Glaucoma is a leading cause of irreversible blindness and is characterized by a progressive degeneration and loss of retinal ganglion cells (RGCs).^1,2 Current estimates suggest glaucoma impacts close to 80 million people across the globe and treatment options primarily target the reduction of intraocular pressure (IOP), the sole clinically validated modifiable risk factor associated with the disease.² Over the last decade, a multitude of new surgical and medical treatment options have been added to the glaucoma treatment landscape, including the introduction of minimally invasive glaucoma surgery (MIGS), a rapidly growing space of surgical options targeting multiple pathways for IOP reduction.^3,4 This innovation has elevated our management of glaucoma.

However, despite the expansion of treatment options, real-world clinical experience has demonstrated that in a number of patients, glaucoma progression continues to occur despite maintaining a “well-controlled” or “target” IOP value.⁵ These patient scenarios suggest that neurodegeneration may occur via an IOP-independent mechanism and owing to the complexity and multifactorial nature of RGC death, there has long been interest in treatment options beyond therapies targeting IOP reduction.^6,7 This has contributed to an interest in neuroprotective strategies and treatment options.⁸

Retinal Ganglion Cell Death

Retinal ganglion cells are the neurons responsible for communicating visual information from the retina to the brain.⁹ In glaucoma, when RGCs die, they are unable to regenerate, leading to irreversible damage and subsequent vision loss. The physiologic process of RGC death is multifactorial and poorly understood to date, although there is a general consensus of several proposed molecular pathways that all lead to a common endpoint: apoptosis.⁶ Although IOP elevation is thought to be the main driver of apoptosis, a number of mechanisms are thought to contribute to RGC death, including ischemia, oxidative stress, excitotoxicity, defective axonal transport and glial activation.^9-13

As neurons, RGCs exist in a delicate environment and are highly sensitive to environmental imbalances or stressors. Imbalances within this delicate environment due to loss of neurotrophic contribution or overstimulation of excitatory molecules can trigger the apoptotic cascade. Thus, it is not surprising that a multitude of different mechanisms have been invoked to explain the death of RGCs.

Neuroprotection

The research exploring the different mechanisms of RGC apoptosis have spurred an interest in neuroprotection.⁸ Neuroprotective strategies aim to protect against RGC damage by targeting the aforementioned listed mechanisms of RGC apoptosis and possibly support IOP-lowering therapies. Various neuroprotective strategies have been proposed, such as dietary supplementation, neurotrophic factors, cell-based therapy, gene therapy, and novel neuroprotective molecules.^6,14-16

A vast array of dietary supplements, primarily antioxidants, have been studied for their potential neuroprotective properties and benefit on measures of visual function in glaucoma. Many of the positive results have been demonstrated in animal models; however, a recent trial reported favorable short-term results in patients with glaucoma.¹⁵ In this small clinical trial, patients were administered nicotinamide (vitamin B₃), which is a precursor to nicotinamide adenine dinucleotide (NAD), combined with pyruvate and showed significant short-term improvements in visual function. The study was performed following multiple studies in glaucoma animal models showing that depletion of NAD (a key molecule in energy metabolism) contributes to RGC susceptibility and supplementation with NAD could offer support to mitochondrial function and increase resistance to oxidative stress. Further, additional studies showed that vitamin B₃ and pyruvate in combination were more protective than each nutrient alone. The promising results of this aforementioned trial have been corroborated by additional work evaluating vitamin B₃ alone.¹⁷ Although this study¹⁵ was relatively small and short-term, the results hold promise for the future of neuroprotective agents in the treatment of glaucoma and may stimulate the development of novel agents supporting cellular vitality.

In addition to adjuvant treatment in the form of oral supplementation, recent work has also explored the role of neuroprotective treatments in the form of topical drops.^14,16 A recent clinical trial evaluated the use of topical citicoline drops as an adjuvant treatment in glaucoma.¹⁴ The potential benefit of citicoline in neurodegenerative diseases such as dementia and stroke has been demonstrated previously, and prior work has also explored its use in glaucoma in the form of oral supplementation or intramuscular injection, but most of the reported benefits have been from small or observational studies.

In a recent trial by Rossetti et al,¹⁴ patients with mild to moderate open-angle glaucoma that were exhibiting disease progression despite an IOP ≤18 mmHg were treated with adjuvant topical citocoline. Although the study had multiple limitations, the results were favorable and suggest that topical citicoline could be of value as a complementary, neuroprotective treatment option in patients with glaucoma that is progressing despite apparent “controlled” IOP.

Preventing Damage

The value of neuroprotective strategies may also be contingent on identifying RGC stress or protecting RGCs in the early stages of glaucoma, prior to permanent damage.¹⁸ Thus, novel technology for identifying RGCs under stress is critical. Recently published work^18-20 has highlighted the value of flavoprotein fluorescence, or FPF, a marker of mitochondrial dysfunction that has been shown to be of value in various ocular diseases, including diabetic retinopathy, central serous retinopathy, and more recently glaucoma. Using FPF, which is a noninvasive imaging test, mitochondrial dysfunction is graded by the presence of oxidized mitochondrial flavoproteins, which increase under conditions of oxidative stress. A recent study by Zhou et al¹⁸ evaluated FPF values at the optic nerve head in patients with POAG and in control eyes. In this study, elevated FPF values were identified in patients with POAG, and the magnitude of FPF was directly correlated to disease severity.

An additional recent study evaluated changes in FPF following 1 month of treatment with a novel glaucoma device.²¹ In this study,¹⁹ subjects wore a multipressure dial (Equinox Ophthalmic Inc), a wearable device consisting of a pair of goggles and corresponding programmable pump that lowers IOP via periocular negative pressure. Nightly wear of the device for 30 days demonstrated a reduction in FPF from baseline. Although a small study, this work suggests that FPF could be used as a tool for assessing the efficacy of novel treatment agents and/or response to treatment.

Conclusion

Although IOP-lowering therapies will surely remain the foundation of glaucoma treatment, it is likely that neuroprotective strategies will play a meaningful role in the management of glaucoma in the future and complement existing therapies. Novel treatment options that confer neuroprotection and aid in halting disease progression could elevate our care and management of glaucoma, particularly in more vulnerable subtypes of disease such as normal-tension glaucoma and severe open-angle glaucoma. GP

Kristin Mohr, OD, is an optometry resident and Tanner J. Ferguson, MD, is a fellow at Vance Thompson Vision in Sioux Falls, South Dakota. Dr. Mohr reports no relevant disclosures. Dr. Ferguson reports consultancy to Equinox Ophthalmic. Reach Dr. Ferguson at tannerferg@gmail.com.

 

 

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