Zeroing in on a Predictor of Who Will Develop Severe Glaucoma — and Why

In glaucoma, elevated intraocular pressure (IOP) leads to the death of retinal ganglion cells (RGCs) in the optic nerve, which are responsible for transporting visual information from the eyes to the brain. These specialized nerve cells do not regenerate, and when enough of them die, irreversible vision loss occurs.

Much of glaucoma treatment, then, has focused on controlling IOP with medication, laser treatment, surgery or a combination of these. But while some patients’ glaucoma remains stable over time with treatment, others’ progresses to severe disease and vision loss. Now, a research collaboration between Wilmer Eye Institute and the Johns Hopkins University Department of Mechanical Engineering is aimed at understanding why.

The team is studying the effect of changing IOP on a part of the optic nerve head called the lamina cribrosa (from the Latin meaning “sieve-like layer”) — known to be a major site of damage to RGCs in glaucoma. The researchers want to know how and why the nerve cells become damaged as they pass through this complex structure.

Harry Quigley, the A. Edward Maumenee Professor of Ophthalmology, likens the lamina cribrosa (LC) to a colander — except, he says, there are 10 colanders in a series, one on top of another, and instead of metal, they’re made of connective tissue. “We’re looking at the layers of connective tissue and what they do when the eye pressure changes, and from that, trying to infer what’s going on in a chronic patient with glaucoma whose eye pressure, we know, is related to the damage the disease is causing,” explains Quigley.

The researchers believe that the strain or displacement of those tissues caused by changing pressure on the optic nerve head holds clues that may allow them to predict which patients are likely to develop severe glaucoma.

Consider the S’More

To understand the concept of strain and how it can affect the LC, it can be helpful to think about the making of a traditional campfire treat: the s’more. Here, a roasted marshmallow is sandwiched between two graham crackers. (There’s also chocolate involved, but we’ll leave that out for the purposes of this discussion.) If you push down on the top graham cracker, the marshmallow changes — it flattens a bit and its sides bulge outward.

In the case of the eye, the researchers theorized that it wasn’t only compressive strain (the marshmallow flattens) or expansile strain (the marshmallow stretches taller when you pull back up on the top graham cracker) that can affect the LC when the pressure is changed, but also a force known as shear strain (the marshmallow deforms due to a combination of sideways pressure and compressive strain — not just up or down, but diagonally). Now, for the first time, they were able to test this theory.

Using a sophisticated system developed by Thao Nguyen, a Johns Hopkins professor of mechanical engineering with a joint appointment in ophthalmology, the team measured the effects of stress on the LC in a group of patients whose IOP was lowered as part of routine postoperative care following glaucoma surgery.

Measuring the eye’s structure before and 20 minutes after lowering the pressure, the researchers were able to prove not only that shear strain is implicated, but that it is as big of a factor in terms of damage as are compressive and expansile strain. But they also found something unexpected.

It has long been thought that the worse glaucoma becomes, the less flexible the eye’s tissues become. If that were true, the eyes of people with worse damage wouldn’t respond as much to increased IOP — they would show less strain because their eyes would be, for lack of a better term, stiffer. But that’s not what happened. Instead, the worse the glaucoma damage, the more the LC strained at the same amount of pressure change.

The question now is whether these patients — whose optic nerve head displaces more with the same amount of pressure — were that way before they developed glaucoma and that’s why they developed greater damage, or whether they became that way as a result of something that occurs over the course of the disease. To find out, the researchers plan a prospective study to look at changes in the eyes over time, rather than at a single point as this study has done.

“The goal,” Quigley says, “is to be able to say to a patient when they walk in the door, you’re one of those who is likely to do well with standard treatments, or, unfortunately, the way your eye responds to changing pressure is indicative of people who got rapidly worse with standard therapy, so we’re going to have to be much more aggressive in either lowering your eye pressure or developing other treatments."