required to cause vasoconstriction are several log units higher than extraluminal levels because of the direct exposure to ET-1 to smooth muscle cells [196]. Nonetheless, the situation is quite different in diseases where the blood-retinal barrier may be compromised. Similarly, vasoactive substances may leak from the choroidal circulation where the endothelial junctions are not as tight. In certain conditions, it is possible that even erythrocytes may leak and could be a possible cause of the characteristic disc haemorrhages which are almost exclusively associated with glaucoma [4].

Under some conditions, such as cold and stress, concentrations of vasoconstrictors such as ET-1 may increase [101, 137]. In turn, ET-1 may leak from vessels with multiple effects including astrocyte activation [149, 185] in addition to vasoconstriction [31, 196].

17.3Evidence Base Supporting the Importance of Ischaemia in Glaucoma

As discussed above, there are several mechanisms whereby reduced blood flow and nutrient supply potentially lead to optic nerve damage in glaucoma. Considerable data have been amassed over the last few decades, both from human and animal research on the issue of association, causality and whether treatment to ameliorate blood flow leads to favourable outcomes in glaucoma.

17.3.1 Association and Causality

17.3.1.1 Reduction in Optic Nerve Head Blood Flow

A considerable body of evidence exists to support the notion that blood flow in the optic nerve head, choroid, retina and indeed outside the eye is reduced in glaucoma [51, 52]. While practically every technique used for measuring blood flow shows alterations in glaucoma, it should be noted that the glaucoma populations were different across studies. For example, many studies only reported findings in glaucoma patients with statistically normal IOP based on the assumption

that glaucoma due to high IOP is due to IOP whereas ischaemic factors may be responsible for damage at normal IOP.

Fluorescein angiography first was used to show filling defects and delayed filling in the choroid, optic nerve and retina [91, 164], though it is unclear how filling defects and angiographic transit times relate to blood flow because of parameters such as vessel diameter and dye transit to the eye. Pulsatile ocular blood flow is derived from changes in IOP measured during the cardiac cycle [169]. These measurements are converted to change in pulse volume due primarily to change in choroidal volume from systole to diastole. In spite of the fact that the optic nerve head component of choroidal blood flow is very small, several reports show a reduction in pulsatile ocular blood flow in glaucoma [98, 105, 181], indicating more global alterations in blood flow.

Doppler-based techniques have been used widely to assess blood flow in glaucoma. Laser Doppler velocimetry has been used to show reduction in retinal blood flow velocity [75], while laser Doppler flowmetry was used to show reduction in optic nerve head blood flow in glaucoma patients and suspects [72, 147]. Scanning laser Doppler flowmetry measurements from several research laboratories report reduction in retinal and optic nerve head blood flow in glaucoma [76, 127, 138]. Finally, colour Doppler imaging of blood velocities in the retrobulbar vessels including the ophthalmic artery, short posterior ciliary arteries and central retinal vein has been used to show reductions in glaucoma patients [24, 59, 81, 139].

Blood flow alterations may be more pronounced in eyes that have faster glaucomatous progression [163, 194]. Spatial correlations between area of reduced blood flow and visual field damage have also been published [10]. Finally, there is some evidence that blood flow may precede development of glaucoma in studies of patients with unilateral glaucoma showing blood flow alterations in the perimetrically unaffected eye [54, 136].

17.3.1.2 Blood Pressure, Intraocular Pressure and Perfusion Pressure

Many systemic conditions such as hypertension are age-related; hence, it is important to elucidate

whether glaucoma and systemic hypertension are co-morbidities. A considerable number of epidemiological studies in glaucoma across diverse populations have been undertaken, yet the relationship between blood pressure and IOP, and blood pressure and glaucoma is complex [38], with possible interactions with racial, genetic and environmental factors.

There is a positive relationship between IOP and both systolic and diastolic blood pressure in European-derived populations [16, 41, 108], a mixed US population [177], Caribbean Blacks [190] and Chinese-derived populations [56, 192]. While statistically significant, every 10-mmHg increase in systolic or diastolic blood pressure accounts for an increase in IOP of less than 0.5 mmHg. Evidence from longitudinal studies [107, 191] also shows that a higher baseline systolic or diastolic blood pressure explains a small (less than 0.5 mmHg) but statistically significant increase in IOP.

Paradoxically, the studies on the relationship between systemic hypertension and glaucoma have yielded opposing results. Epidemiological findings from Italian [16], Dutch [41] and Australian [128] populations show a positive relationship between hypertension and glaucoma, while studies in the United States [177] and Caribbean [114] populations failed to confirm these findings. Furthermore, population-based longitudinal data do not show a relationship between hypertension and incident glaucoma. In fact, the evidence points to the contrary, that is, low systolic blood pressure may be associated with incident glaucoma [118, 119] and progression of existing glaucoma [117], at least in glaucoma with lower IOP.

Perhaps the most equivocal finding relating derivatives of blood pressure to glaucoma is the strong association between diastolic ocular perfusion pressure and the disease (Fig. 17.1). The Baltimore Eye Survey first reported the relationship between the prevalence of glaucoma and diastolic perfusion pressure [177]. There was no effect of diastolic perfusion pressure in the prevalence of glaucoma until the values dropped to below 45 mmHg. The odds of having glaucoma increased by a factor of over 6 in patients with

Fig. 17.1 Increasing prevalence of open-angle glaucoma with lower diastolic perfusion pressure (Data are derived from three population-based studies, the Baltimore Eye Survey (BES) [177], the Egna-Neumarkt Study (ENS) [16] and Proyecto VER (PVER) [155])

diastolic perfusion pressure of <30 mmHg compared to those with values >30 mmHg. These findings provided indirect support for the hypothesis that patients with low perfusion pressure may be unable to autoregulate blood supply to the optic nerve at low perfusion pressure; however, it is unlikely that low perfusion pressure alone accounts for all cases of glaucoma as the number of individuals with such low perfusion pressure was small [177].

Other epidemiological studies have subsequently confirmed the relationship between low diastolic perfusion pressure and glaucoma [16, 114, 155]. These findings however are not supported uniformly. The Blue Mountains Eye Study found only a marginally significant relationship between systolic perfusion pressure and glaucoma, though no significant relationship existed between diastolic or mean perfusion pressure and glaucoma [128]. In the Rotterdam Study, the prevalence of glaucoma with lower IOP was reduced in patients with diastolic perfusion pressure <50 mmHg while the prevalence of glaucoma with higher IOP was increased in patients with diastolic perfusion pressure <50 mmHg [96].

Finally, two longitudinal studies also confirm the importance of perfusion pressure in glaucoma. The Barbados Eye Study showed that

Fig. 17.2 Mean arterial pressure (MAP) at the level of the eye as a function of diastolic (SBP) and systolic (SBP) brachial blood pressure in erect and supine positions. Diagonal lines show iso-MAP values. These values are derived with the assumptions that: (1) MAP = DBP + 1/3

(SBP − DBP); (2) the vertical height difference between the heart and eye = 30 cm and (3) 1 cmH2O = 0.72 mmHg. These data show that for a given IOP and blood pressure, ocular perfusion pressure is significantly higher in the supine position than in the erect position

subjects developing glaucoma 9 years after initial assessment had lower baseline systolic, diastolic and mean perfusion pressure [118]. In the Early Manifest Glaucoma Trial, lower systolic perfusion pressure was associated with progression of existing glaucoma [117]. The associations in these longitudinal studies are notable as they were carried out in racially distinct populations.

17.3.1.3 Nocturnal Hypotension

Systemic blood pressure lowers or dips physiologically at night. There is considerable evidence that in at least some glaucoma patients, the level of dipping is exaggerated compared to non-glaucoma subjects, with the potential of hypoperfusion of the optic nerve head contributing to glaucomatous optic neuropathy [68, 83]. This situation may be exacerbated in those patients taking systemic hypotensive drugs. Subsequent research demonstrated nocturnal dipping was associated with progressive glaucomatous damage [69] and that patients with non-progressive glaucoma had nocturnal retrobulbar blood flow measurements that did not differ from healthy subjects [82]. It has also been suggested that non-dipping is also

associated with glaucoma progression [39, 178]; hence, these findings are paradoxical in regard to perfusion pressure. Recent research showed that fluctuations in mean ocular perfusion pressure were associated with nocturnal dipping and that the level of fluctuation was related to the level of visual field damage at diagnosis [29].

While ocular blood flow parameters are related to blood pressure and perfusion pressure in glaucoma patients, but not healthy subjects [57], it is unlikely that potential ischaemia of the optic nerve head can occur from a nocturnal reduction in blood pressure alone. For a given blood pressure, the ocular perfusion pressure in the supine position is actually higher than in the erect position because the height difference between the heart and eye is eliminated [14]. Figure 17.2 shows mean blood pressure for a range of systolic and diastolic blood pressures in the supine and erect positions. Assuming a systolic blood pressure of 120 mmHg, the mean blood pressure at the level of the eye is approximately equal when the supine diastolic pressure is around 60 mmHg and the erect diastolic pressure is around 90 mmHg. Assuming a diastolic blood

pressure of 80 mmHg, the mean blood pressure at the level of the eye is approximately equal when the supine blood pressure is around 80 mmHg and the erect blood pressure is around 140 mmHg. These figures show that erect blood pressures have to be relatively high and supine blood pressures relatively low to obtain the same mean arterial pressure. The approximately 20 mmHg higher mean blood pressure at the level of the eye in the supine compared to erect position is much higher than the increase in nocturnal IOP to have an impact on ocular perfusion pressure.

Hence, while the evidence suggests that potential nocturnal ischaemia may be a contributing factor in glaucoma, it cannot be explained on the basis of reduced blood pressure at night and decreased ocular perfusion pressure. It is possible that blood flow may be reduced at night because of factors such as increased resistance.

17.3.1.4 Vasospasm

There is considerable evidence that vasospasm (or vascular dysregulation) and its surrogate measures such as migraine are associated with glaucoma. The possible association between vasospasm and glaucoma was first published almost 25 years ago [146] when it was reported that glaucoma patients with lower IOP had a higher prevalence of migraine compared to healthy subjects and those with higher IOP with and without manifest glaucoma. Several subsequent studies have confirmed these findings with patient-reported symptoms [36] or with indirect measurements of ocular vasospasm, such as finger blood flow [45, 162] or nailfold capillaromicroscopy [64, 65], which assess peripheral vasospasm.

Two population-based studies on self-reported migraine and glaucoma led to opposing conclusions – one finding an association between migraine and glaucoma [184], while the other did not [109].

Longitudinal studies have also addressed whether the incidence or progression of existing glaucoma is exacerbated by migraine or vasospasm. The Ocular Hypertension Treatment Study (OHTS) did not find an association between the existence of self-reported migraine and the development of glaucoma [67]. The Collaborative Normal Tension Glaucoma Study (CNTGS) showed that among glaucoma patients randomised to no treatment,

patients with self-reported migraine were 2.5 times as likely to progress compared to those without migraine [43]. Building on previous research suggesting that vasospastic patients have a more IOPdependent disease and therefore presumably more responsive to IOP reduction [162], the CNTGS showed that among those randomised to treatment, migraine patients responded more favourably than non-migraine patients [8]. Findings of the CNTGS were not confirmed by the Early Manifest Glaucoma Trial, another trial which also randomised patients to treatment and no treatment [117].

The Canadian Glaucoma Study (CGS) was designed to specifically test whether patients with objectively measured peripheral vasospasm at baseline had a more favourable outcome under a uniform IOP treatment protocol during prospective follow-up [1]. The CGS failed to statistically confirm this hypothesis, though non-statistically significant trends were reported consistently suggesting that vasospasm may be important in glaucoma; however, in some populations, its effect may be quite small [28].

17.3.1.5 Endothelin and Other Circulating Peptides

Plasma levels of ET-1 in glaucoma patients have been reported, with varying results. Some studies show a higher basal concentration of plasma ET-1 [25, 174], but the majority of subsequent studies have failed to confirm this finding [92, 101, 110, 137, 176]. Under different physiological conditions, however, such as a posture change [101] or cold provocation [137], at least some glaucoma patients show an increase in plasma ET-1 concentration compared to control subjects. The mechanisms whereby a systemic increase in ET-1 concentration contributes to glaucomatous optic neuropathy remain to be elucidated.

Other circulating peptides, such as angio- tensin-1, serotonin and markers of nitric oxide (e.g. cyclic guanosine monophosphate), have been investigated in plasma and aqueous of patients with glaucoma [60]. Several of these studies show alterations in aqueous concentrations in patients with glaucoma with likely effects on IOP, though the impact of altered plasma levels is not clear.