Clinical experience with NMDA receptor antagonists

Ivan Goldberg

Glaucoma is an optic neuro-pathy. While pressure reduction and stabilization helps, this approach doesn’t help everyone, and doesn’t necessarily help any one patient all of the time. As a neurodegenerative disease, glaucoma lends itself to neuroprotective strategies. Neuroprotection refers to the use of therapeutic agents to prevent, retard or reverse neuronal death, which is consequent upon a primary insult. Neuroprotective strategies have been effective in other neurodegenerative disease such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. The strategies we employ to protect glaucoma patients from visual disability depend on the therapeutic index – the balance between potential benefits versus potential harm. Any new paradigm of treatment will depend on how the evidence accumulates. As our treatment strategies become more sophisticated, sequential therapies may be needed. There are multiple pathways and cascades of secondary degeneration and events, which a primary insult can set in motion. As better strategies become available, we will establish targets beyond pressure reduction. As clinicians, we are already looking beyond pressure. At follow-ups, for example, we look for the onset of damage in suspects or progression of damage in patients with the disease. We review their level of risk for worsening, and review our targets, pressure, and the various therapeutic strategies. We try to identify people who are over-treated for systemic hypertension or have nocturnal hypotension, since longitudinal studies have shown these are associated with an increased risk of glaucoma progression. Our ultimate goal, of course, is to maintain our patients’ dignity as human beings by preserving their independence, in turn, by protecting their vision. Neuroprotection will, I think, offer the opportunity to extend our strategies.

Potential use of neuroprotection in glaucoma

Table 1 summarizes an approach we might use to help us to decide when neuroprotection might be appropriate. The strategy is based on disease presence or stage, and risk for progression. With more advanced stages of damage, or a greater risk of progression, the therapeutic approach moves across the cascade from pressure lowering alone, to pressure lowering plus a neuroprotectant.

Table 1.

Advanced glaucoma. For patients with advanced glaucomatous damage in whom visual fixation and their independence as human beings are threatened, we would aim to do everything possible immediately. This would include dropping the pressure as safely and as dramatically as possible as well as adding a neuroprotectant.

Moderate glaucoma with high risk of progression. For patients with moderate damage and high risks for progressive damage that may lead to disability, we would use our usual hypotensive approaches, and other strategies to keep them well including a neuroprotectant if one is available.

Moderate glaucoma with low risk of progression. For patients with moderate damage but lower risks of progression, we would continue dropping pressure as effectively as we could. However, if progression continues despite these measures, or if there is an increase in risk factors that we could not control, we would add a neuroprotectant. This would essentially be a complementary effect added as a second layer to conventional therapy.

Mild glaucoma. For patients with early structural damage or no measurable damage (with standard automated perimetry), we would lower the pressure and address the patient’s general health. We would add a neuroprotectant only if the patient is unable to use hypotensive therapy or is unresponsive to it, or if progression occurs despite its use.

Suspects. For patients with suspected glaucoma, we would follow the usual approaches when indicated, and consider a neuroprotectant only when the patient expresses a strong preference for it, has the resources to use it, is at very high risk of developing damage, or has a particular situation such as one-eyed status.

Clinical use of memantine

Memantine is currently approved in Australia for the treatment of Alzheimer’s disease and dementias associated with Parkinson’s disease in the form of 10mg tablets. For use in glaucoma, we ask patients to sign an informed consent for off-label use. We commence these patients on memantine treatment with half of a tablet (5 mg) in the morning for a month and then build up to half of a tablet twice daily for a month, depending on how well they tolerate it. The two most common side effects of memantine are insomnia, which occurs in less than 10% of patients, and dizziness. If insomnia occurs, we restrict the dose entirely to the morning. For dizziness or problems with coordinated movement, a rare phenomenon, we give the dose at night. If memantine is well tolerated, which is usually the case, we consider increasing the dose up to 15 or 20 mg a day. Currently, we have about a dozen patients taking memantine; most are in the increasing dosage phase.