Newman-Casey et al. reported that hypertension (hazard ratio, HR: 1.17) and diabetes (HR: 1.35) were risk factors for OAG in a large cohort epidemiological study that ran from 2001 to 2007 [13]. Their findings have since been reinforced [14–17], although the identification of conditions associated with metabolic syndrome, such as hypertension and diabetes, as risk factors for glaucoma remains controversial [18–20]. Additionally, low systemic blood pressure has been reported to be a major risk factor for glaucoma [4, 19, 17]. Individuals who experience nightly dips in systemic blood pressure and fluctuation in systemic blood pressure are thought to be particularly vulnerable [21–23]. These irregularities in blood pressure can result in low ocular perfusion pressure and insufficient ocular blood supply [24, 25].

The ophthalmic artery is the major vascular vessel providing blood to the inner retina and optic nerve. The central retinal artery, which branches off the ophthalmic artery and enters the optic nerve approximately 12 mm posterior to the globe, supplies blood to the retinal ganglion cell bodies in the inner retina and nerve fibers. The central retinal artery also provides partial perfusion to the superficial optic disc. The pre-laminar region and lamina cribrosa are mainly supplied from branches of the posterior ciliary arteries (PCA), branching off from the ophthalmic artery and also from other vessels originating from the arterial circle of Zinn-Haller (ZHAC). In addition, fine centripetal branches from the peripapillary choroid provide blood to the pre-laminar region [26–28]. The blood supply in this region is sectorial in nature, similar to distribution of the PCA circulation. These branches from the PCA pierce the sclero-optic junction and enter the lamina cribrosa through the border tissue of Elschnig at the choroid [29]. It is generally assumed that microvessels throughout the optic nerve have characteristics of the blood-brain barrier (BBB), since tracers such as peroxidase do not pass out of the optic nerve capillaries [30]. However, a study of immunohistochemistry using non-BBB markers showed that microvessels in the pre-laminar region of the optic nerve head (ONH) lack typical BBB characteristics and display nonspecific permeability [31], possibly mediated by vesicular transport.

Population-based studies have revealed that low blood pressure and low ocular perfusion pressure (OPP) increase the prevalence of glaucoma. Adequate irrigation of ocular tissues can only be ensured by adequate OPP, which depends on a complex regulation process to balance BP and IOP. The vascular hypothesis of glaucoma pathogenesis is thus based on the premise that abnormal perfusion, with the subsequent deterioration in ONH circulation, plays a major role in the pathophysiology of damage in glaucoma. Many studies performed with a variety of techniques have found that glaucoma is associated with altered ocular blood flow, particularly ocular blood flow in the posterior pole of the eye [44–48]. In eyes with glaucomatous visual field deterioration, retrobulbar blood velocity decreases significantly, and the resistance of the vessels increases significantly [45–49]. In severe glaucoma, deterioration of ocular circulation also increases with the progression of glaucoma and visual field loss [50]. In glaucoma patients with asymmetric visual field loss, the more affected eye also has lower blood velocity in the central retinal artery than the less affected eye [51]. CDI data shows that retrobulbar blood velocity in eyes with glaucoma is significantly correlated with mean blood pressure [52]. In comparison, healthy eyes show a lower, although still significant, correlation. This implies that the vascular autoregulation system in ocular arteries, which acts in response to changes in perfusion pressure [53], is compromised in eyes with glaucoma. LSFG studies of pre-laminar tissue in the ONH of eyes with glaucoma have shown that blood flow in this area is significantly lower than normal and that it correlates to the severity of glaucoma. This is consistent with histological studies, indicating that dropout of the capillaries within the pre-laminar and laminar lesions in the ONH may be occurring.

In myopic eyes, elongation of the axial length leads to stretching of the sclera, and the optic disc becoming elliptical and tilted temporally, changes which are associated with enlarged crescent PPA [54]. Temporal crescent PPA is a common consequence of scleral stretching [55]. Furthermore, there is evidence that myopia leads to the deterioration of ocular circulation. With myopic change, the diameter of the retinal arteries becomes smaller and retinal blood flow in the retinal arteries decreases [56–58]. Retrobulbar blood flow and choroidal circulation also decrease in severe myopia [58, 59].

This leads to the question of whether there is an association between glaucoma and myopic changes in ocular circulation. Nicolela’s classification system of ONH morphology categorizes elliptical ONHs with temporal crescent PPA as the “myopic glaucomatous type” [60, 61]. Myopic eyes with glaucoma tend to significantly younger at the time of diagnosis, with the central vision frequently threatened by glaucomatous scotoma. There are also a higher number of patients of Asian origin. Moreover, in the four glaucomatous optic disc types, retrobulbar circulation in the myopic glaucomatous type shows lower PSV, determined by CDI, in the ophthalmic artery than the focal ischemic type [62]. In the LSFG, tissue circulation in the optic nerve area in myopic glaucoma has also been reported to decrease, in correlation with visual field defects [63]. Figure 8.2 shows the difference in blood circulation between a glaucomatous ONH with myopic deformation and one with focal rim notch. Changes in ocular circulation in myopic eyes thus appear to be one of the mechanisms of glaucoma pathogenesis.

The results of many studies show that ischemia has multiple detrimental effects on the retinal ganglion cells (RGCs) and their axons [80–82]. Mechanisms implicated in RGC death include hypoxia-induced reactive oxygen species (ROS) [83], excitotoxicity, nitric oxide (NO) [84, 85], and the inflammation reaction [86]. There is strong evidence that chronic retinal ischemia also results in a variety of harmful intra-retinal events.

Ischemia and reperfusion induce ROS generation in three phases: in the first phase, mitochondria generate ROS; in the second phase, xanthine oxidase is activated; and in the third phase, Ca2+- dependent ROS generation begins [87]. Investigations of ischemia in RGCs have included ROS generation and cytotoxicity [83] and NO [88]. NO, synthesized by nitric oxide synthase (NOS), has been shown to have neuroprotective and neurotoxic roles [89], and some experiments have shown that NO production contributes to cytotoxicity resulting in cell death [84, 85]. Excitatory amino acids have been also reported to play an important role in the development of hypoxic-ischemic retinal injury [90, 91]. Glutamate excitotoxicity may also facilitate primary and/or secondary degeneration of the RGCs in glaucoma [92, 93].

Ischemia causes increased permeability of the blood-retinal barrier due to vascular endothelial growth factor, NO, free radicals, and aquaporin-4 protein expression resulting in serum leakage into retinal tissue [94]. The compression induced by tissue edema is thought to occur secondarily and to also be a cause of RGC degeneration [95].

Glaucoma is a multifactorial disease with a pathogenesis that remains unclear. However, myopia is known to be a major risk factor for glaucoma, and an understanding of myopia’s role in glaucoma is important. A number of studies have reported that there is an association between ocular circulation deterioration and myopic morphological change. Elucidation of the effect of myopia on ocular circulation might lead to improved knowledge of the pathogenesis of myopic glaucoma (Fig. 8.3, the summary of this chapter).