From ocular hypertension to ganglion cell death: a theoretical sequence of events leading to glaucoma

There is substantial evidence that elevated intraocular pressure (IOP) is a critical risk factor for glaucoma. Even with exhaustive investigation, however, there is still little understanding of the pathologic events that translate increased IOP into the process of retinal ganglion cell death. New studies, particularly in rat and mouse models of glaucoma, have helped elucidate some of the important events associated with the initiation of glaucoma. This review summarizes a 5-stage series hypothesizing that elevated IOP causes deleterious changes to glia in the optic nerve head (stage 1), which activate the autonomous self-destruction of ganglion cell axons (stage 2), leading to the loss of neurotrophic support and apoptotic death of ganglion cell somas in the retina (stage 3). In the initial wave of ganglion cell death, dying cells may, adversely affect their neighbouring cells in a wave of secondary degeneration involving glutamate exposure (stage 4). As ganglion cell structures disappear through the processes of cell death, glia are again involved, but this time to replace the lost neural tissue with a glial scar (stage 5).