.

Fig. 3. Adaptive optics ophthalmoscopy image series showing hyporeflective clump (HRC) migration within complete retinal pigment epithelium and outer retina atrophy (cRORA).

AOO images focused at the level of the photoreceptors on the temporal edge of a cRORA lesion at baseline (a) and 136 min later (b). The cRORA appears as a relatively hyper-reflective area in the lower left half of both images without a visible cone mosaic. The transitional zone appears relatively hypo-reflective, possibly due to HRCs viewed through a partially visible cone mosaic. Marked with full white triangles are the origin and destination of the same HRC in both images, conspicuous by their absence in the matched image (empty triangles). Mobile HRCs are much more apparent in video format, as shown in supplementary video 1. Image c) shows the near infra-red scanning laser ophthalmoscopy image taken shortly after the baseline AOO, with the white square denoting the area captured in the AOO images. The white line shows the section captured in the optical coherence tomography (OCT) B scan (d). On the OCT B scan, HRFs can be seen just above the RPE within the cRORA, as well as in the EZ, Henle’s fibre layer, and the outer nuclear layer in the transitional zone. Multiple HRFs are visible elsewhere in the OCT B scan in various retinal layers.