BIOMECHANICAL RISK FACTORS FOR GLAUCOMA

The biomechanical risk factors for glaucoma may play a central role in the pathophysiology of the disease and modifying some of those risk factors may prevent the disease’s onset and progression, according to research presented at the 10th European Glaucoma Society Congress. “Some risk factors for human glaucoma that we already know about are longer axial length, larger diameter of the optic nerve head, thinner central corneal thickness and lower corneal hysteresis. These are biomechanical features of the eye,†said Harry Quigley MD, Wilmer Eye Institute, Johns Hopkins Medical School, Baltimore, Maryland, US.

The underlying cause of the innate differences in the structure of eyes more prone to glaucoma may also underlie glaucoma’s characteristic pattern of damage to the optic nerve head. Differences in the sclera, in particular, may play a central role, Dr Quigley added. “Many glaucoma patients have normal eye pressure. One reason for that may be that their sclera transmits abnormal force to the optic nerve at normal eye pressure,†he added. He noted that the difference between glaucoma and other optic neuropathies, such as ischemic optic neuropathy, is that although there is axonal loss in both conditions, only in glaucoma is there a connective tissue-mediated backward and outward movement of the lamina cribrosa. The result is the much larger cup/disc ratio in glaucomatous eyes than is the case with ischemic optic neuropathy of similar severity, Dr Quigley said. Research supports the theory that the initial glaucomatous damage sets in motion a chain of events, starting with the injury of axons and a consequent blocking of axonal transport, which in turn blocks trophic factors from reaching the axons, which in its turn initiates the apoptosis of retinal ganglion cells, he added.

Of mice and men

Dr Quigley noted that animal studies with the mouse model of glaucoma that he and his associates have conducted have shown that the standard pigmented B6 variety of mouse had 50 per cent less axonal loss than did the CD1 breed of mouse, which has a longer axial length. The experiments involved artificially inducing ocular hypertensive conditions in the animals, he said. In addition to having longer eyes, the CD1 mice also had thinner scleras, both near the limbus and in the peripapillary area, Dr Quigley noted. The mice that were less susceptible actually thickened their sclera in five out of the six zones, he said. Further research, comparing the CD1 mouse and a mutant myopic strain, with a variant gene for the collagen 8 molecule, showed that the mutant strain had practically no axonal loss at all when challenged with artificially induced ocular hypertension. He noted that collagen 8 is an important component of many ocular structures, including the cornea. This may help explain why thin corneas are a risk factor for glaucoma, he added. “It’s not so much that the cornea is thin and the lamina cribrosa is thin, but it is that eyes that have a thin central cornea may have developed that way because of differences, polymorphisms in their collagen 8 genes, that also affect the sclera and how the sclera responds to ocular pressure,†Dr Quigley added.

If similar variations in human collagen 8 are found in human glaucoma patients it may open the way to new treatment strategies for the disease, possibly based on a principle similar to that of collagen cross-linking in the corneas of eyes with keratoconus. “One treatment to the sclera could alter the sclera for a considerable period of time, potentially even permanently altering how the sclera responds to the intraocular pressure,†Dr Quigley said. Research done in a monkey model of glaucoma supports the importance of connective tissue remodeling with the sclera and lamina cribrosa as important in the disease, said Claude Burgoyne MD. He added that viewing glaucomatous damage from an engineering perspective can offer a fresh perspective on the disease. “The dynamic interplay between intraocular pressure and cerebro-spinal fluid pressure creates engineering stresses and strains within the tissues which also influences the flow of blood through the sclera and the lamina on its way to the optic nerve head,†Dr Burgoyne said.

The pathophysiology of glaucoma has a connective tissue component and axonal or neural tissue component, which are intricately linked by the behaviour of astrocytes and glial cells. The risk factors that influence how connective tissues are damaged include ischemia, physical compression from engineering stresses and strains as well as expansion, all which are likely to be mediated by or contributed to by the astrocytes and glia. He noted that in experiments involving a monkey model of glaucoma, artificially induced ocular hypertension not only induced a bowing of the sclera and lamina, it also resulted in a thickening of the sclera. In later stages of the disease the sclera became thinner. “Our working hypothesis is that connective tissue remodelling is a core component of both the physiology and pathophysiology of ageing and the pathophysiology of glaucomatous damage to the optic nerve head tissues,†he added. He added that their research has also shown that, as glaucoma progresses, the insertion point of the lamina cribrosa migrated back to the eye’s pia and becomes detached from the sclera. Should these changes also occur in humans with glaucoma, detection of the changes with enhanced OCT imaging could enable earlier and more definitive diagnosis of the disease, he said.