Immunopathogenesis of MEWDS and the white dot syndromes: anatomical specificity and mechanistic heterogeneity

The white dot syndromes (WDS) are an umbrella term for a heterogeneous group of idiopathic inflammatory chorioretinopathies—including multiple evanescent white dot syndrome (MEWDS), acute posterior multifocal placoid pigment epitheliopathy (APMPPE), birdshot chorioretinopathy, multifocal choroiditis (MFC), and punctate inner choroidopathy (PIC). MEWDS is the subtype in which the debate over the primary anatomical site of disease initiation has been most intense: three competing hypotheses—choriocapillaritis, photoreceptoritis, and retinal pigment epithelium (RPE) dysfunction—remain unresolved. MEWDS has also accumulated substantial evidence for viral triggers, including SARS-CoV-2 infection and COVID-19 vaccination, whereas other WDS subtypes exhibit distinct mechanistic signatures (HLA-A29 in birdshot, choriocapillaris ischemia in APMPPE, Bruch's membrane disruption in MFC/PIC). This narrative review synthesizes the three MEWDS-specific hypotheses against multimodal imaging, genetic, and immunological evidence published through 2026, and contrasts them with disease-specific mechanisms across the WDS spectrum. Indocyanine green angiography (ICGA) findings support primary choriocapillaritis, whereas optical coherence tomography angiography (OCT-A) has yielded paradoxically preserved flow maps; RPE dysfunction remains plausible given fundus autofluorescence patterns and the RPE's immunoregulatory role. The Multimodal Imaging in Uveitis (MUV) Task Force Report 11 (2026) proposes an anatomical reclassification that assigns MEWDS to the photoreceptor/RPE group. Across WDS, the evidence supports mechanistically distinct diseases and motivates disease-specific, mechanism-driven nomenclature.