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Editors Selection IGR 12-2

Optic Nerve Head: VEGF and cup-disc ratio changes

Comment by Malik Kahook on:

24574 Assessment of optic nerve cup-to-disk ratio changes in patients receiving multiple intravitreal injections of antivascular endothelial growth factor agents, Seth RK; Salim S; Shields MB et al., Retina (Philadelphia, Pa.), 2009; 29: 956-959

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Anti-vascular endothelial growth factors (VEGF), such as bevacizumab and ranibizumab (Genentech Inc., South San Francisco, CA), have become the standard of care for treating wet-age related macular degeneration. Despite the apparent excellent safety profile of both agents, there have been reports of adverse ocular side effects such as inflammation and both acute and chronic elevations in intraocular pressure (IOP).^1-3 In addition, VEGF is known to have neurotrophic properties, and chronic blockade of VEGF may lead to deleterious effects on neuronal tissues.⁴ The combination of potential IOP fluctuations as well as local blockade of neurotrophic effects could theoretically lead to thinning of the retinal nerve fiber layer (RNFL) and optic nerve head (ONH) cupping. A recent report by Seth et al. (1481) investigated the possibility of optic nerve head changes related to transient intraocular pressure rise, frequent intraocular pressure fluctuations, or antivascular endothelial growth factor (VEGF) effects of repeated intravitreal injection of anti-VEGF agents. This was a retrospective review of patients receiving multiple injections of pegaptanib and ranibizumab who had no history of glaucoma or prior history of intravitreal triamcinolone injections. The main study outcome centers around changes in ONH cupping based on evaluations of fundus photos, cropped to isolate the optic nerve, by two glaucoma specialists. The opposite untreated eye served as control when information was available. Twenty-three eyes of 21 patients met the inclusion criteria and the authors found no differences in vertical ONH cupping between treated and control eyes for any of the retrospective analyses 'regardless of whether they received fewer or more than five total injections'. They concluded that, 'short-term intraocular pressure rise and frequent intraocular pressure fluctuation, as well as the anti-VEGF properties of these drugs, do not adversely change the optic nerve C/D.'

This report has many shortcomings, some of which were acknowledged by the authors. They excluded glaucoma patients from their analysis, yet these patients might represent a particularly susceptible group for changes of the kind the authors set out to study. While the authors explored how transient changes in IOP post injection might have influenced C/D, their metrics for analyses were flawed by two important facts. First, they used one drop each of iopidine and timolol/dorzolamide 30 minutes prior to the injection procedure, which is not standard of care in most retina practices and likely blunted any IOP elevation. Additionally, they did not have records of the IOP spikes post injection making any statements that IOP fluctuations post injection did not influence C/D of questionable validity. Second, the primary endpoint measured was that of C/D pre and post treatment, but photos evaluated for this purpose were taken for documentation of retinal disease and not ONH anatomy. Using photos not designed for documentation of the ONH make them of questionable value as a primary endpoint in this study. Additionally, the number of injections was low and the duration of follow-up was likely too short to reveal any effects from chronic injections of these agents, especially as it relates to the neurotrophic effects of VEGF. Future studies with similar aims to this current report should utilize a prospective design or take advantage of a retrospective design with longer term data and more objective metrics designed for following optic nerve head and/or RNFL changes. Whether or not chronic therapy with anti-VEGF agents actually affects the ONH and/or the RNFL remains unanswered.

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