Predicting the progression of proliferative diabetic retinopathy: Pathophysiology, imaging phenotypes, and determinants of disease persistence despite therapy.

Proliferative diabetic retinopathy (PDR) is a leading cause of severe vision loss in working-aged adults and represents the end stage of chronic neurovascular injury in diabetes. Despite advances in screening and treatment, including panretinal photocoagulation (PRP), intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents, and pars plana vitrectomy (PPV), outcomes remain heterogeneous: many eyes stabilise, whereas others progress to vitreous hemorrhage, tractional retinal detachment, or neovascular glaucoma despite apparently adequate therapy. This review synthesizes current knowledge on the pathophysiology, morphological phenotypes and treatment paradigms of PDR, with a specific focus on predictors of onset, progression, and recurrence. PDR is contextualised as a multifactorial neurovascular and inflammatory disease, integrating data on hypoxia-driven angiogenesis, glial activation, microvascular rarefaction, neurodegeneration, and vitreoretinal interface remodeling. Histopathological and multimodal imaging characteristics of neovascular complexes and the vitreoretinal interface are described, highlighting how phenotypes on color fundus photography, widefield fluorescein angiography, optical coherence tomography (OCT), and OCT angiography relate to ischemic burden and clinical behaviour. Systemic, ocular, imaging, biomarker, and genetic factors associated with progression from non-proliferative diabetic retinopathy to PDR and with progression within established PDR after PRP, anti-VEGF therapy, and PPV are critically appraised. Across modalities, younger age, diabetes duration, poor glycemic control, renal disease, extensive non-perfusion, high neovascular burden, complex fibrovascular proliferation, and incomplete or unsustained treatment consistently emerge as determinants of guarded outcomes. Outstanding gaps in mechanistic understanding, risk stratification, regenerative therapy, and implementation are identified, alongside a proposed research agenda aimed at delivering mechanistically grounded risk-prediction tools and disease-modifying interventions for PDR.