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Intraocular pressure–independent mechanisms

Local vascular factors

Optic disk hemorrhage is a significant predictor of disease progression for POAG and NTG (Allingham et al., 2005; Krupin et al., 2005; Martus et al., 2005). These hemorrhages are gross clinical signs of vascular abnormalities, though cause and effect relationships cannot be proven. Animal models of glaucoma have shown that retinal ganglion cells die by the process of apoptosis (Quigley et al., 1995), which is a form of cell death in which a programmed sequence of events leads to the destruction of cells without releasing inflammatory substances into the surrounding area. Vascular dysfunction (decreased perfusion, vasospasm or autoregulation deficit) may result in apoptosis of retinal ganglion cells via glutamate-mediated toxicity and neurotrophin withdrawal (Harris et al., 2005) (Fig. 9). As shown in the figure, both increased IOP and vascular factors can induce pathologic changes in glaucoma. Accordingly, several studies have shown a correlation between reduced ocular blood flow and optic disk filling defects to glaucomatous visual field loss (Harrington, 1969; Melamed et al., 1998).

In patients with asymmetric glaucoma, hemodynamic abnormalities were found to correlate with the extent of glaucomatous damage (Nicolela et al., 1996). Additionally, interocular differences in glaucoma progression have been associated with interocular differences in blood flow independent of IOP (Schumann et al., 2000). Studies have also shown that patients with NTG have lower retrobulbar flow velocity and higher vessel resistance than healthy subjects (Rojanapongpun et al., 1993; Butt et al., 1995). It is important to note that these are simply relationships, and do not necessarily represent cause and effect.

Chronic vascular insufficiency of the optic nerve may be caused by systemic abnormalities. Many studies have documented nonocular conditions with vasospasm, such as migraine and Raynaud’s phenomenon, to occur at higher frequencies in NTG (Phelps and Corbett, 1985; Cursiefen et al., 2000; Drance et al., 2001; Allingham et al., 2005). Cardiovascular conditions such as asymptomatic myocardial ischemia were much more common in NTG (45%) than in normal subjects (5%) (Waldmann et al., 1996). Also, a greater nocturnal drop in blood pressure has been reported in NTG than in the healthy population (Meyer et al., 1996). Hayreh et al. (1994) performed 24-h blood