Ординатура / Офтальмология / Английские материалы / Mechanisms of the Glaucomas_Shields, Tombran-Tink, Barnstable_2008

Intraocular Pressure, Perfusion Pressure, and Optic Nerve Energy Metabolism 501

the perfusion pressure is in the normal range, the oxidation/reduction state is not changed with minor changes in perfusion pressure indicating the autoregulation. As the perfusion pressure decreases, the autoregulation is overwhelmed and the cytochromes become more reduced or ischemic (see Fig. 10). It is interesting to note that the curves are practically identical regardless of whether the perfusion pressure is changed by changing the IOP or the mean arterial blood pressure. From the standpoint of the energy metabolism of the cells, it is only the perfusion pressure of the eye that matters and not the absolute levels of IOP or mean arterial blood pressure as such (see Fig. 10).

OPTIC NERVE OXYGEN PHYSIOLOGY AND GLAUCOMA

The goal of laboratory medical research is to understand basic principles that give us insight into the clinical problems of our patients. The physiological studies of the relationship between the perfusion pressure of the eye and optic nerve oxygen tension or cytochrome oxidation, on one hand, and the relative risk of optic nerve atrophy in glaucoma patients, on the other hand, is a clear example of this principle. Tielsch et al. (62) examined the relative risk of optic nerve atrophy in primary open angle glaucoma patients in the Baltimore Eye Survey. They found that if the perfusion pressure of the eye was above 50 mmHg, the risk of optic nerve atrophy was low. This risk roughly doubled if the perfusion pressure was between 30 and 49 mmHg and increased more than sixfold if the perfusion pressure fell below 30 mmHg (see Table 1). The clinical findings correlate exactly with the physiological findings. It is amazing to see how good the correlation is despite the fact that the clinical findings come from human patients and the physiological data from cats and pigs. If the perfusion pressure is above 50 mmHg, the cytochromes in the cat optic nerve are well oxidized (see Fig. 10) and the oxygen tension of the pig optic nerve is also in the normal range (see Figs 6 and 7). When the perfusion pressure goes below this range, the oxygen tension falls in the pigs and the optic nerve cytochromes become reduced in the cats. At this perfusion pressure range, the risk of glaucomatous atrophy in the human patients is increased. If the perfusion pressure goes below 30 mmHg, the pig optic nerves are clearly hypoxic and 50% or more of the cytochromes are reduced. This level of perfusion pressure is associated with a severe disturbance in the energy metabolism in the optic nerve in the laboratory animals and also with a high risk of glaucomatous optic atrophy in the human glaucoma patients.

Table 1

The Relationship Between the Risk of Progressive Optic

Atrophy in Primary Open Angle Glaucoma (POAG) and

the Perfusion Pressure of the Eye in Human Glaucoma

Patients (62)

It is remarkable, although not surprising, that the perfusion pressure levels that are associated with functional damage or ischemia in the eye are in the same range in a large number of studies using different techniques and experimental subject. In all cases, the optic nerve seems to do well if the perfusion pressure is above 50–60 mmHg, and in all cases, the function is disturbed or hypoxia is present if the perfusion pressure is below 30 mmHg (40–42,49,52,61). This is true for the oxygen tension studies and cytochrome oxidation results cited above and also for human clinical studies (62). However, we must be careful when we link experimental animal work and human disease. Healthy animals may of course show physiological responses that are different from unhealthy humans. It is possible, even likely, that in human glaucoma factors such as deficient regulation of ocular perfusion play an important role.

The relationship between the perfusion pressure (IOP), the energy metabolism of the optic nerve (oxygen tension and cytochrome oxidation), and the risk of optic nerve atrophy in glaucoma patients also sheds light on the treatment of glaucoma. Lowering the IOP will increase the perfusion pressure of the eye and improve the oxygen tension and oxidation of the mitochondria, thereby improving the energy metabolism, if this has been compromised. It should not matter whether the IOP is lowered with filtration surgery, argon laser trabeculoplasty, cyclodestructive procedures, or various glaucoma drugs. The physiological studies allow us to see glaucoma and its treatment quite simply as an ischemic disease with disturbance in energy metabolism that can be manipulated by changing the IOP. This theory would predict that changes in blood pressure should be equally important and the studies of Tielsch and associates in the Baltimore Eye Survey (see Table 1) indicate this as well as several examples of the influence arterial hypotension can have on glaucoma.

Perfusion pressure is defined as the difference between the arterial and the venous pressure. In the eye, venous pressure is equal to or slightly higher than IOP. Although IOP is very weakly positively correlated with blood pressure (63), systemic hypotension is clearly a risk factor for glaucomatous optic neuropathy (63–76). Among glaucoma patients who eventually lose their sight, the proportion of patients with systemic hypotension is larger than in other glaucoma patients (70). Blood pressure drops, when related to major events such as hemorrhages, can lead to glaucomatous optic neuropathy (77). Also, patients with orthostatic reactions have a higher chance of developing glaucomatous optic neuropathy (66). Blood pressure on average is significantly lower, both in normal-tension glaucoma patients and in high-tension glaucoma patients who progress despite normalized IOP (74). Although there is no doubt that systemic hypotension increases the risk of glaucomatous optic neuropathy, either alone or by increasing sensitivity to raised IOP, not all patients with low blood pressure develop glaucomatous optic neuropathy (1).

Very strong support for the role of ischemia came in the work of Tezel and Wax (78). They examined tissue hypoxia in the retina and optic nerve head of glaucomatous eyes by the assessment of a transcription factor, hypoxia-inducible factor 1alpha (HIF1alpha), which is tightly regulated by the cellular oxygen concentration. They found an increase in the immunostaining for HIF-1alpha in the retina and optic nerve head of glaucomatous donor eyes compared with the control eyes. In addition, the retinal location of the increased immunostaining for HIF-1alpha in some of the glaucomatous

Intraocular Pressure, Perfusion Pressure, and Optic Nerve Energy Metabolism 503

eyes was closely concordant with the location of visual field defects recorded in these eyes. These findings strongly support the presence of tissue hypoxia in the retina and optic nerve head of glaucomatous patients (79).

OCULAR BLOOD FLOW IN GLAUCOMA

Flammer and associates (2002) summarize the findings of ocular blood flow studies in glaucoma. They manage to find general conclusions despite the fact that various authors use different techniques, measure different aspects of ocular circulation (80), include glaucoma patients at different stages (e.g., early vs. late), study different types of glaucoma (e.g., normal-tension glaucoma vs. high-tension glaucoma), and some include provocation tests, whereas others do not. Flammer et al. (1) conclude that the vast majority of studies report reduced ocular perfusion in glaucoma patients. Blood flow decreases with increasing damage; however, the reduction occurs in both early and late stages of glaucoma (81).

The reduction in blood flow involves different parts of the eye, including the optic nerve head (ONH) (82), choroid (83) and retinal circulation, as well as retrobulbar and even peripheral blood flow. Blood flow disturbances generally seem to be more pronounced in normal-tension glaucoma than high-tension glaucoma (77). In most of the studies applying provocation tests, differences between glaucoma and normals were more pronounced under provocation (84,85), and finally, blood flow reduction is more pronounced in progressive than non-progressive eyes (86,87). Blood flow studies in glaucoma are carefully reviewed by Flammer and associates (1), showing that ocular blood flow is reduced in some glaucoma patients. Reduced blood flow was found in all ocular tissues including the choroid, the optic nerve head, and peripapillary area (88–90). The question is not whether blood flow is reduced in glaucoma, but whether this is a primary event and the cause of glaucomatous optic atrophy, or a secondary consequence of this atrophy, where autoregulation reduces blood flow in response to decreased metabolic demand and oxygen consumption in an atrophic tissue (91,92).

Good arguments may be made for the primary role of ischemia in glaucomatous optic atrophy: In some patients, blood flow reduction precedes glaucomatous optic atrophy (93). Experimental studies have produced glaucomatous-like optic nerve damage by application of endothelin-1 in animals with normal IOP (94–97).

Poiseuille’s equation (page 492) predicts that ocular blood flow is reduced with increased IOP and decreased perfusion pressure unless this effect is nullified by an autoregulatory change of the vascular resistance. Retinal blood flow will only be reduced if the autoregulation is malfunctioning or overwhelmed, but the choroidal circulation is more directly affected by perfusion pressure changes. A decrease in blood flow could be due to either decreased perfusion pressure or increased resistance, either from increased viscosity of blood or narrowing of vascular diameters. The most likely players here are perfusion pressure and impaired autoregulation. Change in viscosity (80,98–101) and a general change in vascular resistance from arteriosclerosis, etc., does not seem likely (1,102).

Flammer et al. (1) have proposed that vascular autoregulation is impaired in glaucoma, and this would be a major cause of impaired blood flow and energy

metabolism in glaucoma normal tension glaucoma (NTG) (103–107). This subject is beyond the scope of this chapter, and the reader is referred to Flammer et al. (1).

CARBONIC ANHYDRASE INHIBITORS AND OCULAR BLOOD FLOW

About 1000 mg acetazolamide given orally increases the blood flow in the human ophthalmic artery, measured by using Doppler flowmetry (108,109), and by using the technique of laser interferometric measurements of the fundus, an increase of blood flow in the choroid is also seen (108). Also, there is an increase in retinal blood flow volume after systemic administration of 500 mg acetazolamide shown by using laser Doppler velocimetry and digital image analysis of monochromatic fundus photographs (110). However, Grunwald et al. (111) examined the macular blood flow by using the blue-field simulation technique and did not find a change after 500 mg acetazolamide i.v.

An intravenous injection of 500 mg dorzolamide or 500 mg acetazolamide increases optic nerve oxygen tension in the pig also when IOP is clamped at 14 mmHg (52). The increase in optic nerve oxygen tension is dose-dependent (48), as is the relationship between acetazolamide and cerebral blood flow (112).

The effect of topical carbonic anhydrase inhibitors on blood flow in the eye is widely debated. Martinez et al. (113) found that most hemodynamic parameters of intraocular and periocular vessels improve after application of topical dorzolamide in both normal control and glaucomatous eyes. Harris et al. (114) reported hastened retinal arteriovenous passage of fluorescein dye, and accelerated capillary dye transit in the macula and optic nerve head 2 h after one drop of dorzolamide hydrochloride 2% in healthy subjects using a scanning laser ophthalmoscope, whereas color Doppler imaging found no effect in the blood flow of the retrobulbar vessels (114). Treatment with dorzolamide hydrochloride 2% for 1 month in normal-tension glaucoma patients accelerates arteriovenous passage of fluorescein dye in the retina but does not affect the flow velocity in the central retinal artery or the ophthalmic artery after 4 weeks (115,116). In contrast, Grunwald et al. studied a retinal vein in normal subjects 2 h after one drop of dorzolamide hydrochloride 2% by using bi-directional laser Doppler velocimetry and monochromatic fundus photography and found no effect on either blood flow or vessel diameter (117). Also, Bergstrand et al. (118) found no effect after 6 weeks of treatment with dorzolamide HCl 2% on retrobulbar or retinal flow parameters in newly diagnosed glaucoma patients, using color Doppler flow imaging and scanning laser ophthalmoscopy. Only a few studies have looked at the effect of topical dorzolamide on retinal hemodynamics in experimental animals (119–121), and only one study in our laboratory on optic nerve oxygen tension. Barnes et al. (119) found that 2% topical dorzolamide and brinzolamide, applied twice daily for 7 days, caused an increase in optic nerve blood flow. However, Tamaki et al. (121) found no effect of 1% topical dorzolamide, applied twice daily for 20 days, on retinal tissue circulation in rabbits measured with the laser speckle tissue analyser.

The diverging results from the effect of topical treatment on blood flow in the eye may be due to different experimental setups, different treatment modalities, and groups. Additionally, the techniques used in measuring blood flow are problematic to compare because they measure different parts of the circulation in the eye. Also, the techniques may have difficulties in measuring small changes in blood flow. However, the results

Fig. 12. An experiment where two probes have been placed into the same pig eye. A polarographic oxygen electrode is situated above the optic disc, and the oxygen tension reading is shown in the upper line. A laser Doppler probe is also placed in the same eye above the optic disc, and the laser Doppler tracing is shown as the lower tracing. The injection of 500 mg of dorzolamide intravenously in the pig is indicating with the arrow. Reproduced with permission from Progress in Retinal and Eye Research (4).

CARBONIC ANHYDRASE INHIBITORS AND OPTIC NERVE OXYGEN TENSION

Carbonic anhydrase inhibitors have long been known to increase the blood flow in the brain (123). Studies on the effect of carbonic anhydrase inhibitors on the blood flow in the retina have given controversial results as was reviewed earlier (110,111,114,117). Some of this controversy can be attributed to differences in techniques and technical difficulties in measuring relatively small amounts of blood flow and relatively small changes especially with topical application of the drugs. Also, blood flow in itself is a highly variable parameter. Oxygen tension tends to be much more stable in biological tissues, and therefore, oxygen tension measurements are more likely to show the pharmacologic effect of carbonic anhydrase inhibitors in the optic nerve and retina. Stefansson et al. (48) were the first to report the effect of carbonic anhydrase inhibitors on the oxygen tension in the optic nerve. We studied the oxygen tension of the optic nerve in pigs using the technical approach described earlier. Injecting dorzolamide intravenously produced a significant and a substantial increase in the oxygen tension of the optic nerve (see Fig. 13). The mean optic nerve PO2 was found to be 24 ± 12 mmHg when breathing room air, and 51 ± 29 mmHg while the animals were breathing 100% O2, (mean ± standard deviation; n = 15; p < 0.001). Intravenous injections of 500 mg dorzolamide raised the optic nerve PO2 from 16 ± 6 to 27 ± 12 mmHg, or 53 ± 21% (n = 5; p = 0.017). A dose-dependent effect on optic nerve PO2 was seen with intravenous dorzolamide doses of 1000, 500, 250, 125, 63, 27, 15, and 6 mg