Neuroprotection in glaucoma: a new paradigm in vision preservation

Neuroprotection, a strategy to slow or prevent the death of retinal ganglion cells, offers the possibility of slowing the rate of glaucomatous progression and preventing blindness. But although the underlying theory appears to be sound, much has yet to be learned through basic and clinical research before neuroprotection could become an integral part of glaucoma therapy.

At a breakfast symposium held at the Venetian Hotel, panelists provided an update on the science of neuroprotection and its clinical applications. Robert N. Weinreb, MD, distinguished professor of ophthalmology and director, Hamilton Glaucoma Center, University of California, San Diego, La Jolla, described glaucoma as an optic neuropathy in which patients lose visual field despite lowering of IOP.

"Neuroprotection targets the final common pathway of retinal ganglion cell injury and is aimed at blocking primary destructive events or enhancing the survival of functions of the retinal ganglion cells or their axons," he said. "It's also directed at the damage that occurs during the progressive secondary stage of injury in which we have changes in the extracellular milieu."

"It's not sufficient to just preserve the ganglion cells and their axons; we need to preserve their physiologic function," he added.

Neuroprotection has been studied for therapeutic application in various conditions, including Alzheimer's disease and stroke; studying its potential benefit in glaucoma therapy is difficult because disease progression is an extremely slow process and trials would require many years and a large number of patients, Dr. Weinreb said. He suggested that the currently used IOP-lowering drugs could be evaluated for any neuroprotective ability, which might lessen the time before a neuroprotective strategy could be proven to be safe and effective.

The future of glaucoma therapy unquestionably will continue to include lowering of IOP to prevent optical nerve damage, but it will almost certainly include neuroprotection as well, Dr. Weinreb said.

"There should be no question at this time that neuroprotection to directly prevent retinal ganglion cell death and to preserve their function independent of IOP lowering is coming," he said. "It is the future, and it's needed in glaucoma."

Dr. Weinreb was co-chairman of the program, along with Jeffrey M. Liebmann, MD, clinical professor of ophthalmology, New York University School of Medicine.

Continuing to explain the foundations of neuroprotection, Neeru Gupta, MD, PhD, outlined the connections between the eye and the brain. Dr. Gupta is associate professor, department of ophthalmology and visual sciences and department of laboratory medicine and pathobiology, St. Michael's Hospital, University of Toronto, Ontario, Canada.

Numerous mechanisms are implicated in neurodegeneration, and one of the most abundant neurotransmitter is glutamate, which can be toxic if present in excess.

"If we can block glutamate with a drug such as memantine, we can relieve some of the insult that is being generated," Dr. Gupta said.

Memantine hydrochloride, a moderate affinity NMDA-receptor antagonist, has been used in Parkinson's disease for over 20 years, and it has also been approved for Alzheimer's disease under the name Namenda (Forest Laboratories). In a study of memantine for glaucoma in a monkey model, the drug protected the neurons from shrinkage.

"This is important because there are studies that relate cell size to cell function," Dr. Gupta said.

Memantine is being studied in a worldwide clinical trial with visual field as the endpoint, but some ophthalmologists already offer it to their patients off-label. Two of the panelists at the symposium said that they suggest this drug to patients who have exhausted all other therapeutic options.

Beyond the theoretical underpinnings, other speakers explained how neuroprotection could be applied in clinical practices. Ananth Viswanathan, MD, FRCOphth, described measurement of neuroprotection through visual field testing, and David S. Greenfield, MD, explained measurement through imaging of the optic disc and retinal nerve fiber layer. Dr. Viswanathan is consultant surgeon, glaucoma service, Moorfields Eye Hospital, London; Dr. Greenfield is professor of ophthalmology, Bascom Palmer Eye Institute of the Palm Beaches, University of Miami School of Medicine, Palm Beach Gardens, FL.

While waiting for results of studies of neuroprotection and for new technologies for measuring the structure and function of the optic to emerge, clinicians have practical technologies for predicting progression that can be applied now, Dr. Viswanathan said.

Progression analysis can either be trend-based or event based. Event analysis defines a baseline then looks at the end of a series of images, such as visual fields, and compares the two. If there is any difference, progression has occurred.

Trend analysis takes one location and looks at how it behaves over time. A line is fitted to a series of images; if there is significant downward slope, the point has progressed, and if not, it is stable.

Event-based analysis has already been proven to be effective in clinical trials, and at least one study suggests that trend-based analysis could also be applicable in a research setting, Dr. Viswanathan said.

But barriers to clinical utility must be overcome before it can be applied to the practice setting. These include perimetric artifacts, the learning effect, and fluctuation. Filtering methods are being tested that will improve the repeatability of these approaches to progression analysis, and it is likely that both trend-based and event analysis will soon be practical in clinical use, Dr. Viswanathan added.

Dr. Greenfield also discussed practical applications of neuroprotection, noting that clinicians need to look at the optic disc more frequently and more critically to measure the effect of neuroprotection. An expanding body of evidence indicates that imaging devices can detect change, although to do so the structural endpoints-optic disc photographs as well as other ancillary measures-must be extremely precise. Also, two-dimensional maps will probably be the best type of scan.

"Neuroprotection can be assessed in clinical practice," Dr. Greenfield concluded. "You have the ability to do that, but remember never to forget acquiring optic disc photographs and carefully evaluating them at periodic intervals. Selective structural testing using the GDx, the HRT, and the OCT does have the capacity to better identify glaucoma structural progression, given its greater reproducibility, increased sensitivity, and more robust identification of structural endpoints and perhaps a shorter period of time. It probably will require much more frequent evaluation and much more frequent ancillary diagnostic testing. Confidence limits need to be established based on the stage of glaucoma, we certainly need more robust software algorithms to identify progression, and we need validation of those algorithms in randomized clinical trials."

Dr. Liebmann concluded the presentations with a preview of the implications of neuroprotection for management of glaucoma patients.

"Over the next 10 years neuroprotective agents will be available to us, and it's going to change the way we manage and evaluate our patients," he said.

Clinicians will need to give more thought to treatment of non-pressure dependent pathways and pressure-independent risk factors, he added.

Among the questions to be addressed are who to treat with neuroprotective agents and when, and the effectiveness of treatment.

"Even though we don't have those medications available to us today, over the next year or so we need to come up with paradigms that will allow us to determine who should we treat and who should not be treated. Essentially, will we consider neuroprotection for selected patients only, or for many patients in our medical practices?" Dr. Liebmann asked.

The initial inclination of most physicians is to reserve a new therapy for the most advanced cases, but neuroprotection could be approached differently.

"I believe we will apply neuroprotection to the vast majority of glaucoma patients," he said.

The program was jointly sponsored by the New York Eye and Ear Infirmary, which received a financial benefit from Allergan Inc., and by CME², an independent subsidiary of Advanstar Communications, publisher of Ophthalmology Times.