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Primary open angle glaucoma (POAG) is a chronic, asymmetric bilateral eye disease charac-terised by open drainage angles and progressive optic neuropathy that may or may not be associated with a statis-tically-elevated intraocular pressure (IOP). The optic neuropathy is expressed as progressive cupping of the optic disc with nerve fibre layer loss and typical abnormalities of the visual field.
The pathogenesis of primary open angle glaucoma is still debated.1 The main risk factor is raised IOP, however, other factors, including family history, age, race and vascular changes, may be more important in some patients. Indeed, while there is an increasing prevalence of optic nerve injury as IOP increases, 20 to 30% of patients with POAG do not exhibit the primary risk factor.2 Many patients have progressive optic neuropathy despite normal IOPs being found on repeated measurements. Moreover, 20 to 30% of patients with POAG progress despite therapy, even if the IOP is lowered into the sub-normal range.3 Because of these observations, it is clear that elevated IOP cannot explain all the nerve damage occurring in patients with POAG, and other mechanisms, including vascular changes, have been invoked to explain glauco-matous optic neuropathy.
Vascular Changes in Patients With POAG
It has been observed that some glaucoma patients have a vasospastic tendency. Isolated areas of vasospasm have been observed in patients with POAG around the optic nerve head, and it would appear that these areas correlate with the regions of greatest nerve fibre loss and cupping (Figure 1).4
| Figure 1. Focal vasospasm adjacent to a cupped optic nerve head. |
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Gasser and Flammer have also measured capillary blood flow velocities in the fingertips of 30 patients with normal tension glaucoma (NTG) after the contra-lateral hand was cooled in iced water.5 These patients were com-pared with 30 subjects who had high tension glaucoma (HTG) and 30 control patients. It was discovered that 25 of the 30 NTG patients had capillary stand- still of 12 seconds or more compared with only a few of either the patients with HTG or the controls having any measurable capillary standstill.
Nocturnal systemic hypotension also appears to correlate with visual field progression,6,7 while other investigators have demonstrated that diastolic per-fusion pressure, or the difference between the diastolic blood pressure and the IOP appears to be linked to glaucoma risk (see table 1).8
| Table 1. Diastolic perfusion pressure versus glaucoma risk. |
| DPP (mmHg) ratio |
Glaucoma risk
|
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> 50
40 - 49
30 - 39
< 30 |
1.00
1.72
2.14
6.22
|
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| Abbreviations: DPP = diastolic perfusion pressure |
Evidence for vascular impairment has also followed improvements in technologies for measuring ocular blood flow. In particular, colour Doppler imaging (CDI) has been widely used to investigate vascular disturbances in patients with POAG.9 Table 2 summarises the findings of several investigators who suggest that there are reduced velocities of blood flow in the ophthalmic, central retinal and posterior ciliary arteries that occur in both HTG and NTG.10-12
| Table 2. Results of colour Doppler imaging from three authors. |
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Abbreviations: NTG = normal tension glaucoma;
POAG = primary open angle glaucoma; OA = ophthalmic artery; CRA = central retinal antery; PCA = posterior ciliary artery; vel = velocity |
Whether reduced velocities correlate precisely with flow in these vessels is unclear. It has also been suggested that such changes might reflect decreased metabolic demand or other changes secondary to the disease process rather than a relation to the primary cause of the disease.13 Nonetheless, blood flow has been shown to be abnormal in patients with glaucoma and some therapies that possibly improve blood flow may also improve visual field survival.14
Kitazawa et al.15 have demonstrated improved visual field performance in 6 of 25 patients with NTG using oral nife-dipine, an L-channel calcium antagonist that produces vasodilatation. Others have shown that the use of these agents slow the progression of NTG but not HTG.16 This suggests that therapeutic concepts other than lowering IOP need to be considered for such patients.
 
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Mechanical Damage of Retinal Ganglion Cells
It is acknowledged that the axon, either in the pre-laminar or laminar optic nerve, is the site of the damage to retinal ganglion cells in POAG. Direct compression of axons by distorted laminar beams from raised IOP may interfere with axoplasmic flow.17 This, in turn, may disturb the normal retrograde flow of trophic factors from the axon terminal to the cell body and so trigger apoptosis and cell death.
Neuronal apoptosis in the developing nervous system results from inadequate neurotrophic support.18 Neuroprotective factors that promote survival in cultures of human retinal ganglion cells (RGCs) include basic fibroblast growth factor (bFGF), brain derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (cNTF). What and how many trophic factors arise from the lateral geniculate nucleus (LGN) and are transported back to the retina is unknown. In vitro, BDNF seems the most potent at protecting RGCs from death after axotomy. During the development of the retina, growing RGC axons that contact these LGN cells survive, probably through the release of BDNF into the axon terminals of the RGCs. Other cells undergo apoptosis.
The maintenance of such trophic support is thought to be essential for ongoing survival of the RGCs and distur-bances of axoplasmic transport could induce apoptosis in susceptible cells.19 Some studies have linked inadequate neurotrophic support with mitochondrial dysfunction and defective energy production.20 In non-neural cells, a fall in mitochondrial membrane potential is one of the earliest events in apoptosis. The outward pumping of protons produces a gradient that drives the conversion of adenosine diphosphate to adenosine triphosphate. Falling energy production produces a rise in reactive oxygen species and could be the trigger for apoptosis in normal development and in diseased cells.
Apoptosis of Retinal Ganglion Cells
The characteristic optic nerve morphol- ogy reflects progressive death of RGCs. Although the exact mechanism of the optic neuropathy is unclear and, in particular, whether mechanical or ischaemic insults damage RGC axons, RGCs do die by a process of pre-programmed cell death called apoptosis.21 The possible pathways leading to apoptosis of RGCs are summarised in figure 2.
| Figure 2. Mechanism of neuronal cell damage. |
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Apoptosis is a gene-directed form of cell death that is essential for normal development and continued health.22 Apoptosis occurs in a variety of tissues in the body and is the mechanism by which most, if not all, developmentally programmed cell death occurs. It can be initiated by a variety of stimuli and is distinct from other types of cell death such as necrosis, which are associated with inflammation. Apoptosis produces cleavage of DNA into short segments followed by the shutdown of protein synthesis and all cell function, with eventual consumption of cell structures by neighbouring cells.23
Abnormally high levels of apoptosis have been linked to various neuro-degenerative diseases.24 A number of neurodegenerative disorders including stroke, epilepsy, Parkinson's disease, AIDS dementia and amyotrophic lateral sclerosis are all due, at least in part, to the process of apoptosis. Cells with evidence of apoptosis are 10 times more prevalent in glaucoma patients than in controls. Moreover, after initial injury, functional damage may continue in some diseases even after the primary stimulus for neuronal apoptosis has been removed.25 Research into the central nervous system (CNS) has defined pro-cesses that produce secondary degene-ration, where initial damage spreads to adjacent healthy neurones that escaped the primary injury. Delayed functional loss in glaucoma patients is well known, with many patients showing continuing progression even after the primary risk factor of raised IOP is removed.26
An increasing number of triggers have been identified that lead to apoptosis. Excitatory amino acids induce both acute membrane depolarisation and also latent cellular toxicity in many neurological disorders. Increases in excitatory amino acids lead to increased potassium, calcium and free radicals within the cell. Indeed, glutamate toxicity has been implicated in the secondary degeneration of retina ganglion cells in POAG. Dreyer27 has reported elevated levels of glutamate in the vitreous of glaucomatous eyes under-going cataract surgery. The concentration of glutamate in the posterior vitreous of monkeys with untreated glaucoma was also found to be elevated more than 7-fold and was directly toxic to the RGCs at this level.
Activation of the N-Methyl-D-Aspartate (NMDA) receptor by glutamate increases intracellular calcium and potassium concentration and raises free radicals, which all precede the appearance of apoptotic nuclear changes.
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