Loss of visual function precedes RNFL thinning in glaucoma
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Functional vision loss is predictive of retinal nerve fiber layer thinning in patients with glaucoma, according to a study published in Investigative Ophthalmology and Visual Science.
“Several previous studies have suggested that structural changes may be detectable prior to functional changes in glaucoma. However, the focus of those studies was not on which modality shows true change first, but on which shows detectable change first,” Stuart K. Gardiner, PhD, of Devers Eye Institute, and colleagues wrote. “This is complicated by the issue of variability, which is higher for standard automated perimetry (SAP) than for retinal nerve fiber layer thickness (RNFL) thickness. ... In this study, we ask whether there is evidence of a time lag between changes in structure and function in human glaucoma.”
To identify the temporal relation between true changes between RNFL thickness and function, 164 patients (n = 318 eyes), either diagnosed with glaucoma or with likelihood of glaucoma development, underwent analysis. Researchers conducted SAP tested and OCT testing at study examination visits (approximately every 6 months) and calculated rates of change over 1,135 pairs of consecutive visits (mean 207 days between visits). Researchers further used structural equation models to determine the rate of change in function (mean linearized total deviation, AveTDLin) across set time intervals defined as two visits occurring in a consecutive 6-month period.
Study results showed the rate of functional change in the previous interval was predictive of the rate of structural change in the current interval (P = .007; 95% CI, 0.308-1.953). Further, the rate of RNFLT change was not predicted by concurrent AveTDLin change after adjusting for its previous rate while the rate of AveTDLin change in the previous time interval did improve prediction for the current rate of RNFLT change (P = .005).
“We present evidence of a time lag of several months, whereby loss of visual function precedes and is predictive of thinning of the RNFL in human glaucoma. This does not negate previous findings suggesting that change in RNFL thickness may be detectable sooner using current testing techniques. ... However, the presence of a time lag should be taken into account when considering the pathophysiologic mechanisms that cause glaucomatous damage,” Gardiner and colleagues concluded. “It also encourages the development of improved and less variable functional testing and use of alternative structural measures, which may allow earlier detection of damage and provide better prognostic information about disease progression.”
Perspective
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The chicken and egg “structure vs. function” debate often comes up in clinical glaucoma discussions. Research has shown that the lack of correlation between the two is mainly caused by structural (OCT) units being linear and functional (automated visual field) units being logarithmic and more variable. Whether structural lags functional change or vice versa is often contingent on how individual studies frame their hypotheses.
This study provides clarity and reinforces findings from experimental glaucoma studies showing that, from a pathophysiological standpoint, RNFL axons likely cease to be functional prior to retinal ganglion cell apoptosis, and detectable RNFL thinning follows loss of axon function. The separation of “true” from “detectable” change is an important distinction we need to understand in practice. Although this study reaffirms that structural change may be detectable first, true structural change actually lags behind true functional change. Simply because one technology is more reproducible in practice should not discount what is actually happening at the cellular level. Ultimately, these findings underscore the necessity of continuing to strive for functional testing with less variability that better approximates glaucomatous damage in real time and, in the interim, using both structural and functional tests in a complementary manner in clinical practice.
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