For a given ONH, IOP generates low or high levels of stress depending upon the 3D architecture (geometry) of the ONH connective tissues (size and shape of the canal, thickness of the lamina and sclera) - (Susceptibility 1). Some ONHs will have relatively low stress at high IOP (d). Others will have high stress at low IOP (e). Whether a given level of IOP-related stress is physiologic or patho-physiologic depends upon the ONH's microenvironment (Susceptibility 2). Strong connective tissues, a robust blood supply and stable astrocytes and glia increase the chance of Normal ONH Aging (right – bottom). While the existence of a neuropathy of aging is controversial, the difference between “normal” age-related axon loss (if it is shown to exist) and the development of glaucomatous damage is a matter of ONH susceptibility. Reprinted with permission from Burgoyne, et al64).

In our biomechanical paradigm, IOP-related strain influences the ONH connective tissues and the volume flow of blood (primarily) and the delivery of nutrients (secondarily), through chronic alterations in connective tissue stiffness and diffusion properties (explained in Figures 1 and 2). Non-IOP related effects such as auto-immune or inflammatory insults (yellow) and retrobulbar determinants of ocular blood flow (red) can primarily damage the ONH connective tissues and/or axons, leaving them vulnerable to secondary damage by IOP-related mechanisms at normal or elevated levels of IOP. Once damaged, the ONH connective tissues can become more or less rigid depending upon lamina cribrosa astrocyte and glial response. If weakened, ONH connective tissues deform in a predictable manner (Figure 4) which underlies a laminar component of clinical cupping (Figure 3).

Upper: Normal lamina cribrosa (unhatched), scleral flange (hatched), prelaminar tissue (beneath the internal limiting membrane - brown line), Bruch's membrane (solid orange line), Bruch's Membrane Opening (BMO) zero reference plane (dotted orange line), Border tissue of Elschnig (purple line), choroid (black circles) are schematically represented in the upper illustration. Lower: Overall changes in the ONH surface and subsurface architecture at the onset of CSLT-detected ONH surface change in experimental ocular hypertension in young adult monkey eyes are depicted below. Posterior bowing of the lamina and peripapillary scleral flange, thickening of the lamina and thickening (arrows) not thinning of the prelaminar neural tissues (brown shading) underlie posterior deformation of the ONH and peripapillary retinal surface (dotted brown to solid brown ILM). Thus, while expansion of the clinical cup and deformation of the surface are clinically detectable at this early stage of the neuropathy, because they occur in the setting of prelaminar tissue thickening, (not thinning), clinical cupping in experimental ocular hypertension in these young adult eyes is “laminar” in origin, without a significant “prelaminar” component (Figure 3). Because aged eyes will have (on average) stiffer connective tissues, we predict they will demonstrate less laminar and more prelaminar cupping at the onset of clinically detectable ONH surface change. (Adapted from Yang, et al50)

“Deep”, “laminar” or “glaucomatous” cupping is a manifestation of ONH connective tissue damage which can be caused by either IOP-related or non-IOP related insults (See Figure 5). However, regardless of the primary insult to the ONH connective tissues, their deformation (if present) is driven by IOP-related connective tissue stress and strain. Thus the presence of ONH connective tissue deformation in any optic neuropathy is evidence that the level of IOP at which it occurred, (whether normal or elevated) is too high for the connective tissues in their present condition. (A) Schematic of normal laminar thickness (x) within the scleral canal with scleral tensile forces acting on the scleral canal wall. (B) Early IOP-related damage in the monkey eye (Figure 6)45-50 includes posterior bowing of the lamina and peripapillary sclera accompanied by neural canal expansion (mostly within the posterior (outer) scleral portion) and thickening (not thinning) of the lamina (y). In our studies to date this appears to represent mechanical yield (permanent stretching) rather than mechanical failure (physical disruption) of the laminar beams (C) Progression to end-stage damage includes profound scleral canal wall expansion (clinical excavation) and posterior deformation and thinning of the lamina (z) by mechanisms that are as yet uncharacterized99, 100. If all other aspects of the neuropathy are identical, the stiffer the lamina, the more resistant it will be to deformation. Whether this is better or worse for the adjacent axons is a separate question that remains to be determined.

A. Normal ONH. To understand the two pathophysiologic components of clinical cupping, start with (B) a representative digital central horizontal section image from a post-mortem 3D reconstruction of this same eye (white section line in (A)) - vitreous top, orbital optic nerve bottom, lamina cribrosa between the sclera and internal limiting membrane (ILM) delineated with green dots. (C) The same section is delineated into principle surfaces and volumes (Black – ILM; purple - prelaminar neural and vascular tissue; cyan blue line – Bruchs Membrane Opening (BMO)-zero reference plane cut in section; green outline – Post-BMO Total Prelaminar area or a measure of the space below BMO and the anterior laminar surface). (D) Regardless of the etiology, clinical cupping can be “shallow” (E) or “deep” (F) (these clinical photos are representative and are not of the eye in (A)). A prelaminar or “shallow” form of cupping (G, black arrows) is primarily due to loss (thinning) of prelaminar neural tissues without important laminar or ONH connective tissue involvement. Laminar or “deep” cupping (H, small white arrows depict expansion of the green shaded space) follows ONH connective tissue damage and deformation that manifests as expansion of the total area beneath BMO, but above the lamina. Notice in (H) that while a laminar component of cupping predominates (white arrows) there is a prelaminar component as well (black arrows). While prelaminar thinning is a manifestation of neural tissue damage alone, we propose that laminar deformation can only occur in the setting of ONH connective tissue damage followed by permanent (fixed) IOP-induced deformation. Reprinted with permission from Yang, et al.50).

The ONH is made up of prelaminar, laminar and retrolaminar regions (A). Within the clinically visible surface of the Normal ONH (referred to as the optic disc) (B), central retinal vessels enter the eye and RGC axons appear pink due to their capillaries (which are principally supplied by branches from the posterior ciliary arteries (PCA) in (C). The primary site of RGC axon insult in glaucoma is within the lamina cribrosa (schematically depicted with axon bundles in (D), isolated by trypsin digest in a scanning electron micrograph in (E) and drawn with stippled extracellular matrix (ECM), central capillary (red) and surrounding astrocytes (yellow with basement membranes in black) (F). Blood flow within the ONH, while controlled by autoregulation, can be affected by non-IOP-related effects such as systemic blood pressure fluctuation and vasospasm within the retrobulbar portion of the PCAs. Additional IOP-induced effects may include compression of PCA branches within the peripapillary sclera (due to scleral stress and strain) and compression of laminar beam capillaries reducing laminar capillary volume flow (C and F)135. There is no direct blood supply to the axons within the laminar region. Axonal nutrition within the lamina (F) requires diffusion of nutrients from the laminar capillaries, across the endothelial and pericyte basement membranes, through the ECM of the laminar beam, across the basement membranes of the astrocytes, into the astrocytes, and across their processes to the adjacent axons (vertical lines). Chronic age-related changes in the endothelial cell and astrocyte basement membranes, as well as IOP-induced changes in the laminar ECM and astrocyte basement membranes may diminish nutrient diffusion to the axons in the presence of a stable level of laminar capillary volume flow. The clinical manifestation of IOP-induced damage to the ONH is most commonly “deep cupping” (G) but in some eyes cupping can be shallower accompanied by pallor (H). Z-H = circle of Zinn-Haller; PCA= posterior ciliary arteries; NFL = nerve fiber layer; PLC = prelaminar region; LC = lamina cribrosa; RLC = retrolaminar region; ON = optic nerve; CRA = central retinal artery. (A) Reprinted with permission from Arch Ophthalmol54; (C) reprinted with permission from The Glaucomas. St. Louis: Mosby; 1996:177–97139; (D) reprinted with permission from Optic Nerve in Glaucoma. Amsterdam: Kugler Publications; 1995:15–36140; (E) reprinted with permission from Arch Ophthalmol141; (F) reprinted with permission from Arch Ophthalmol142