Chapter 1 - Glaucoma pathology

Abstract

Glaucomatous pathology is marked by characteristic degeneration of the optic nerve and loss of retinal ganglion cells (RGCs). Degeneration is first initiated in ganglion cell axons in the optic nerve head and is associated with an increase in strain placed on the optic nerve head tissues by ocular hypertension. The steps that transition increased strain to axonal degeneration are not fully understood. Here we provide a unifying hypothesis that takes into account many of the clinical and research observations made on this tissue. The hypothesis predicts that ocular hypertension that creates an increase in strain that exceeds normal physiological parameters leads to changes in tissue architecture and material properties that cause both compression and behavioral changes in supporting glial cells. This creates a metabolic challenge for RGC axons to support transport mechanisms through a region of already high metabolic demand due to the translaminar pressure gradient. As a result, the axons reach an energy demand crisis that shuts down axonal transport leading to distal axon degeneration and the suppression of retrograde flow of neurotrophic support to the ganglion cell somas. The result is activation of the intrinsic apoptotic program leading to their death. Various factors, such as blood flow, metabolic deficiency, and neuroinflammation, are considered potential modifiers of susceptibility and rate of degeneration in this model.