WOC symposium: Neuroprotection as possible wave of the future in glaucoma therapy

Do pressure-independent factors play a role in glaucoma? That would seem to be the case, since the disease progresses in many patients despite IOP reduction. Enter a new line of thinking about the disease, neuroprotection, which was the topic of a symposium held here in conjunction with the World Ophthalmology Congress.

According to Robert N. Weinreb, MD, distinguished professor of ophthalmology and director, Hamilton Glaucoma Center, University of California at San Diego, La Jolla, CA, elevated IOP is only one of the risk factors in glaucoma. The disease, he said, is neurodegenerative, characterized by injury to the optic nerve and retinal ganglion cells (RGC).

That's why neuroprotection, a therapeutic strategy that aims to prevent glaucoma progression by modulating IOP-independent pathways to delay or prevent injury to neurons in the visual pathway, may become an important element of glaucoma therapy.

"We anticipate that neuroprotective therapy, if and when it's available, will be complementary to IOP-lowering therapies," Dr. Weinreb said.

Keeping RCGs alive and functionally connected to targets in the brain is the idea, agreed Theodore Krupin, MD, clinical professor, Department of Ophthalmology, Feinberg School of Medicine, Northwestern Memorial Hospital, Chicago.While IOP is a major risk factor for glaucoma development and progression, Dr. Krupin proposed that a better strategy might be therapy directed to RGCs independent of IOP, ocular blood flow, or other mechanisms. He suggested that a rethinking of glaucoma-related terminology might be in order.

"We hear terms such as normal tension, normal pressure, low pressure, but my personal preference is 'low-pressure glaucoma,' " Dr. Krupin said. "IOP is 'normal' only in a statistical sense, not in a pathogenic or pathological sense. I find it difficult to use the term 'normal' when discussing glaucoma with these patients who are worried about going blind, in spite of their IOP in the normal range.

"The only 'tension' is within the patient and the ophthalmologist who is faced with a frustrating and baffling clinical problem," he added.

Dr. Krupin added that low- and high-pressure open-angle glaucoma cannot be separated by a single IOP level.

"At the present, we are unable to determine an individual's optic nerve susceptibility to a given IOP level," he said. "Patients show marked variation in degree of harm caused by a given IOP, as well as a wide variation in level of IOP tolerated without harm."

However, rest assured that the search for neuroprotective therapies is on, Dr. Krupin said. For example, preclinical data have suggested that brimonidine (Alphagan P, Allergan) may protect neurons in the visual pathway independent of its IOL-lowering properties.

In addition, clinical trials are under way on the monoamine oxidase inhibitor memantine HCl (Namenda, Forest Pharmaceuticals), which is approved to treat the symptoms of Alzheimer's disease, as a potential glaucoma therapy.

"The progression of glaucoma was significantly lower in patients receiving the higher dose of memantine compared with patients receiving the low dose but not compared with the placebo," said Larry Wheeler, PhD, senior vice president, Biological Sciences Discovery Research, Allergan, Irvine, CA.

Although initial memantine trails did not meet the primary endpoints, the reasons may have been unanswered dosing questions, or the fact that the patients already were being treated with IOP-lowering agents.

Neuroprotection may be the wave of the future in glaucoma therapy. As new treatment modalities are discovered, clinicians will gain a better understanding of which patient types are likely to benefit from such treatments, added Ivan Goldberg, MD, clinical associate professor, University of Sidney, and director, Eye Associates Glaucoma Services, Sydney Eye Hospital, Sydney, Australia.

"For our patients' benefit, we need to be alert to new treatment paradigms, be constructively skeptical, maintain our common sense, and apply new agents relevantly," Dr. Goldberg said.