Future of glaucoma hinges on innovations in diagnosis, evaluation, management

SAN DIEGO – The definition of glaucoma is the first item that needs to be addressed as we progress in our understanding and therapy of glaucoma, according to Robert N. Weinreb, MD, in the AGS Lecture here at the American Glaucoma Society Meeting. In his lecture in honor of Paul L. Kaufman, MD, Dr. Weinreb listed 10 vital aspects of glaucoma diagnosis and treatment.

Murray Fingeret

Over the past 2 decades the definition of glaucoma has evolved from a condition defined by the level of IOP to one thought of as a progressive optic neuropathy. Visual field loss may be a presenting sign, depending upon when individuals are identified; it is difficult in some to detect optic nerve or retinal nerve fiber layer (RNFL) damage.

Need for predictive models

The second item that must be addressed, said Dr. Weinreb, is the need for predictive models for who will develop glaucoma. Until the release of the Ocular Hypertension Treatment Study (OHTS), there was little evidence describing which individuals with elevated IOP would develop the disease.

Since the release of data from the OHTS, a series of tools have become available that allow clinicians to assess one’s risk to convert to glaucoma from ocular hypertension (OHTN). These tools are slowly evolving as new information becomes available. They offer clinicians another important piece of information as the decision to treat OHTN is weighed.

Currently, no predictive models indicate which individuals with large cupping or risk factors such as family history are most likely to develop glaucoma. Also, a predictive model would be useful to alert clinicians to which glaucoma patients are at greatest risk for progressing.

Optic nerve damage

Determining what damages the optic nerve was the third item on Dr. Weinreb’s list. Glaucoma develops for different reasons, starting with elevated IOP, which does not explain the etiology for each new case. Multiple studies have shown that about one-third of all cases of glaucoma never experience elevated IOP. Other causes include reduced blood flow, ischemia, toxicity, connective tissue issues and other unknown reasons. This recognizes the need for discovering other ways to treat the condition in addition to reducing the IOP.

Glaucoma models needed

Dr. Weinreb recognized the need for easy-to-use models that mimic glaucoma, which ties into the third item. Whether it is in the rat, mouse or zebrafish, models are needed to demonstrate why glaucoma develops and also to serve as surrogates for therapeutic alternatives.

Imaging the retinal ganglion cell

The need for clinical imaging of the retinal ganglion cell for glaucoma screening was the fifth item on Dr. Weinreb’s list. Over the past 2 decades, imaging has progressed from measuring the optic disc size and neuroretinal rim area to indirectly measuring the RNFL thickness. Recent improvements in imaging have led to the visualization and segmentation of the RNFL. Experimental models incorporating adaptive optics have led to direct ganglion cell visualization. From here we may be able to study the function of individual cells.

Ophthalmic optics are able to compensate for the aberrations found in the eye’s optical system and improve the optical resolution of any instrument that incorporates them. Further improvements will allow single ganglion cells to be imaged as well as metabolism and blood flow to be measured in real time.

Assessing clinical pathways

“Clinical methods are needed to assess the entire clinical pathway,” Dr. Weinreb specified as his sixth item. Growing evidence indicates that damage related to glaucoma is not limited to the eye, but rather extends to the brain. It affects the entire visual pathway going from the retinal ganglion cells to the retinal nerve layer to the lateral geniculate nucleus (LGN) in the brain. Ample evidence shows that all three layers of the LGN are affected as glaucoma progresses.

Brain imaging may become an alternative method for diagnosing glaucoma in the future.

Prevention, restoration

Dr. Weinreb listed his seventh item as “Preventing retinal ganglion cell death and restoring the optic nerve independent of lowering IOP.” The concept of neuroprotection has existed nearly 20 years, and varying animal models have shown methods to prevent further damage once glaucoma begins.

Many of the drugs studied have been used with other neurodegenerative conditions such as Parkinson’s disease or Alzheimer’s disease. While some of these medications have worked in animal models and for other neurodegenerative conditions in humans, none have been shown to be useful in humans for glaucoma.

The other concept to be explored is optic nerve restoration. Can the damaged nerve be healed and visual function restored once glaucomatous damage occurs? Retinal ganglion cells have the capacity to regenerate, although within the confines of the nervous system, many constraints and inhibitory mechanisms need to be modified. While it sounds like science fiction, research is moving closer to the goal of optic nerve restoration.

Lifestyle modification

Dr. Weinreb pointed to the need to understand and improve lifestyles that are deleterious to glaucoma as his eighth item. Lifestyle changes associated with cardiovascular disease, such as diet, smoking, exercise and obesity, are commonly addressed Can any of these principles be applied to the management of glaucoma?

Studies have shown that certain fish oils, when used in an animal model, were associated with reduced IOP. Experimental evidence indicates that modifications in diet may also have an impact on the optic nerve and its ability to withstand damage associated with elevated IOP. Oxidative stress and other proposed mechanisms associated with glaucoma damage might be positively affected with a modification in diet.

The question remains: How do we apply information found in the lab into clinical practice?

IOP, glaucomatous damage

A better understanding of the role of IOP in causing glaucomatous damage was Dr. Weinreb’s ninth item. Surprisingly, little is known about how IOP behaves during the 24 hours of the day. We measure IOP for a brief second every few months and guess what it is the rest of the time.

With systemic hypertension, a 24-hour blood pressure monitor allows measurements to be taken over a long period of time and automatically recorded. No tool is available for glaucoma yet, while some individuals get worse even though their IOP appears to be well controlled.

Liu and colleagues have shown that 66% of IOP spikes occur outside of office hours. The problem is that we do not know which individuals have the spikes. Twenty-four-hour IOP monitoring devices are around the corner, starting with those embedded in a contact lens. A new tool may be available in the near future to illustrate which individuals are at greatest risk due to IOP spikes.

Cellular, molecular mechanisms

Item number 10 is the need to “understand the cellular and molecular mechanisms that regulate aqueous humor outflow through the trabecular meshwork and uveoscleral pathway,” Dr. Weinreb said. This has implications in understanding why the IOP rises as well as potential therapeutic strategies.

The next decade will witness a series of important developments, starting in the ability to recognize glaucomatous damage by visualizing the retinal ganglion cells and continuing to the ability to regenerate the optic nerve if damage occurs.

For more information:

• Murray Fingeret, OD, is chief of the optometry section at the Department of Veterans’ Affairs Medical Center in Brooklyn and Saint Albans, N.Y., and a professor at SUNY College of Optometry. He may be contacted at St. Albans VA Hospital, Linden Blvd. and 179th St., St. Albans, NY 11425; (718) 298-8498; fax: (516) 569-3566; e-mail: murrayf@optonline.net.