Histopathologic Findings and Knowledge Gaps in Glaucomatous Neurodegeneration

Glaucoma is the leading cause of irreversible blindness globally, characterized by progressive retinal ganglion cell (RGC) dysfunction and death, resulting in optic nerve head remodeling and optic nerve degeneration. Although substantial progress has been made in understanding basic mechanisms of glaucomatous neurodegeneration in animal models, significant knowledge gaps remain regarding the histopathologic substrate of this disease in human tissue. This review synthesizes current understanding of established histopathologic findings in glaucomatous eyes, including RGC degeneration, synaptic pathology, axonal transport dysfunction, lamina cribrosa remodeling, glial cell responses, extracellular matrix changes, and structure-function relationships. It ends by identifying major gaps in knowledge regarding cellular heterogeneity in RGC vulnerability, circuit-level retinal remodeling, temporal sequence of pathologic events, functional consequences of astrocyte and microglial activation, and mechanisms linking structural pathology to functional vision loss. Addressing these gaps requires integrated approaches combining classical histology with modern molecular profiling, greater access to human postmortem tissue with rigorous disease staging, and systematic investigation of RGC subtype-specific pathology in the human retina and optic nerve.