Choriocapillaris Dysfunction in Retinal Diseases: Multimodal Imaging Biomarkers, Pathophysiological Insights, and...

The choriocapillaris is the terminal capillary bed that sustains the retinal pigment epithelium (RPE) and the outer retina, and its integrity is inseparable from that of the RPE-Bruch's membrane complex it supplies. Histopathological work established decades ago that choriocapillaris density declines with age and falls further in disease, but for most of that period, the layer could not be assessed reliably in living eyes. Optical coherence tomography angiography (OCTA), particularly with swept-source instrumentation, signal compensation and validated thresholding, has changed this: choriocapillaris flow deficits can now be quantified reproducibly and followed over time. A flow deficit is, however, a signal-level measurement that does not by itself establish anatomical capillary loss, and this distinction is maintained throughout. This review examines what that capability has revealed. We first summarize choriocapillaris anatomy, its functional coupling to the RPE through polarized vascular endothelial growth factor secretion, and the mechanisms implicated in its failure, including complement-mediated endothelial injury, Bruch's membrane thickening, oxidative stress and venous overload. We then address the methodology in detail-slab definition, shadow compensation, binarization, averaging and the artefacts that inflate or mask flow deficits-because the comparability of published values depends almost entirely on these choices. The clinical sections review choriocapillaris involvement in age-related macular degeneration, where baseline flow impairment has been associated with subsequent drusen formation and with the rate of geographic atrophy enlargement, an association that is temporal rather than proven causal and that rests on a small number of cohorts; in the pachychoroid spectrum, where the layer is thought to be compressed rather than primarily diseased; and in diabetic retinopathy, myopia, inherited retinal dystrophies, inflammatory chorioretinopathies and systemic vascular disease. We conclude by considering structure-function relationships with outer retinal integrity and visual sensitivity, the relevance of choriocapillaris metrics as trial endpoints and stratification variables in the complement inhibitor era, and the standardization, validation and automation required before these biomarkers can be used in individual patients.