Prospects for Neuroprotection in Glaucoma

A promising concept but yet to be proven.

By John R. Samples, MD

There are numerous risk factors for glaucoma, including ethnicity, diabetes, age and use and/or overuse of certain medications. A family history of glaucoma is certainly a major risk factor for glaucoma. When there is a family history of blindness from glaucoma, the clinician needs to be particularly concerned about elevations of intraocular pressure and the appearance of the optic nerve. Currently, all of the FDA-approved treatments for glaucoma lower the pressure in the eye with the hope that this will then stop the loss of nerve fibers. However, another therapeutic target for glaucoma is the optic nerve itself. Some glaucoma researchers have adopted the view that glaucoma is a neurodegenerative disease, with loss of neuron structure and function in a way that is common to other neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's and amyotrophic lateral sclerosis.

This hypothesis has led to a quest for identifying neuroprotective agents that can be used to safeguard the optic nerve. Here, I will discuss the concept of neuroprotection as it relates to glaucoma and the attempts that have been made to utilize neuroprotection as part of the therapeutic arsenal in our efforts to combat this difficult disease.

The Basic Concept

The hypothesis behind neuroprotection is that — with medication — one can directly protect the optic nerve without any pressure-lowering effect upon the eye. This notion appears to have been first published in 1996 by Schwartz et al. in the Journal of Glaucoma¹ and in Steven Drance's update on vascular risk factors and neuroprotection in glaucoma.²

The Concept is Appealing

Conceptually, neuroprotection is very appealing for the treatment of glaucoma. Much has been written since 1996 but it has yet to be proven to be clinically useful.

In other fields, particularly neurology and neurosurgery, neuroprotection has, in some senses, already been achieved. Namenda (memantine) and Aricept (donepezil) have both been shown to be of benefit in some types of dementia. High-dose corticosteroids are often used in acute brain injury. Many potential neuroprotection candidate compounds are being developed for non-glaucoma uses.

The problem with neuroprotection in glaucoma is not the concept, but in establishing efficacy. In 2006, Allergan undertook a clinical trial of memantine to determine its efficacy for neuroprotection in glaucoma. That trial did not meet the primary endpoints and the results have yet to be published. However, secondary endpoints of the research may have been met.

Some glaucoma specialists use memantine whenever they see progression at relatively low intraocular pressures, even in the absence of good multi-center prospective peerreviewed high quality evidence that it is effective, but out of a desire to do something to at least theoretically stop progression. I use memantine in this fashion myself, but only after consenting the patient carefully. I always document that we have had a discussion about its off-label use, since this is an area where we want to be completely transparent and as careful as possible from a medical-legal perspective. As a side note, as in the clinical trial, the use of memantine in desperate situations has evoked interesting anecdotal reports of patients reporting improved memory associated with its use.

It is to Allergan's credit that the company was the first to undertake a multi-million dollar effort to prove that neuroprotection in glaucoma could work, and many specialists are disappointed that this did not result in the deployment of a clinical product. However, hope remains. In the face of good potential candidates, the big question is: who is willing to take the leap to invest in another trial? Lessons learned may save some of the extensive costs that Allergan sustained and it may indeed be possible to do a study with fewer resources, though the costs will still be very substantial. In the absence of funding for these types of studies, it is likely that we will see the glaucoma community continue to resort to off-label use or borrow heavily from other areas of clinical medicine, particularly neurology and neurosurgery.

Proving the Concept

What does it take to establish efficacy? When memantine trials were initially being considered, I suggested that black box measures of retinal ganglion cells could be a useful surrogate for the lengthy trials required with visual field and optic nerve measurements.³ What is needed is a means of showing efficacy of a neuroprotectant in a shorter time frame than is required with traditional measures. Devices that can achieve this could significantly accelerate the development of neuroprotective drugs. However, more sensitive psychophysical tests that might provide a shortcut for some other measures require a select population and are not easily deployed across multiple clinical centers. Objective tests that can provide useful measures in glaucoma, but which do not require three to five years for large studies, may yet prove useful.

Spectral domain OCTs from both Optovue and Carl Zeiss Meditec have been augmented by new progression software, for instance, which seems both clinically useful and may provide a needed boost in the area of research into neuroprotectants. The conclusion that all of the optic nerve image analyzers are approximately equal⁴ was based on a prior generation of machines. The spectral-domain nerve fiber analyzers from the aforementioned companies are achieving rapid advances in their capabilities, making it difficult for studies to keep up with the almost monthly advent of new software developments. The progress in measuring the optic nerve is substantial and has converted many glaucoma specialists who were skeptical of the early generations of these machines into believers who find the latest iterations to actually be clinically useful.

Neuroprotectants Available Today

Omega-3 fatty acids, which are substantially proven to have positive effects on blood pressure and cardiovascular health, are diminished in the blood of patients with open-angle glaucoma.⁵ It has been suggested that in addition to these documented benefits, fish oil may also protect the optic nerve.⁶ I often suggest that patients take fish oil or, if they have dry eye then combined flaxseed fish oil products. Even if the neuroprotective effects are questionable, there is still a well-documented cardiovascular benefit for almost all patients.

Ginkgo has been suggested as a neuroprotectant; papers have established its efficacy, but each ginkgo preparation is varied and so what works in one instance may not work in another.⁷

A previously withdrawn-from-the-(US) market prostaglandin, Rescula (Novartis, Unoprotone) remains popular in Japan. Individual experiences with its efficacy at lowering intraocular pressure were varied. However, it has made a neuroprotection claim and may see a clinical rebirth in the next year.⁸ A claim that alpha agonists may be neuroprotective has been made in the past but never proven. My personal view has always been that it is more likely than not. Alpha agents such as brimonidine can easily penetrate the central nervous system, which is what makes them undesirable for use in children. We showed long ago that this class of agents increases the production of a specific growth factor in the trabecular meshwork — fibroblast growth factor — which often confers health upon cells, and so we have always thought it likely that the same thing could occur in the optic nerve. This is an area that certainly deserves further investigation, not with just brimonidine, but with other members of the alpha-agonist class and other small molecules which may stimulate the release of beneficial growth factors in the optic nerve.

The science behind neuroprotection requires recognition that glaucoma at the optic nerve head is as much about extracellular matrix and the supporting glial elements as it is about the retinal ganglion cells themselves. There are cells in the optic nerve that have a supporting role for the actual neural elements. These cells are involved in providing support for the neurons and may themselves be a useful target for a drug that protects the optic nerve.

A recent and controversial paper in the prestigious Proceedings of the National Academy of Science included the Nobel Prize-winning scientist Rita Levi-Montacini and presented data suggesting that the topical use of nerve growth factor could restore visual fields.⁹ The observations were most likely due to patients undergoing repeat visual fields testing, since a protein the size of nerve growth factor molecule would not be expected to readily penetrate the eye. Repeat visual fields notoriously produce improvement due to the patient learning how to take the test better, which may be only one of several explanations for these findings. In any event, more large-scale, controlled studies need to be conducted in this area of research.

My Personal Choices

What is the best neuroprotectant available at present? There is no good Level I clinical evidence for any neuroprotectant at present. I have all my patients on fish oil (4,000 mg a day if they can tolerate it), feeling that even if it doesn't help the nerve, the scientific evidence is sound that it will be good for their heart. The matrix metalloprotineases in the meshwork and the optic nerve require zinc, so we also want all our patients to be on a multivitamin containing minerals including zinc.

In truly desperate situations where there is progression at low intraocular pressure, I, like many of my colleagues, use medications for which we wish the proof of efficacy were better, such as memantine. Some glaucoma doctors use centrally acting calcium channel blockers where nothing else seems to work and the patient is sustaining ongoing progression. Not every glaucoma specialist uses these medications because the scientific basis is lacking. Based on immunologic theories, trials of neuroprotection with the injection of Copolymer I have been underway for a number of years but have not reported results recently, and the potential of an immune system-mediated approach to neuroprotection remains a possibility.¹⁰

Conclusion

The barrier to new neuroprotectants is the cost of proving efficacy. In our present health economy, that barrier seems almost insurmountable. It is unlikely that we are going to see the National Institutes of Health fund clinical trials of multiple potential nerve-protecting compounds even though there are some good candidates within sight. The key to proving efficacy may be for the FDA to embrace better tests of visual function and optic nerve progression as satisfactory markers of progression rather than relying exclusively upon older time-tested technologies such as Humphrey visual fields and optic nerve photographs, which can take years to detect change. There is no need to develop entire new classes of medication in this area, as the neurology and neurosurgery literatures contain an abundance of new potentially useful compounds. Ultimately, we may use these new compounds, but we must be mindful of the fact that they will be used off-label, with all the legal consequences that entails, and we will want to make sure that we consent our patients appropriately. OM

References

1. Schwartz M, Belkin M, Yoles E, Solomon A. Potential treatment modalities for glaucomatous neuropathy: neuroprotection and neuroregeneration. J Glaucoma. 1996;5:427-432.
2. Drance SM. Primary chronic open angle glaucoma — are there vascular risk factors? Klin Monbl Augenheilkd. 1996;208(6): A9-A13.
3. Eisner A, Samples JR. Profound reductions of flicker sensitivity in the elderly: can glaucoma involve the retina distal to ganglion cells? Appl Opt. 1991;30:2121-2135.
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5. Schnebelen C, Pasquis B, Salinas-Navarro M, et al. A dietary combination of omega-3 and omega-6 polyunsaturated fatty acids is more efficient than single supplementations in the prevention of retinal damage induced by elevation of intraocular pressure in rats. Graefes Arch Clin Exp Ophthalmol. 2009;247:1191-1203.
6. Ren H, Magulike N, Ghebremeskel K, Crawford M. Primary open-angle glaucoma patients have reduced levels of blood docosahexaenoic and eicosapentaenoic acids. Prostaglandins Leukot Essent Fatty Acids. 2006;74:157-163.
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9. Lambiase A, Aloe L, Centofanti M, et al. Experimental and clinical evidence of neuroprotection by nerve growth factor eye drops: Implications for glaucoma. Proc Natl Acad Sci U S 2009 Aug 3. [Epub ahead of print]
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11. Benozzi J, Jaliffa CO, Firpo Lacoste F, Llomovatte DW, Keller Sarmiento MI, Rosenstein RE. Effect of brimonidine on rabbit trabecular meshwork hyaluronidase activity. Invest Ophthalmol Vis Sci. 2000;41:2268-2272.
12. Wen R, Cheng T, Li Y, Cao W, Steinberg RH. Alpha 2-adrenergic agonists induce basic fibroblast growth factor expression in photoreceptors in vivo and ameliorate light damage. J Neurosci. 1996;16:5986-5992.
13. Kong GY, Van Bergen NJ, Trounce IA, Crowston JG. Mitochondrial dysfunction and glaucoma. J Glaucoma. 2009;18:93-100.
14. Sena DF, Ramchand K, Lindsley K. Neuroprotection for treatment of glaucoma in adults. Cochrane Database Syst Rev. 2010 Feb 17;(2):CD006539.