Introduction

A long-standing hypothesis in age-related macular degeneration (AMD) is that accumulated Bruch’s membrane debris originated as photoreceptor outer segment membranes that were phagocytosed and processed by the retinal pigment epithelium (RPE) [1]. New concepts based on direct assay of human tissues and experimental studies suggest a dual origin of Bruch’s membrane lipid constituents, with the fatty acids largely derived from diet [2]. Using serial retinal imaging over a 7-year follow-up, we report an unusual case of progressive soft drusen accumulation and remodelling occurring without overlying photoreceptors within a chronic full-thickness macular hole. We discuss the potential implications for the current understanding of lipids contributing to Bruch’s membrane lipoprotein deposition.

Case description

A woman in her 80s was followed in our institution for exudative neovascular AMD in her right eye (OD) and a large, chronic, full-thickness macular hole in her left eye (OS) after an unsuccessful vitrectomy. Past medical history was relevant for hypertension. Best-corrected visual acuity was 20/100 OD and counting fingers OS. The anterior segments were unremarkable except for bilateral pseudophakia. Serial colour fundus photographs over 7 years documented progressive soft drusen accumulation within the full-thickness macular hole OS (Fig. 1). Serial tracked optical coherence tomography demonstrated drusen growth and coalescence within the hole where photoreceptors were absent (Fig. 2).

Fig. 1: Fundus photographs of the full-thickness macular hole OS.
figure 1

A Colour photograph performed at baseline showing a full-thickness macular hole with minimal drusen accumulation within the macular hole area. B Confocal colour photograph performed 7 years later showing marked increase in drusen deposition within the macular hole area.

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Fig. 2: Longitudinal tracked optical coherence tomography (OCT) B-scans of a full-thickness macular hole OS.
figure 2

A Macular OCT B-scan performed at baseline showing discrete sub-retinal pigment epithelium (RPE) deposits (red arrowhead) within the macular hole area. The green line in the near-infrared reflectance image indicates the position of the OCT B-scan. Follow-up tracked macular OCT scans performed 3 years later (B) and 7 years later (C) show progressive drusen growth and coalescence into larger sub-RPE deposits (red arrowheads) within the macular hole area. The green lines in the near-infrared reflectance image indicate the position of the OCT B-scans.

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Discussion

In aging and AMD, Bruch’s membrane undergoes cross-linking, thickening, calcification and lipidization [2]. Soft drusen and basal linear deposits (BLinD) on histology are primarily composed of apolipoproteins B and E-containing lipoproteins secreted by the RPE in a physiologic lipid-recycling system [2]. Evidence that plasma lipoproteins are the major fatty acid sources to Bruch’s membrane lipids derived from high-performance liquid chromatography assays showing that all lipid classes in Bruch’s membrane are largely dominated by the fatty acid linoleate (implicating dietary sources) with little docosahexaenoate (implicating outer segment membranes) [3]. Therefore, soft drusen and BLinD have been conceptualized as sharing mechanisms with an atherosclerotic progression, which also initiates with lipoproteins, of hepatic and intestinal origin [2].

Our case provided a rare opportunity to observe in vivo clinical findings directly supporting these experimental findings. We show that soft drusen may accumulate in the sub-RPE space even in the absence of overlying photoreceptors. This gives credence to the concept that lipid-recycling pathways of RPE-secreted lipoproteins are predominantly driven by diet [2]. This also supports experimental studies showing sub-RPE deposition of drusen components without exposure to photoreceptor outer segments by highly differentiated and well-polarized RPE cells in culture [4, 5].

Xanthophyll carotenoid pigments, of dietary origin, are concentrated in the fovea, as are soft drusen [2]. The RPE expresses receptors to take up plasma high-density and low-density lipoproteins carrying these pigments for transfer to the retina [2]. Our proposed model suggests that the RPE re-packages and releases the unneeded lipids in its own linoleate-rich lipoproteins to the circulation [2]. These may accumulate as the choriocapillaris fails [2].

In summary, using serial imaging over a long-term follow-up, we demonstrated continuous sub-RPE deposit accumulation in the absence of photoreceptors, which further suggests that diet rather than outer segment phagocytosis is the principal driver of RPE lipoprotein secretion into Bruch’s membrane.