The Morphological Difference Between Glaucoma and Other Optic Neuropathies

Abstract

The clinical phenomenon of cupping has two principal pathophysiologic components in all optic neuropathies: prelaminar thinning and laminar deformation. We define prelaminar thinning to be the portion of cup enlargement that results from thinning of the prelaminar tissues due to physical compression and/or loss of Retinal Ganglion Cell axons. We define laminar deformation or laminar cupping to be the portion of cup enlargement that results from permanent, intraocular pressure-(IOP) induced deformation of the lamina cribrosa and peripapillary scleral connective tissues following damage and/or remodeling. We propose that the defining phenomenon of glaucomatous cupping is deformation and/or remodeling of the neural and connective tissues of the optic nerve head (ONH), which is governed by the distribution of IOP-related connective tissue stress and strain, regardless of the mechanism of insult or the level of IOP at which that deformation and/or remodeling occurs. Said in another way, “glaucomatous cupping” is the term clinicians use to describe the clinical appearance and behavior the ONH assumes as its neural and connective tissues deform, remodel or mechanically fail: 1) in a pattern and 2) by the several pathophysiologic processes governed by IOP-related connective tissue stress and strain. ONH Biomechanics explains why a given optic nerve head will demonstrate a certain form of “cupping” and at what level of IOP that might happen. Animal models are allowing us to tease apart the important components of cupping in IOP-related and non-IOP-related forms of optic neuropathy. A paradigm change in spectral domain optical coherence tomography ONH, retinal nerve fiber layer and Macular imaging should improve our ability to phenotype all forms of damage to the visual system including glaucoma.

The Connective Tissue Components of Optic Nerve Head Cupping in Monkey Experimental Glaucoma Part 1: Global Change

“…20 Shallow forms of cupping can be due to neuroretinal rim loss alone, and can confound the clinical interpretation of all forms of optic neuropathy. 19,20 While the mechanistic, predictive and treatment implications of their detection are not yet certain, we propose that in any optic neuropathy, the presence or progression of the connective tissue phenomena we describe suggest that an IOP-related mechanism may be present whether or not an IOPrelated insult is the primary cause of the neuropathy and without regard for the level of IOP at which the primary insult or progression has occurred.…”

“…20 Shallow forms of cupping can be due to neuroretinal rim loss alone, and can confound the clinical interpretation of all forms of optic neuropathy. 19,20 While the mechanistic, predictive and treatment implications of their detection are not yet certain, we propose that in any optic neuropathy, the presence or progression of the connective tissue phenomena we describe suggest that an IOP-related mechanism may be present whether or not an IOPrelated insult is the primary cause of the neuropathy and without regard for the level of IOP at which the primary insult or progression has occurred. In these regards, while our own longitudinal study detected progressive laminar deformation using SDOCT early in monkey EG, 25 two subsequent studies have failed to demonstrate SDOCT-detected laminar deformation in the monkey experimental optic neuropathies of surgical CSF lowering 37 and surgical optic nerve transection (Ing E, et al IOVS 2015;56:ARVO E-Abstract 999).…”

“…How RGC axons are damaged in the presence of the connective tissue phenomena we describe, their sequence, and their underlying cellular mechanisms are currently under study in a separate cohort of animals. 10,20 …”

“…[18][19][20] The connective tissue components of cupping are also important because the cellular mechanisms of each will likely contribute to the cellular mechanisms of glaucomatous retinal ganglion cell (RGC) axon insult within the ONH. 10,21 The use of these connective tissue components to stage and phenotype the optic neuropathy of glaucoma and study its mechanisms of insult are not the focus of this study but will be the subject of future reports.…”

Optic Nerve Head Morphology in Nonarteritic Anterior Ischemic Optic Neuropathy Compared to Open-Angle Glaucoma

“…[11][12][13][14][15][16] The LC stabilizes intraocular pressure (IOP) by forming a barrier between the intraocular space and the extraocular space, and it has been considered the principal site of retinal ganglion cell mechanical axonal injury in glaucomatous damage. 17 Burgoyne 18 has proposed that only ''laminar'' or ''deep'' forms of ONH cupping are pathognomonic for glaucoma and that laminar deformation in nonglaucomatous optic neuropathy, such as that induced by experimentally reduced cerebrospinal fluid pressure in monkeys, might be minimal. [19][20][21] However, histologic studies may be prone to the effects of tissue swelling or shrinkage from fixation processes.…”