Glaucomatous Optic Neuropathy
Characteristic changes in the optic nerve head are the defining feature of glaucoma (Fig 4-5). Histologic examination reveals that early glaucomatous cupping begins with structural damage to the lamina cribrosa. Subsequently, there is apoptotic loss of RGCs and their axons, blood vessels, and glial cells. RGC axonal damage begins at the level of the lamina cribrosa. It is most pronounced at the superior and inferior poles of the ONH. In many cases, although not always, structural optic nerve changes may precede detectable functional loss as measured by standard perimetry.
Glaucomatous optic neuropathy is a progressive degeneration of RGCs and their axons in association with lamina cribrosa damage characterized by rupture of the laminar beams and enlargement of the optic disc cup. Transsynaptic neurodegeneration extends from the optic nerve to the major vision centers in the brain, such as the lateral geniculate nucleus and occipital cortex. Intraocular pressure (IOP) plays a major role in the development of glaucomatous optic neuropathy in most affected individuals and is considered the most significant risk factor. IOP can cause mechanical stress and strain on the posterior structures of the eye, particularly the lamina cribrosa, which is the weakest point in the posterior wall of the eye, and its adjacent tissues. IOP-induced stress and strain may result in compression, deformation, and remodeling of the lamina cribrosa with consequent mechanical axonal damage and disruption of axonal transport. Studies involving cats and monkeys with experimentally induced ocular hypertension have also demonstrated blockade of both orthograde and retrograde axonal transport at the level of the lamina cribrosa. Blockage of axonal transport occurs early in the pathogenesis of glaucoma and interrupts retrograde delivery of essential trophic factors to RGCs from their brainstem target (relay neurons of the lateral geniculate nucleus). Disrupted axonal transport also results in collections of vesicles and disorganization of microtubules and neurofilaments in the prelaminar and postlaminar regions. Similar ultrastructural changes in optic nerve fibers are observed in postmortem human eyes with glaucoma.
Figure 5-4 Two views of glaucomatous optic nerves. A, Glaucomatous optic nerve (anterior ONH and transverse view, right eye). Note thinning, undermining, and focal notching (FN) of inferior neuroretinal rim; enlarged central cup with visible laminar fenestrations (LF); nasal shift of retinal vessels; and peripapillary atrophy. B, Clinical view of glaucomatous ONH demonstrating extensive loss of the neuroretinal rim.
(Part A reprinted with permission from Wright KW, ed. Textbook of Ophthalmology. Williams & Wilkins; 1997. Part B courtesy of Ronald L. Gross, MD.)
Although the role of IOP as a risk factor for the development and progression of glaucoma has been well established, up to one-third of primary open-angle glaucoma (POAG) patients in North America have IOP levels within statistically normal limits. For reasons that are unclear, an even larger proportion of POAG patients in certain Asian populations, such as Japanese and Korean, have normal IOP. In Japan, for example, 90% of POAG patients have statistically normal IOP. Whether there are any pathophysiological differences between glaucoma at low and high pressures is unknown (see Chapter 7). Impaired microcirculation, altered immunity, excitotoxicity, and oxidative stress may also contribute to the pathogenesis of glaucomatous damage. Current thinking recognizes that glaucoma comprises a heterogeneous family of disorders mediated, most likely, by many factors.
Excerpted from BCSC 2020-2021 series: Section 10 - Glaucoma. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.