The connective tissue phenotype of glaucomatous cupping in the monkey eye - Clinical and research implications

Abstract

In a series of previous publications we have proposed a framework for conceptualizing the optic nerve head (ONH) as a biomechanical structure. That framework proposes important roles for intraocular pressure (IOP), IOP-related stress and strain, cerebrospinal fluid pressure (CSFp), systemic and ocular determinants of blood flow, inflammation, auto-immunity, genetics, and other non-IOP related risk factors in the physiology of ONH aging and the pathophysiology of glaucomatous damage to the ONH. The present report summarizes 20 years of technique development and study results pertinent to the characterization of ONH connective tissue deformation and remodeling in the unilateral monkey experimental glaucoma (EG) model. In it we propose that the defining pathophysiology of a glaucomatous optic neuropathy involves deformation, remodeling, and mechanical failure of the ONH connective tissues. We view this as an active process, driven by astrocyte, microglial, fibroblast and oligodendrocyte mechanobiology. These cells, and the connective tissue phenomena they propagate, have primary and secondary effects on retinal ganglion cell (RGC) axon and laminar beam and retrolaminar capillary homeostasis that may initially be “protective” but eventually lead to RGC axonal injury, repair and/or cell death. The primary goal of this report is to summarize our 3D histomorphometric and optical coherence tomography (OCT)-based evidence for the early onset and progression of ONH connective tissue deformation and remodeling in monkey EG. A second goal is to explain the importance of including ONH connective tissue processes in characterizing the phenotype of a glaucomatous optic neuropathy in all species. A third goal is to summarize our current efforts to move from ONH morphology to the cell biology of connective tissue remodeling and axonal insult early in the disease. A final goal is to facilitate the translation of our findings and ideas into neuroprotective interventions that target these ONH phenomena for therapeutic effect.

Optic nerve head cupping in glaucomatous and non-glaucomatous optic neuropathy

“…Yang et al 16 proposed a framework for the pathophysiology of glaucomatous ONH damage. They proposed that optic nerve ‘cupping’ in a monkey study has two main components common to all optic neuropathies: prelaminar thinning and laminar deformation.…”

“…The second component of ‘cupping’ is laminar deformation or laminar cupping, which results from permanent, IOP-induced deformation of the LC and peripapillary scleral connective tissues following ONH connective tissue damage and deformation 16. Burgoyne19 showed that the laminar component of cupping predominates in glaucomatous optic neuropathy and is characterised by progressive posterior displacement of the surface of the ONH.…”

Protruded retinal layers within the optic nerve head neuroretinal rim

“…However, it is important to recognize that also glaucoma affects non‐neural tissues also (Yang et al. , , ) and that while the inclusion of these components may result in a less than perfect alignment with functional loss, it does not mean that diagnostic accuracy for glaucoma is adversely affected.…”

“…Current technology does not allow subtraction of all non-neural components from the width, area or volume measurements currently in use; however, accounting for blood vessels, suggested by some authors (Knighton et al 2012;Patel et al 2014;Ye et al 2016) and adjusting rim measurements accordingly for the PRL, could help in this regard. However, it is important to recognize that also glaucoma affects non-neural tissues also (Yang et al , 2015(Yang et al , 2017 and that while the inclusion of these components may result in a less than perfect alignment with functional loss, it does not mean that diagnostic accuracy for glaucoma is adversely affected.…”

Imaging of the lamina cribrosa and its role in glaucoma: a review

“…It is well known that IOP‐related stresses may induce extracellular matrix remodelling and chronic changes to the ONH that results in the typical excavated or cupped appearance of a glaucomatous optic disc, which is for the most part irreversible even after the reduction of IOP. Through experimental glaucoma models in monkeys, it has been established that early glaucomatous changes to the ONH include posterior bowing of the lamina and peripapillary sclera that is accompanied by scleral canal expansion, thickening of the LC, and outward migration of the laminar insertion from the sclera into the pia mater .…”