Ganglion cell death may be caused by vascular damage

A new hypothesis suggests that ganglion cell death is caused by vascular insults at the optic nerve head and offers a new treatment for glaucoma.

ByMichael J. Walsh

OXFORD, England – A new hypothesis on the cause of glaucomatous damage suggests that surgeons should primarily be looking at the back of the eye, where the damage occurs.

In a recent study published in the British Journal of Ophthalmology, Neville N. Osborne, PhD, DSc, and colleagues reported that the pattern and progression of visual field loss in patients with glaucoma indicates that ganglion cells do not die simultaneously. He believes both visual field loss and neuroretinal rim loss follow typical patterns, and there is experimental evidence of a preferential loss of ganglion cells in the peripheral retina.

In particular, Prof. Osborne said sustained or intermittent vasogenic insults to groups of astrocytes and other components in the optic nerve head region may explain ganglion cell death. Sufficient risk factors, including sustained elevation of the IOP, affect the quality of the blood supply in the optic nerve head, he said. As a result, the nutritional supply to the optic nerve head is slowly compromised, particularly affecting astrocytes, microglia and ganglion cell axons.

The hypothesis asserts that while the ganglion cell axon may be affected in the initial stages of the insult, the whole cell will eventually be affected with glutamate particularly being “non-physiologically” released into the extracellular space. Astrocytes and microglial cells are also likely to release a variety of protective and damaging factors, he said.

“Increased glutamate is potentially toxic to many retinal cells. Müller cells eventually become inefficient, further increasing glutamate and GABA levels. The ganglion cells, being at a lower homeostatic status, are particularly susceptible. At a particular point, excessive glutamate will result in ganglion cell death,” Prof. Osborne wrote.

He said he believes the death rate is variable, depending on the number of excitatory and inhibitory receptors associated with the neuron. This hypothesis suggests that the initial insults to the ganglion cells occur in the optic nerve head. Prof. Osborne said there are numerous vasoprotective and neuroprotective strategies that may be targeted for pharmacological intervention, including prevention of toxic substance release from astrocytes/microglia, prevention of glutamate toxicity to retinal neurons and administration of neurotrophic factors.

Birth of a hypothesis

Prof. Osborne noted that it is now commonly accepted that glaucoma is a progressive optic neuropathy with characteristic optic disc changes and associated visual field defects. He said studies have shown the pattern and progression of visual field loss due to ganglion cell death varies between glaucoma patients, suggesting there is some variability in the magnitude of the insult responsible for the cell loss.

“Ganglion cell death with a spatial and temporal distribution typical of ‘glaucoma’ can be experimentally induced in animals. One way to try and mimic glaucoma in experimental animals is to raise the IOP,” he said.

“It is clear from such studies that ganglion cells do not all die at the same time. Furthermore, the rate of deterioration of ganglion cells is proportional to the magnitude of the insult. The reason for the initiation of ganglion cell death in glaucoma is unknown, but a number of explanatory theories have been proposed with the vasogenic theory perhaps the most widely accepted hypothesis,” he said.

However, Prof. Osborne said raised IOP is not the sole factor responsible for glaucomatous retinal damage.

“Only 10% of patients with increased IOP (22 mm Hg) have glaucoma, and between one-third and one-half of patients with glaucoma initially do not have elevated IOP. Furthermore, as many as one-sixth of patients with glaucomatous damage do not appear to have elevated IOP.

“It is therefore clear that raised IOP is not synonymous with having glaucoma. Nevertheless, high IOP is arguably the most important risk factor and it is clearly associated with ganglion cell death in glaucoma patients,” he said.

He pointed to other studies that have shown that vascular insufficiency at the optic nerve head plays an important role in the pathogenesis of glaucomatous optic neuropathy and that glaucomatous optic neuropathy is a multifactorial disease.

Prof. Osborne noted that there is now strong support for the view that an alteration in the quality of blood supply in the optic nerve head can lead to glaucoma.

“The main blood supply to the optic nerve head is from the posterior ciliary artery via the peripapillary choroid and short posterior ciliary arteries or the circle of Zinn-Haller. It is the quality of the blood supply from these vessels that may be particularly affected, rather than the blood flow in the central retinal artery,” he said.

“An alteration in the quality of blood supply in the optic nerve head capillaries could be indirectly triggered to a greater or lesser extent by increased IOP, abnormal blood pressure, altered rheological characteristics of the blood, local vasospasm, possibly hemorrhage, autoregulatory defects or changes in the physiological and/or physical characteristics of the blood vessels in question.”

Prof. Osborne said if an alteration in blood flow occurs, the tissues in the optic nerve head might suffer oligemic and/or hypoxic insults as a result of the alteration of the local oxygen supply.

Visual field loss patterns

“Both visual field loss and neuroretinal rim loss appear to follow typical patterns in glaucoma, which would imply that certain ganglion cells are more susceptible than others,” Prof. Osborne said.

“Also, a preferential loss of ganglion cells in the peripheral retina seems to occur in experimental glaucoma both in monkeys and rats. It would appear, therefore, that a differential rate of death of ganglion cells occurs. In the present review, we hypothesize that both axonal injury at the optic nerve and the repertoire of inhibitory and excitatory receptors of each ganglion cell have a major role in determining the cell’s fate in glaucomatous neuropathy,” he said.

He noted it is important to remember that glaucomatous visual field abnormalities have been reported to precede structural changes of the optic nerve head and nerve fiber layer. Structural changes at the optic nerve head may therefore be apparent before total loss of ganglion cell function, supporting the opinion that the initial insult in glaucoma occurs at the optic nerve head and that the death of the ganglion cell soma is not the cause for cupping.

Prof. Osborne pointed out a number of possible factors that might cause damage to the ganglion cells. An increase in the intracellular calcium concentration in ganglion cell axons as a result of oligemia/hypoxia may trigger disruption of axonal transport and cytoskeletal breakdown as demonstrated in isolated optic nerves under hypoxic conditions. Sustained or intermittent insults to groups of astrocytes in the optic nerve head region could also cause them to become “reactive,” change shape, possibly swell and even die. Astrocytes in the lamina cribrosa and prelaminar region of the optic nerve head provide structural and cellular support and participate in forming the extracellular matrix.

“A recent population study revealed that ‘cupping’ of the optic nerve head is found in 92% of eyes with arteritic anterior ischemic optic neuropathy and in 2% of eyes with non-arteritic anterior ischemic optic neuropathy. The reasons for the low incidence of ‘cupping’ in nonarteritic anterior ischemic optic neuropathy are unknown, but it has been proposed by Hayreh that the ischemic process may not be as marked and massive as in arteritic anterior ischemic optic neuropathy.

“It may well be that similar alterations in the quality of the blood supply to certain regions of the optic nerve head develop both in glaucoma (in a chronic, slowly progressive way) and arteritic anterior ischemic optic neuropathy (in an acute, rapidly progressive way) leading to a similar, although not identical, ‘cupping’ of the optic disc,” Prof. Osborne said.

He pointed out that astrocytes are abundant in the optic nerve head as well as throughout the remainder of the retina and have the capacity to communicate with their respective neighboring astrocytes via gap junctions as well as with Müller cells.

“Astrocytes therefore have the capacity to communicate with other glial cells throughout the retina. An insult in the form of reduced energy to a collection of these cells in the optic nerve head may theoretically, then, be signalled to many other retinal astrocytes. Studies on cultures of astrocytes strongly support this view,” he said.

Prof. Osborne said that astrocytes are thought to play a major part in the process of spreading depression in the retina with potassium, calcium and other substances including glutamate being involved.

“Spreading depression is known to increase glucose consumption and to place an additional energy demand upon cells. It has also been demonstrated to occur in brain tissues during hypoxia. Thus, oligemia/hypoxia to the optic nerve head may cause astrocytes in this region to no longer function efficiently.

“For example, they may become unable to maintain the correct ionic homeostasis or to communicate information to regions outside the retinal optic nerve head area. They may also release substances such as nitric oxide, prostaglandins, glutamate or other factors into the extracellular milieu, which could exacerbate injury to ganglion cells and other neighboring structures such as microglia and the lamina cribrosa,” he said.

His hypothesis also suggests that the cascade of events that leads to ganglion cell death in glaucoma proceeds at a slow and variable rate depending on the nature of the oligemic/hypoxic insult to the optic nerve head. The insult may either be gradual, continuous or variable in intensity and may occur over many years.

Reducing cell death

The key in reducing ganglion cell death may be in halting the risk factors that cause the oligemic/hypoxic-like insult in the optic nerve head, Prof. Osborne said.

“If instances were found where raised IOP was identified as the major cause of the insult, then reducing IOP either by surgery or with a pharmacological agent would be the ideal approach. Lowering IOP, nevertheless, often proves beneficial even in patients with normal-tension glaucoma, suggesting that there is a level of ‘tolerable’ IOP which depends on other accompanying factors, such as the quality of blood supply to the optic nerve head,” he said.

“In such cases, one approach might be to correct whatever causes the change in the quality of blood supply in the microvasculature of the optic nerve head. This could mean simply increasing blood flow in the optic nerve head, assuming such a strategy is feasible. Until it is possible to establish reasons for any alterations in the quality of the blood supply in the optic nerve head, it will be difficult to devise an appropriate treatment,” he said.

Prof. Osborne said he believes the term “neuroprotection,” in the context of glaucoma, implies that an agent reaches the retina and slows down the cascade of events leading to ganglion cell death. A number of substances have been shown to attenuate ganglion cell death in animal experiments. These include certain neurotrophins, NMDA-receptor antagonists, free-radical scavengers, calcium-channel blockers, adrenoceptor agonists, betaxolol and nitric oxide synthase inhibitors.

“It remains to be investigated whether a drug that stops spreading depression will benefit glaucoma patients. It is known that some compounds (such as MK-801) are able to inhibit retinal spreading depression associated with astrocytes and can also protect against ischemia-induced damage,” Prof. Osborne said.

Pharmacological agents that counteract changes to optic nerve head astrocytes caused by an oligemic/hypoxic insult may also benefit glaucoma patients, according to Prof. Osborne.

“It has been shown that nitric oxide synthase is altered in optic nerve head astrocytes in both glaucoma patients and also in animals following a sustained elevation of IOP,” he said.

For Your Information:

Neville N. Osborne, PhD, DSc, can be reached at Nuffield Laboratory of Ophthalmology, University of Oxford, Walton Street, Oxford OX2 6AW, United Kingdom; +(44) 1-865-24-8996; fax: +(44) 1- 865-79-4508; e-mail: neville.osborne@eye.ox.ac.uk.

Reference:

Osborne N, Melena J, et al. A hypothesis to explain ganglion cell death caused by vascular insults at the optic nerve head: possible implication for the treatment of glaucoma. Br J Ophthalmol. 2001;85:1252–1259.