It is well known that glaucoma is a multifactorial, progressive optic neuropathy characterized by the loss of retinal ganglion cells.^1-2 For decades, glaucoma was diagnosed and monitored via clinical exam and serial optic disc photography to document optic nerve cupping and automated perimetry to detect functional vision loss.

With the realization that damage caused by glaucoma can precede detection by perimetry² and the development of OCT and laser polarimetry in the 1990s, measurement of the ganglion cell axons in the circumpapillary retinal nerve fiber layer (cpRNFL) was added to the glaucoma diagnostic regimen. The more recent development of spectral-domain OCT (SD-OCT), which features faster speeds and higher resolution, has enabled segmentation of the ganglion cell complex (GCC) from the full thickness of the retina.

This capability may allow for earlier diagnosis of glaucoma and more precise monitoring of disease progression because the GCC contains not only the RNFL, but also the ganglion cell layer, which consists of the ganglion cell bodies, and the inner-plexiform layer (IPL), which consists of the ganglion cell dendrites. All three layers are affected by glaucoma.³

Measuring Ganglion Cell Complex Thickness in the Macula

Zeimer and colleagues were the first to correctly hypothesize that the macula is an area of interest in glaucoma and to report an association between glaucoma and decreased macular thickness.⁴ The macula contains a substantial proportion of the retinal ganglion cells and is the only area of the retina where the ganglion cell layer is more than one cell layer thick. The central 20 degrees of the macula can contain up to 50% of the retinal ganglion cells.

Furthermore, the anatomy of the optic nerve head varies across subjects more than the macular anatomy. For these reasons, glaucomatous changes may be more easily detected in the macula.

Rao and colleagues⁵ compared SD-OCT macular measurements of ganglion cell/IPL thickness with visual sensitivity measurements from standard automated perimetry and microperimetry and found that the former performed better in the diagnosis of glaucoma. Lee and colleagues⁶ also investigated the relationship between central visual field sensitivity and macular ganglion cell/IPL thickness in glaucoma. They reported a correlation between inferotemporal ganglion cell/IPL thickness and corresponding visual field sensitivity in early to moderate glaucoma, and a correlation between superotemporal ganglion cell/IPL thickness and corresponding visual field sensitivity in advanced glaucoma.⁶

Interestingly, a study by Bowd and colleagues⁷ indicated the lack of a floor effect for SD-OCT measurement of ganglion cell/IPL thickness. The study showed that a significant amount of ganglion cell/IPL tissue is spared in advanced glaucoma compared with other structural measurements, suggesting this may be a valuable parameter for detecting glaucoma progression⁷ (See Case 2, page 22) and supporting a role for SD-OCT in advanced glaucoma.

The Avanti Widefield OCT system (Optovue) performs GCC thickness measurements and offers trend analysis that tracks change in both GCC and RNFL thickness and provides an estimate of the rate of future progression. Additional metrics are designed to increase the sensitivity and specificity of the analysis. Focal loss volume (FLV) measures the average amount of focal, or isolated, loss over the entire GCC map, while global loss volume measures the average amount of GCC loss over the entire GCC map. Trend analysis with widefield OCT requires only three OCT scans to generate an evaluation of progressive changes. In comparison, trend analysis with other OCT systems typically requires at least five separate scans.

The parameters tracked by different systems differ as well. One system, for example, monitors optic nerve cupping and RNFL loss over time to create a trend analysis. A recent study demonstrated a non-linear relationship between neuroretinal rim loss and RNFL loss in glaucoma, leading the investigators to hypothesize that structural changes in peripapillary connective tissue and axons followed by retinal ganglion cell axon loss may account for this non-linear relationship.⁸ It follows that trend analysis based on optic nerve cup-to-disc ratio and RNFL thickness is likely redundant.

Hollo and Zhou⁹ were the first to investigate progression rates of RNFL thickness and GCC in healthy eyes, eyes with ocular hypertension, and eyes with glaucoma using widefield OCT. They concluded that an average RNFL thickness progression rate faster than -1.5 µm/year and an average GCC progression rate faster than -1.3 µm/year are suggestive of glaucoma progression.⁹

Similarly, Hollo and Naghizadeh¹⁰ evaluated the latest version (6.12) of the RTVue OCT (Optovue) software with regard to its detection of macular GCC and RNFL changes by imaging healthy eyes, eyes with ocular hypertension, and eyes with glaucoma at 6-month intervals for an average of 5 years. Comparing the new software with a previous version (6.3), they concluded that the new software reduces long-term measurement variability across the spectrum of glaucoma severity and provides “steeper GCC progression slopes” and “more cases of significant GCC progression slopes in glaucoma,” which may serve to “improve detection of glaucomatous progression in clinical practice.”¹⁰

Zhang and colleagues with the Advanced Imaging for Glaucoma Study Group, evaluated RTVue measurements of the optic disc, cpRNFL thickness, and macular GCC thickness and prediction of the development and progression of visual field loss.^11,12 They found that GCC-FLV was the most powerful single predictor of conversion to perimetric glaucoma. Eighty-two percent of visual field conversion was preceded by an abnormal OCT variable. A lag of 23 +/- 17 months existed between visual field conversion and an OCT abnormality. A borderline GCC-FLV carried a 3.8-fold conversion risk, while an abnormal GCC-FLV carried a 5-fold conversion risk. Based on Kaplan-Meier survival curves, eyes with a borderline or abnormal GCC-FLV at baseline had a nearly 4 times greater risk of visual field conversion after 6 years compared with eyes with normal GCC-FLV. The strongest risk factor for visual field progression was GCC-FLV, with NFL-FLV a close second. Eyes with a borderline or abnormal GCC-FLV at baseline had a significantly rapid visual field index (VFI) decline; the slope of VFI deterioration was twice as steep in eyes with abnormal GCC-FLV at baseline compared with eyes with borderline GCC-FLV.

Another interesting finding was that eyes with decreased inferior GCC thickness were more likely to progress compared with eyes with decreased inferior NFL thickness.

GCC Analysis in My Practice

I routinely use the widefield OCT to assist me as I manage my glaucoma and glaucoma-suspect patients. The addition of GCC analysis with FLV and GLV metrics provides me with an even more comprehensive view of each patient’s disease status, as the following cases illustrate.

Case 1

A 73-year-old woman with asymmetric optic disc cupping and mild sensitivity depression on perimetry had IOP in the mid to high teens that had occasionally risen to more than 20 mmHg. Her total, superior, and inferior GCC thickness averages were initially normal OD, but deteriorated to abnormal or borderline at the most recent visit (Figure 1). Total, superior, and inferior GCC thickness averages OS, initially borderline, progressed to abnormal (Figure 2). Also over time, GLV had progressed to abnormal while FLV remained normal, which indicates a more diffuse glaucomatous damage pattern.

The initial scans showed borderline superior RNFL thickness that deteriorated to abnormal OU by the time of the most recent scans. Average RNFL thickness followed a similar course. At the most recent visit, overall, superior, and inferior RNFL averages were all decreased. At the same time, no significant change occurred in cup/disc ratios or neuroretinal rim areas.

Trend analysis OD showed an RNFL rate of change of -1.94 µm/yr and a GCC rate of change of -1.31 µm/yr. Trend analysis OS showed an RNFL rate of change of -2.21 µm/yr and a GCC rate of change of -1.29 µm/yr. Visual field trend analysis showed no significant progression in either eye.

Based on disease progression documented with OCT, selective laser trabeculoplasty (SLT) was performed OU to achieve tighter control of IOP.

Case 2

This case involves a 49-year-old man with initial average IOPs of 16 mmHg OD and 32 mmHg OS, thin central cornea OU, mild superior arcuate visual field defects OD, and dense superior and inferior arcuate visual field defects OS. Both FLV and GLV were reduced bilaterally and were worse in the left eye. RNFL and GCC thickness continued to decrease in both eyes as FLV and GLV also worsened (Figure 3).

For tighter control of IOP, the patient received SLT OD and trabeculectomy OS. FLV/GLV continued to worsen, but the damage was likely non-pressure-dependent and may have been a result of continued apoptosis and cell death even after IOP was well controlled.

In this case, OCT demonstrates the absence of a floor effect for GCC measurements as opposed to the floor effect observed for RNFL measurements. Progression is noted in both the RNFL and GCC measurements OD. In contrast, RNFL progression levels off OS, while GCC progression continues because in late glaucoma, RNFL progression is slower than GCC progression; this demonstrates the lack of a GCC floor effect in late glaucoma and the need for GCC trend analysis in such cases.

Case 3

An 81-year-old man with secondary open-angle glaucoma following laser iridotomy OU had also been diagnosed with pseudoexfoliative glaucoma. Despite therapy with three IOP-lowering drops OU and IOPs in the mid-teens, OCT detected progression of GCC and RNFL thickness loss.

The rate of GCC loss was greater than the rate of RNFL loss OD, and the rate of RNFL loss was greater than the rate of GCC loss OS, demonstrating that progression in these two parameters is not necessarily synchronous and GCC loss can outpace RNFL loss. Initially, FLV and GLV values were normal OD and abnormal OS. Progression, significant OD and mild OS, occurred in both parameters.

Based on the OCT trend analysis, in an effort to stop disease progression, SLT was performed OU.

Benefits for Patients and Physicians

OCT technology continues to improve our ability to accurately diagnose and monitor glaucoma. The addition of a more direct way to measure the macular GCC in combination with the cpRNFL and optic disc analysis improves risk prediction as well. This comprehensive analysis further enables individualized treatment protocols for the best possible patient care. GP

References

1. Quigley HA, Dunkelberger GR, Green WR. Retinal ganglion cell atrophy correlated with automated perimetry in human eyes with glaucoma. Am J Ophthalmol. 1989;107(5):453-464.
2. Quigley HA. Ganglion cell death in glaucoma: pathology recapitulates ontogeny. Aust N Z J Ophthalmol. 1995;23(2):85-91.
3. Tan O, Chopra V, Lu AT-H, et al. Detection of macular ganglion cell loss in glaucoma by Fourier-domain optical coherence tomography. Ophthalmology. 2009;116(12): 2305-2314.
4. Zeimer R, Asrani S, Zou S, Quigley H, Jampel H. Quantitative detection of glaucomatous damage at the posterior pole by retinal thickness mapping: a pilot study. Ophthalmology. 1998;105(2):224-231.
5. Rao HL, Hussain RS, Januwada M, et al. Structural and functional assessment of macula to diagnose glaucoma. Eye (Lond). 2017;31(4):593-600.
6. Lee JW, Morales E, Sharifipour F, et al. The relationship between central visual field sensitivity and macular ganglion cell/inner plexiform layer thickness in glaucoma. Br J Ophthalmol. Epub ahead of print Jan. 11, 2017.
7. Bowd C, Zangwill LM, Weinreb RN, Medeiros FA, Belghith A. Estimating optical coherence tomography structural measurement floors to improve detection of progression in advanced glaucoma. Am J Ophthalmol. 2017;175:37-44.
8. Patel NB, Sullivan-Mee M, Harwerth RS. The relationship between retinal nerve fiber layer thickness and optic nerve head neuroretinal tim tissue in glaucoma. Invest Ophthalmol Vis Sci. 2014;55(10):6802-6816.
9. Holló G, Zhou Q. Evaluation of retinal nerve fiber layer thickness and ganglion cell complex progression rates in healthy, ocular hypertensive, and glaucoma eyes with the Avanti RTVue-XR optical coherence tomograph based on 5-year follow-up. J Glaucoma. 2016;25(10):e905-e909.
10. Holló G, Naghizadeh F. Influence of a new software version of the RTVue-100 optical coherence tomograph on the detection of glaucomatous structural progression. Eur J Ophthalmol. 2015;25(5):410-415.
11. Zhang X, Loewen N, Tan O, et al., for the Advanced Imaging for Glaucoma Study Group. Predicting development of glaucomatous visual field conversion using baseline Fourier-domain optical coherence tomography. Am J Ophthalmol. 2016;163:29-37.
12. Zhang X, Dastiridou A, Francis BA, et al. Baseline Fourier-domain optical coherence tomography structural risk factors for visual field progression in the Advanced Imaging for Glaucoma Study. Am J Ophthalmol. 2016;172:94-103.

Dr. Rothstein is the founder of Eyenamics NY in Forest Hills, NY, where he provides comprehensive eye care and specializes in neuro-ophthalmology and all stages of glaucoma.