Noninfectious Posterior Uveitides — Atypicals, Variants, and Masquerades: The Jungle of Differential Diagnosis

Purpose: Consensus efforts by the Multimodal Imaging in Uveitis (MUV) Task Force have established standardized diagnostic criteria for the major non-infectious posterior and panuveitides (NIPUs), historically referred to as “white dot syndromes”. Nevertheless, a substantial proportion of cases deviate from classical presentations and fall into diagnostic “grey zones”, blurring boundaries between diseases entities and complicating both differential diagnosis and management. This paper aims to describe the broad spectrum of atypical, variant, and secondary forms of NIPUs as well as masquerade syndromes. Methods: Perspective article with narrative review and illustrative cases. Results: Atypical multiple evanescent white dot syndrome (MEWDS) includes bilateral presentations or complicated courses, while multifocal choroiditis and panuveitis/punctate inner choroiditis (MFCPU/PIC) with outer retinal atrophy emerges as a notable entity with unclear therapeutic implications. Inflammatory reactions resembling both MEWDS and MFCPU/PIC may also occur as secondary phenomena, triggered by other chorioretinal disorders, most notably inherited retinal diseases (IRDs). Placoid chorioretinopathies, including acute posterior multifocal placoid pigment epitheliopathy, persistent placoid maculopathy, serpiginous choroiditis, and relentless placoid chorioretinitis, are often distinguished only a posteriori based on disease course, but likely represent a continuum of disorders unified by choroidal ischemia. Atypical presentations of birdshot chorioretinopathy may feature extensive outer retinal damage, mimicking IRDs. Equally important is the consideration of masquerade syndromes in all suspected cases of NIPUs, as they can present with similar features yet require entirely different treatments. Infectious masquerades include tuberculosis-associated serpiginous-like choroiditis, acute syphilitic posterior placoid chorioretinopathy, and West Nile virus chorioretinitis, whereas vitreoretinal lymphoma is the most frequent neoplastic masquerade. Conclusions: Integrating clinical context with high-quality multimodal imaging remains essential to navigate the jungle of differential diagnosis in NIPUs. Future studies should aim to integrate imaging phenotypes with immunologic and molecular biomarkers to refine disease classification and support more targeted therapeutic strategies.