A fundamental issue of how vascular disorders could affect the ONH is the process of autoregulation.144,145 The body exercises

various control mechanisms to maintain perfusion through myogenic and metabolic feedback loops. These include global control through cardiac output and blood pressure, local control for the regional distribution of flow, and hormonal control for prioritization of various vascular beds. Autoregulation refers to the initiation of a local response to control blood flow within a range of physi-

ologic parameters.20 Such autoregulation is lacking in the choroid but present in both the retina146 and optic nerve.147–149 The exten-

sive intraneural capillary bed in the ONH appears to be primarily responsible for this regulation. Deficient autoregulation has been reported both in the ONH and in the retina of glaucomatous eyes.150 The specific mechanisms of damage and response, however, remain elusive.

Another vascular phenomenon that has been extensively studied in glaucoma is fluorescein angiography of the disc.151–157 Focal

areas of ‘filling defects’ can be seen in areas of excavation, but these are almost certainly non-specific, secondary changes due to the

loss of capillaries in focal areas of optic nerve atrophy (Figs 12-6 and 12-7).4,158–161 Moreover, disc angiograms record the vascular

bed of the SNFL, derived from branches of the CRA. As such, little information about vascular events within the lamina cribrosa, where glaucomatous damage first manifests, is apparent.

Related aspects of disc angiography are the patterns of choriocapillaris and choroidal perfusion, which can demonstrate ‘watershed zones’ of relative hypofilling between the end-vessel territories of the lateral and medial posterior ciliary arteries.13 Allegedly

this accounts for the spectrum of both glaucomatous and anterior ischemic optic neuropathy.14,107 A related concept is that of a

watershed zone between the ONH and the peripapillary choroid that is potentially vulnerable to ischemia.12,19,162 Reservations

about the relevance of these angioarchitectural findings for the pathogenesis of glaucoma are based on several grounds, including: (1) the absence of any asymmetric vascular supply that would account for the pathognomonic asymmetric polar excavation of the glaucomatous ONH and arcuate defects respecting the horizontal raphe; (2) the absence of diffuse tissue damage as a result of ischemia; and (3) the virtual absence of clinical syndromes in which a diseased choroid effects glaucoma-like disc and visual field changes and vice versa.

Conversely, investigations using ever-sophisticated new technologies to assess the retrobulbar large vessels are yielding consistent

evidence of vascular abnormalities associated with glaucomatous eyes. Such techniques include disc and choroidal angiography with the scanning laser ophthalmoscope, using either fluorescein or indocyanine green dyes; laser and scanning laser Doppler flowmetry to assess flow velocities of the disc surface and surround-

ing choroid; and color Doppler imaging of flow in the ophthalmic artery and its branches.138,163–177 It is certainly conceivable that

poor perfusion can exacerbate other factors for ganglion cell loss.

How Do Ganglion Cells Die?

Just as the plethora of findings from various areas of investigation are increasing our understanding of how clinical risk factors are expressed at the histopathologic level to cause ganglion cell injury, the final act of how ganglion cells die also is being pieced together. One finding of great interest is that higher levels of glutamate, a neurotoxin usually seen as a result of ischemia, may be present in glaucomatous eyes.49–52 The source and pathway of this potent marker have yet to be elucidated.

Currently apoptosis is the most cogent explanation for ganglion cell death in glaucoma. Apoptosis refers to the preprogrammed genetic mode for individual cellular suicide; it is one of the ‘pruning’ mechanisms operative embryologically.178,179 Electron micro-

scopic and biochemical evidence point to this as one mechanism for cell death in experimental glaucoma180–182; in-vivo detection of

RGC death by apoptosis-sensitive binding proteins has recently been decribed.183 Clinically speaking, apoptosis is consistent with the total absence of ischemic signs in advancing glaucoma, such as the swollen axons appearing as cotton-wool spots in retinal microangiopathy.

Apoptosis may well be initiated by the loss of the normal retrograde flow of neurotrophic growth factors along the damaged axon due to insults in the lamina. Without such sustaining factors reaching the cell body, the ‘suicide’ program is triggered, as it is in embryologic cells that do not make their central neural connections and subsequently die.

As we have seen, the axons in the ONH are subject to a variety of potentially adverse mechanical, vascular, and biochemical events. Interrupting axonal integrity at this vulnerable anatomical transition zone triggers the death of its retinal-dwelling ganglion cells.The continued elaboration of toxic influences and cascades of injury will hopefully lead to the identity of many more potential areas for therapeutic intervention.

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