Damage to the Lamina Cribrosa in Early Glaucoma

The eye can be modeled as a thick-walled, spherical shell full of fluid that exerts an outward pressure on all of the interior surfaces (like a water balloon, only with a more rigid skin). The posterior two thirds of the eye is lined with a tissue called the retina, which is made up of the cells that receive incoming light and transmute it into electrical signals and the nerves that carry the electrical signals to the brain. More than a million of these nerves converge at the back of the eye, combine into a smaller number of nerve bundles, make a 90 degree turn, and exit the globe through an opening called the scleral canal. The opening of the scleral canal is spanned by several layers of thin sheets of tissue perforated with many holes, through which the nerve bundles pass, like spaghetti through a series of sieves. These perforated sheets form a scaffolding that physically supports the nerve bundles and also guides them on their outward path. On the other side of the scleral canal, the nerve bundles coalesce to become the optic nerve, which travels a complex pathway to the brain where the electrical signals are converted to what we know as vision. Glaucoma is generally thought to be caused by an increase in the fluid pressure inside the eye resulting from reduced fluid outflow. How this increased pressure is translated into the signs and symptoms of the clinical disease we call glaucoma is not known. Our theory is that the increased fluid pressure changes the fundamental character of the connective tissues that make up the scleral canal. Although the walls of the globe are generally sufficiently strong to resist the increased fluid pressure, the perforated tissues of the scleral canal are more delicate and, therefore, are more severely affected. Because these tissues have both nerves and their blood supply running through them, any force that damages their structural integrity or causes them to move from their normal positions may have serious consequences for the health of the nerves. Impairment in the health of these nerves may ultimately be reflected in loss of vision. Our hypothesis is that damage to the structural tissues precedes damage to the nerves and the onset of this damage is predictable on the basis of the distribution of force within the eye. We believe that the force of increased fluid pressure causes changes in the way the tissues respond to the force, at first temporary changes and then, with continued pressure, permanent changes. We have found that artificially induced, short-term increases in pressure result in increased movement of the surface above the perforated tissue sheets that support the nerves in the scleral canal. We consider this to be the beginning of the progression of structural damage that leads to glaucoma. We have found that these short-term episodes of increased pressure result in reversible changes in the behavior of the tissues, but that with long-term increased pressure, the tissues lose their ability to recover, much like an elastic band becomes permanently enlarged by constant stretching. Thus, with the movement and “stretching” of the support tissues, the nerves and their blood supply lose their structural support and sight-threatening damage ensues. These ideas are not only supported by our preliminary laboratory studies, but also can be used to explain the pattern of nerve damage and peculiar changes in the back of the eye, known as “optic disc cupping,” that are observed in human patients with glaucoma. Although these ideas explain what we believe and what we see, however, there is as yet little hard evidence proving that these phenomena actually occur. Thus, one specific aim of our studies is to show that movement under increased pressure occurs not only at the surface of the tissues at the entrance to the scleral canal, which we observe clinically as “cupping,” but also in the underlying support tissues, which we cannot see. To this end, we will induce short-term increased pressure in one eye of a monkey and keep the other eye at normal pressure, then carefully compare with hundreds of serial sections the entire architecture of this part of the eye to determine how the pressure increase physically affects the underlying structures. A second specific aim is to demonstrate that continued high pressure (experimental glaucoma) alters the “normal” movement response of the surface and underlying tissues into an abnormal and excessive level of deformation. In these experiments, experimental glaucoma will be induced in one eye of a monkey, with the other eye kept at normal pressures. Short-term increases in pressure will be applied at regular intervals and the amount the tissues move will be measured, until it becomes apparent that there is an increased “give” in the tissues, that is, the amount of deformation or movement of the tissues for a given change in intraocular pressure has increased. At that time, serial sections of both eyes will be compared to determine that the amount of increased movement seen clinically is present at a microscopic level. We will use highly sophisticated imaging and statistical techniques to detect the changes in these comparisons, and one of our immediate goals is to accumulate a large database of images with which we can do two things: 1) develop the first structural engineering model of the effect of forces in eyes with glaucoma, and 2) perform the first three-dimensional reconstruction of the vulnerable anatomical areas in the normal and early glaucomatous eye. Both of these projects will not only provide the basis for our future studies, but will also provide an important resource for other researchers to use in advancing our knowledge of the pathology of this disorder. A long-term goal is to use this information to construct a finite element model of the distribution of force within the normal and the glaucomatous eye. With this kind of model, each variable can be examined independently, so that we can look at theoretical alterations in physiological processes and anatomical changes and determine their effect on the progression to glaucoma. Ultimately, our goal is to identify the physical principles that underlie this disorder, in order to discover new approaches to early diagnosis, prevention, and evaluation of treatment for this debilitating disease.

Grantee institution at the time of this grant: Louisiana State University Health Sciences Center—Shreveport