The PERG has been thought of and used as an important indicator of retinal ganglion cell function in glaucoma. In recent publications, PERG has been shown to be reduced in glaucoma suspects, and ocular hypertensive and glaucoma patients.27–29
Many attempts have been made to correlate the structure and function of the optic nerve in glaucoma.30–36
Structural measurements have been made in the past measuring the size of the optic nerve, and the thickness of the optic nerve and RNFL. The function of the optic nerve has been assessed with standard automated perimetry. In general, there is some amount of structural abnormality before any functional abnormality is observed. PERG is thought to be abnormal before any structural abnormality is observed.2,3
It has been proposed that abnormality in the PERG indicates dysfunction predating cell death and, thus, would signal a suitable time for intervention.
We found that patients with significantly reduced baseline PERG amplitudes had lower baseline RNFL thicknesses. Importantly, the highest rate of RNFL thinning occurred in the subgroup with the most reduced baseline PERG amplitudes. These results demonstrated that PERG amplitude, when reduced significantly, indicates that a glaucoma suspect needs closer monitoring or treatment as he or she will have a higher rate of RNFL thinning.
The time lag between changes in the PERG, and structural abnormality, and functional abnormality is not well known. In our study we were able to make an estimation of the time lag between the PERG and structural abnormality as measured by time domain OCT. We demonstrated that in our study population of glaucoma suspects, it takes an average of approximately 2 years for a 10% change in PERG and 10 years to see a 10% change in RNFL. This indicates that there is a time lag of approximately 8 years between changes in PERG and RNFL. To our knowledge, this is the first estimation of a time lag between potentially reversible ganglion cell dysfunction and permanent structural loss of ganglion cell axons. Others have studied the structural/functional correlation between RNFL and perimetry. Ajtony et al. demonstrated that an RNFL of less than 70 μm was correlated with visual field abnormality when measured by time domain OCT and standard automated perimetry.37
Wollstein et al. used spectral domain OCT and standard automated perimetry, and demonstrated that a structural loss of 17% was necessary to be able to detect a functional loss of vision.35
Both studies measured structural loss compared to permanent visual loss in perimetry. Hood and Kardon, in a review of cross-sectional data in subjects with manifest glaucoma, found evidence for a linear relationship between peripapillary thinning and loss of field sensitivity when both are expressed in linear units.38
Their model does not exclude a time lag between RNFL loss and visual field loss. They argue that which test is detected first will depend upon the initial level of sensitivity and RNFL thickness when the eye is healthy, and on the relative standard deviation of the measures. In our longitudinal study of glaucoma suspects the initial level of sensitivity (PERG amplitude) and RNFL thickness did not influence the model. The relevant measure was the slope of change with time (expressed in linear units for PERG and OCT), and the variability of the estimate that was accounted for in the analysis of pooled data. Previous longitudinal studies of our group27
have reported progressive PERG changes in glaucoma suspects that were not associated with significant visual field changes.
Our study measured RGC dysfunction with permanent structural change. We assumed that the structural change measured by OCT is a permanent irreversible change. It is possible that there is some amount of reversibility or even cell shrinkage before cell death.
With respect to the effect of medications, Ventura et al.13
have demonstrated that in some eyes the initiation of IOP lowering medications alters the slope of PERG amplitude losses, but this effect was not found in our analysis. There are two likely causes for this. A total of 78% of eyes followed in our study either received no medications or were taking them at all follow-up visits. Also, this effect did not extend to all eyes in the previous publication. It perhaps is not surprising that this heterogeneous effect would not be observed in a study group featuring relatively few eyes with pre- and postmedication onset experience.
Limitations to our study included that some of the patients received treatment. This potentially could confound the results, since if RGC dysfunction is reversible, directional shifts in IOP over follow-up could lead to over- or underestimation of PERG loss rates, but have no effect on the OCT. However, analysis with or without accounting for IOP changes over the observation period yielded very similar PERG amplitude slopes. We cannot rule out the possibility of regression to the mean influencing the slopes or PERG losses. However, a strong effect of regression to the mean seemed unlikely for the following reasons: We computed PERG baselines using three consecutive measurements made over a 12-month interval, which minimized the regression to the mean. If regression to the mean were operating, one would expect a negative slope in the >90% stratum (which was the case) and a positive slope in the ≤50% stratum (which, instead, had a slope close to zero). Further, one would expect a majority of visits with PERG amplitudes smaller than baseline in the >90% stratum as opposed to a minority of visits in the ≤50% stratum. Instead, all strata had a majority of visits with PERG amplitudes smaller than baseline.
Based on the results, we demonstrated it would take approximately 10 years to observe a 10% loss in RNFL in this study population. The study was performed only for 5 years on average, which is approximately half as long as the expected time needed to see a change in OCT. It would be more accurate to continue following the study population for longer to confirm the changes, but this would require much more follow-up.
In summary, we observed that when PERG amplitude is reduced to 50% of its age-adjusted norm, the rate of decrease in OCT RNFL is greatest. We also estimated that there is an 8-year time delay between seeing a 10% reduction in potentially reversible PERG amplitude to seeing a 10% irreversible structural RNFL reduction. This represents a substantial window for intervention before permanent loss of structure from glaucoma.