**Background:** Glaucoma is a multifactorial eye disease characterized by progressive degeneration of retinal ganglion cells (RGCs) and their axons, leading to irreversible vision loss. Worldwide prevalence is projected to increase by 74% between 2013 and 2040. While elevated intraocular pressure (IOP) remains a key risk factor and therapeutic target, other factors such as impaired mitochondrial activity, oxidative stress, glial activation, and excitotoxicity contribute to RGC damage. Understanding RGC structure and function is crucial for improving diagnosis and management.
**Methods:** This is a narrative review that synthesizes current knowledge on RGC anatomy, pathophysiology of glaucoma, imaging techniques, and therapeutic approaches. The review covers basic RGC subtypes (midget, parasol, small bistratified, ipRGCs) and their distinct visual functions. It discusses five major theories of RGC vulnerability: mechanical (IOP-induced strain on lamina cribrosa), vascular (impaired perfusion, autoregulation, neurovascular coupling), excitotoxicity (excessive glutamate/NMDA receptor activation), neurotrophic factor deprivation (reduced BDNF/TrkB signaling), and oxidative stress/inflammation (ROS, microglial activation, complement). Structural imaging modalities reviewed include optical coherence tomography (OCT), confocal scanning laser ophthalmoscopy (cSLO), and adaptive optics (AO). Functional assessments include pattern electroretinography (PERG), photopic negative response (PhNR), multifocal ERG, standard automated perimetry (SAP), short-wavelength automated perimetry (SWAP), frequency doubling technology (FDT), and detection of apoptosing retinal cells (DARC). Therapeutic strategies discussed include neuroprotective agents (brimonidine, memantine), calcium channel blockers (flunarizine, nilvadipine), antioxidants (CoQ10), neurotrophic factors (BDNF, CNTF, NGF, GDNF), gene therapy (targeting mSncg, complement C3, CaMKII, NMNAT, XIAP, BCLX_L), stem cell therapy, IOP management, and blood flow enhancement (ginkgo biloba extract).
**Key Results:** The review reports specific quantitative findings from cited studies: elevated IOP from 5 to 50 mmHg over 24 h caused 79 μm posterior deformation of central lamina in human donor eyes; acute IOP increase from 10 to 25 mmHg caused 12 μm displacement. Ocular perfusion pressure (OPP) below 30 mmHg reduced volume flow in prelaminar and anterior laminar capillary beds. In the Low-Pressure Glaucoma Treatment Study (LoGTS), brimonidine showed 9% visual field progression vs. 39% with timolol. PERG changes precede RNFL changes by approximately 8 years in glaucoma suspects. PERG identified glaucoma four years before visual field alterations with 75% sensitivity and 76% specificity. CoQ10 promoted 29% RGC survival in mouse oxidative stress models. GDNF microspheres increased RGC density 3.5-fold in a spontaneous glaucoma model at 15 months. Gene therapy targeting NMNAT2 restored NAD+ levels and provided neuroprotection in optic nerve crush models.
**Clinical Implications:** The review emphasizes that while IOP reduction remains the only clinically proven treatment, direct neuroprotective strategies targeting RGCs are under development. Advanced imaging enables earlier detection of structural and functional changes, potentially allowing intervention before irreversible vision loss. The heterogeneity of RGC subtypes and their differential vulnerability suggests that personalized treatment approaches may be necessary. Emerging therapies such as gene therapy and stem cell transplantation offer hope for not only slowing but potentially reversing glaucomatous damage, though significant challenges remain in delivery, safety, and functional integration. The integration of artificial intelligence and machine learning may further enhance early detection and treatment planning.