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Glaucoma Dialogue IGR 16-1
Response
Comment by Robert Casson on:
56225 Glucose-induced temporary visual recovery in primary open-angle glaucoma: a double-blind, randomized study, Casson RJ; Han G; Ebneter A et al., Ophthalmology, 2014; 121: 1203-1211
See also comment(s) by Jonathan Crowston • Jeffrey Goldberg • Keith Martin •We would like to thank the editorial team at IGR for selecting our paper for discussion and the reviewers for their generous comments.
About ten years ago, we serendipitously noted that elevated vitreous glucose levels provided a robust neuroprotective effect against ischemic retinal injury.
Based on this finding, and the work of others, particularly Barry Winkler, we have been struck by the retina's unusual energy metabolism. We have pursued the possibility that we might manipulate it to clinical advantage in diseases where energy failure is part of the problem, a disease set that probably includes primary open-angle glaucoma (POAG), at least in some individuals.
Our current study aimed to translate laboratory findings to the clinic using a modified outcome paradigm. In the broadest sense, neuroprotection refers to the relative preservation of neurons against actual or potential threat. This is easy to measure in acute animal models. But for chronic diseases, like POAG, neuroprotection implies a reduction in the rate of neurodegeneration, requiring many months, if not, years to determine. The statistical test on the primary result of the EMGTS was a basic two-sample test of proportions after at least four years follow-up. Although it is likely that alternative creative study designs including recruitment of rapid progressors and Bayesian rather than frequentist statistical approaches could shorten clinical trial durations, a convincing demonstration of neuroprotection is a high-hanging fruit.
A convincing demonstration of neuroprotection is a high-hanging fruit
In 1940, at Harvard University, McFarland and Forbes demonstrated recovery of dark adaptation in hypoxic human subjects after inducing hyperglycemia. We believe this finding and our current findings are a manifestation of 'neurorecovery'. Although not neuroprotection per se, the findings imply a recoverable neuronal state, and that energy deficiency is producing functional visual deficits. The advantage of neurorecovery as the primary outcome is that it is rapid and inexpensive to measure.
Although we believe it is unlikely that elevating vitreal glucose levels is a viable treatment for chronic glaucoma, similar strategies could conceivably be developed for acute glaucoma and other ocular conditions where energy failure is part of the pathogenesis. Importantly, further research is needed to better understand retinal metabolism. For example, it is unclear whether retinal ganglion cells actually display a Pasteur effect. In fact, the preferred energy substrate of CNS neurons, including retinal neurons, remains controversial. We believe this would be a fruitful area of research for glaucoma and other retinal and optic nerve diseases.
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