Vision loss from glaucoma is directly related to the progressive degeneration of the optic nerve. Slit-lamp biomicroscopy and optic disc photography are conventional techniques used to examine glaucomatous changes of the optic nerve head. However, these techniques are subjective with high inter-observer variability, even among glaucoma specialists.¹ OCT provides an objective platform to quantify the configuration of the optic nerve head and thickness of the retinal nerve fiber layer (RNFL).

The RNFL is composed of the axons of retinal ganglion cells. Documenting RNFL thickness is therefore important both for diagnosing and monitoring glaucoma. With a low test-retest variability, OCT RNFL thickness measurements are useful for determining progressive RNFL thinning in glaucoma patients.^2,3 Here, I will examine recent research findings supporting progressive RNFL thinning measured by OCT as a useful tool for prediction of future visual field loss in patients with glaucoma.^4,5

Is progressive RNFL thinning predictive of visual field loss in glaucoma patients?

In a 5-year prospective study, my colleagues and I investigated whether progressive RNFL thinning is predictive of progressive visual field (VF) loss in glaucoma.⁴ We analyzed 139 primary open-angle glaucoma patients (240 eyes) by performing RNFL imaging and VF testing at 4-month intervals over 5 years. RNFL measurements were obtained from the Cirrus HD-OCT (Zeiss) using the “optic disc cube” scan, generating an RNFL thickness map in an optic disc region of approximately 6x6 mm². Progressive RNFL thinning was then determined by Guided Progression Analysis (GPA) (an event-based change analysis) and Trend-based Progression Analysis (TPA) of serial registered RNFL thickness maps (Figure 1).

We found that 27.1% and 48.8% of eyes had progressive RNFL thinning based on GPA and TPA, respectively, and 12.5% of eyes had VF progression by the Early Manifest Glaucoma Trial (EMGT) criteria (likely progression) during follow-up. The specificities of GPA and TPA were between 81.7% and 100% (determined by the proportion of eyes with significant RNFL thinning in 25 normal subjects followed weekly for 8 consecutive weeks and the proportion of eyes with significant RNFL thickening in the glaucoma group). Notably, eyes with progressive RNFL thinning detected by GPA and TPA had approximately 4-fold and 8-fold increases in risk of development of VF progression, respectively.

Eyes with progressive RNFL thinning also had a faster rate of decline of visual field index than eyes without. Our findings that progressive RNFL thinning determined by GPA and TPA is predictive of detectable functional decline verifies the significance of detecting progressive RNFL thinning and its relevance to the consideration of initiation or augmentation of IOP-lowering treatment for glaucoma patients.

The study provides long-term prospective data indicating that progressive RNFL thinning is a useful biomarker to inform disease deterioration behavior. This study also highlights two elements in the interpretation of OCT findings.

1. Although the two-dimensional circumpapillary RNFL thickness measurements are widely adopted in many OCT instruments for analysis of RNFL abnormalities, the RNFL thickness map brings a wealth of data to reveal the three-dimensional topology of the distribution of RNFL. Analysis of longitudinal RNFL thickness map data with GPA/TPA is useful to detect progressive RNFL thinning that is relevant to the risk assessment of VF loss in glaucoma.
2. GPA and TPA respectively perform event-based and trend-based analyses of RNFL thicknesses at individual superpixels (50x50) of the RNFL thickness map (6x6mm). The map format is a powerful means for change analysis because it allows a fenced-in approach in a topographical fashion to show reduction of RNFL thickness over time. GPA tells us whether change has occurred. TPA not only shows us whether change has occurred but also shows the rate of change.

Is the rate of change of RNFL thickness predictive of visual field loss in glaucoma patients?

In a follow-up study, we demonstrated that glaucoma patients who had a faster rate of RNFL thinning carried a higher risk of visual field loss.⁵ We examined the rates of RNFL thinning in 89 patients with primary open-angle glaucoma who showed progressive RNFL thinning by TPA in the original study. We found that the mean and the peak rates of RNFL thinning, but not the area of progressive RNFL thinning, measured from the rates of change of RNFL thickness map (Figure 2) were indicative of VF worsening. For each micrometer-per-year increase in the peak and the mean rates of RNFL thinning, the hazard ratios of development of VF progression were 1.12 and 1.39, respectively. While progressive RNFL thinning is not necessarily associated with VF worsening, our findings underscore the relevance of using TPA to measure the rates of RNFL thinning to inform the risk of VF loss in glaucoma.

How does detection of progressive RNFL thinning impact the management of glaucoma patients?

Clinicians manage glaucoma patients by lowering the IOP. The rationale of lowering the IOP is predicated on all landmark glaucoma treatment trials, which have consistently demonstrated reduction of IOP to be associated with a reduced risk of VF progression. For example, in the Early Manifest Glaucoma Trial, each mmHg increase in IOP during follow-up was associated with 12% increase in risk of development of VF progression.⁶

Initiation or addition of IOP lowering therapy should therefore be seriously considered in eyes detected with progressive RNFL thinning as eyes with progressive RNFL thinning are also at a higher risk of development of VF progression compared with those without (4-fold increase in risk for progressive RNFL thinning detected by GPA and 8-fold increase in risk for progressive RNFL thinning detected by TPA). Treatment decision of glaucoma patients should not be based on IOP levels alone. Glaucoma patients may progress in relatively normal IOP levels and a significant proportion of glaucoma patients in Asia do not have high IOP at presentation. Following the changes of the RNFL with OCT is a powerful means to inform clinicians when to treat and when to increase treatment in patients with glaucoma.

Conclusions

Detection of progressive RNFL thinning with GPA/TPA represents an important change in the management of glaucoma patients. Progressive RNFL thinning is a powerful indicator for us to know whether a patient would have a high risk of developing visual field loss. It is exciting to make use of this important information in our clinical practice because it carries meaning to our management of glaucoma patients. GP

References

1. Jampel HD, Friedman D, Quigley H, et al. Agreement among glaucoma specialists in assessing progressive disc changes from photographs in open-angle glaucoma patients. Am J Ophthalmol. 2009;147:39-44.
2. Leung CK, Cheung CY, Weinreb RN, et al. Retinal nerve fiber layer imaging with spectral-domain optical coherence tomography: a variability and diagnostic performance study. Ophthalmology. 2009;116:1257-1263.
3. Leung CK, Yu M, Weinreb RN, Lai G, Xu G, Lam DS. Retinal nerve fiber layer imaging with spectral-domain optical coherence tomography: patterns of retinal nerve fiber layer progression. Ophthalmology. 2012;119:1858-1866.
4. Yu M, Lin C, Weinreb RN, Lai G, Chiu V, Leung CK. Risk of visual field progression in glaucoma patients with progressive retinal nerve fiber layer thinning: a 5-year prospective study. Ophthalmology. 2016;123:1201-1210.
5. Lin C, Mak H, Yu M, Leung CK. Trend-based progression analysis for examination of the topography of rates of retinal nerve fiber layer thinning in glaucoma. JAMA Ophthalmol. 2017;135:189-195.
6. Leske MC, Heijl A, Hyman L, Bengtsson B, Dong L, Yang Z; EMGT Group. Predictors of long-term progression in the early manifest glaucoma trial. Ophthalmology. 2007;114:1965-1972.

Dr. Leung is a professor and head of the Department of Ophthalmology and Visual Sciences at The Chinese University of Hong Kong.