Review of Longitudinal Glaucoma Progression: 5 Years after the Shaffer Lecture

Abstract

In 2013, the senior author delivered the American Academy of Ophthalmology Robert N. Shaffer Lecture entitled “Glaucoma Changes—Reality Bites.” This talk focused on describing the longitudinal structure–function relationships in glaucoma progression. The study was based on a 10-year longitudinal dataset created by calibrated measurements across multiple OCT generations with corresponding visual fields (VFs). The prior held observation was that functional damage follows structural damage. The lecture posited that structure and function change at similar times, but that current measurement technology limits our ability to detect functional abnormalities and change early in glaucoma, as well as to measure structural change late in the disease. The Shaffer lecture provided evidence that structure and function change concordantly and that any apparent discordance in the relationship was due to technologic limitations to measure glaucomatous change. Furthermore, we observed 5 longitudinal relationships of concordance and discordance that can exist with structure–function interactions. Concordance: (1) structure–structure progression, (2) structure–function tipping point, (3) structural floor tipping point. Discordance: (4) functional progression in a “stable” VF with structure–function correlation, (5) functional progression with “normal” structure. In this review article, we will review longitudinal glaucoma progression studies with long-term follow-up and discuss the clinical relevance of relationships of concordance and discordance that can exist with structure–function interactions.

Glaucoma is a progressive optic neuropathy with death of retinal ganglion cells (RGCs) that results in thinning of the retinal nerve fiber layer (RNFL) and characteristic cupping of the optic nerve head (ONH) that may result in vision loss and blindness. The structural and functional relationship in glaucoma has been studied extensively. However, the detection of glaucomatous structural and functional progression is challenging because the measurement technology is limited by variability, lack of a gold standard, and confounding age-related changes. As such, it is important to realize that many historical observations on glaucoma structural and functional relationships were artifactual because of reliance on measurement devices with inherent limitations.

Early investigation of the structural and functional relationship suggested that RNFL loss on fundus photography may precede Goldmann visual field (VF) loss beginning as early as 5 years (mean, 1.5 years).¹ Further research suggested that functional loss follows structural loss, but results varied according to the technology used for detection. Histologic studies demonstrated that approximately 40% to 50% of the RGC axons had to be lost before there was a functional deficit detected by Goldmann perimetry.² However, only 30% of the RGC axons needed to be lost before there is a functional deficit detected by standard automated perimetry (SAP).³ Even less structural loss was necessary before the visual defect was detected by short-wavelength automated perimetry.⁴ When measuring RNFL loss with OCT, approximately 17% to 20% needed to be lost to detect a VF defect with SAP.⁵ The detection of glaucoma by OCT has been estimated to provide up to 8 years of lead time before a defect appears on SAP.⁶ Although these and many other studies have indicated that structural change precedes functional change, there is a growing body of evidence that calls this axiomatic position into question.

Corresponding coincident loss of structure and function has been demonstrated.^7–11 Also, the sensitivity of detecting visual function abnormality depends on which technology is used; short-wavelength automated perimetry identifies loss of visual function before SAP.¹² Even with very early glaucomatous VF loss, patients may report a reduced quality of life.^13,14 These findings suggest that although structural abnormality or change may be detectable clinically before identifiable VF loss, it does not necessarily precede true functional abnormality, and the discordance is an artifact of how we measure visual function.

Early longitudinal observations confirmed that structural RNFL loss was associated with future functional VF defects.^15,16 Previous studies proposed models to relate structural and functional measures of glaucomatous damage but were unable to determine the structural threshold at which functional changes can be detected clinically.^17,18 Ajtony et al¹⁹ were first to propose that a mean RNFL thickness of 70 μm may represent a threshold value in glaucomatous structural change.¹⁹ Since then, our research group used a broken stick statistical model to determine this threshold to be approximately 75 μm (95% confidence interval, 68.9–81.8).⁵ This structural and functional tipping point defined the OCT-measured mean RNFL threshold where we expect to find a strong association with VF abnormalities up to the OCT measurement floor.²⁰ However, values above the tipping point had little correspondence between structure and function because of higher variability of VF measurements in the early stage of glaucoma.^17,18,21 These findings corroborate that the discordance between structural and functional glaucomatous progression results from the different sensitivities of the respective measurement devices at different stages of the disease.

The aforementioned structural and functional investigations on detecting glaucoma progression are primarily based on cross-sectional studies, and the limited longitudinal data used short-term cohorts. As such, it was critical to examine the glaucomatous structural and functional progression relationship in an extended long-term longitudinal cohort.

Shaffer Lecture

In 2013, the senior author delivered the American Academy of Ophthalmology Robert N. Shaffer Lecture entitled “Glaucoma Changes—Reality Bites.” That presentation focused on describing the longitudinal structural and functional relationships in glaucoma progression. The study was based on a 10-year longitudinal dataset created by calibrated measurements across multiple generations of OCT devices with corresponding VFs. The prior held observation was that functional damage follows structural damage. The lecture posited that structure and function change at similar times, but that the current measurement technology limits our ability to detect functional abnormalities and change early in glaucoma, as well as to measure structural change late in the disease. Schuman et al presented longitudinal data that validated the tipping point as a relationship that represents the average trajectory for individuals over time.

Much has changed since the 2013 presentation, in large part because of the rapid innovation of ophthalmic imaging tools. More important, although calibrating measurements across multiple OCT generations was novel, the resulting systematic/random error adjustments to normalize structural measures limited the clinical generalizability to everyday practice. Since 2013, multiple longitudinal studies have been completed with longer follow-up across a single generation of OCT with corresponding VFs.

The Shaffer lecture provided evidence that structure and function change concordantly, and any apparent discordance in the relationship was due to technologic limitations to measure glaucomatous change. Furthermore, we observed 5 longitudinal relationships of concordance and discordance that can exist with structure–function interactions: Concordance (1) structure–structure progression, (2) structure–function tipping point, (3) structural floor tipping point; Discordance (4) functional progression in a stable VF with structure–function correlation, (5) functional progression with seemingly normal structure.

In this article, we will review longitudinal glaucoma progression studies with long-term follow-up and discuss the clinical relevance of relationships of concordance and discordance that can exist with structure–function interactions.

Longitudinal Glaucoma Studies with ≥5-Year Follow-up

Medeiros et al⁷ followed 53 glaucoma suspects (53 eyes) who had normal SAP VFs at baseline and developed repeatable (3 consecutive) abnormal test results during a median follow-up of 6.7 years (Table 1). The goal of the study was to estimate RGC losses associated with the earliest development of VF defects in glaucoma. An age-matched control group was included in the study consisting of 124 eyes from 124 healthy participants. The authors estimated the amount of RGC loss from a combination of RNFL assessment with OCT (Cirrus HD-OCT; Carl Zeiss Meditec, Dublin, CA) and SAP.²² The study concluded that compared with the average number of RGCs in the healthy group, glaucoma eyes had an average RGC loss of 28.4%, ranging from 6% to 57%, at the time of the earliest VF defect on SAP. At the time of glaucoma conversion, the average RNFL thickness was 76.0 ± 9.9 μm. Twenty-two of the 53 glaucoma eyes (42%) developed superior VF defects, 14 eyes (26%) developed inferior defects, and 17 eyes (32%) had defects that were seen both superiorly and inferiorly. In all eyes, RGC counts corresponding to the contralateral hemiretina to VF defect were significantly lower. For the 124 healthy eyes, there was no significant difference between RGC counts in the superior and inferior hemiretinas. The RGC counts performed significantly better than the spectral domain OCT (SD-OCT) average RNFL thickness parameter in discriminating glaucomatous from healthy eyes with receiver operating characteristic curve areas of 0.95 ± 0.02 versus 0.88 ± 0.03, respectively.

Table 1.

Longitudinal Glaucoma Studies with Greater than 5 Years of Follow-up

Study, year (Reference)	Follow-up (yrs)	Subjects	Number of Eyes	Device	Progression Standard	Progression Parameters	Summary
Medeiros et al 2013	6.7	Glaucoma suspect	53	Cirrus SD-OCT (Carl Zeiss Meditec, Dublin, CA)	VF	RGC count	Compared with the average number of RGCs in the healthy group, glaucoma eyes had an average RGC loss of 28.4%, ranging from 6% to 57%, at the time of the earliest VF defect on SAP. RGC counts performed significantly better than the SD-OCT average RNFL thickness parameter in discriminating glaucomatous from healthy eyes.
		Healthy	124
Kuang et al 2015	6.3	Glaucoma suspect	75	Stratus TD-OCT (Carl Zeiss Meditec) Cirrus SD-OCT	VF	RNFL	Significant loss of the RNFL was detected by OCT several years before the development of VF loss. A lead time of up to 8 yrs could be obtained in some patients by using OCT.
		Healthy	75
Yu et al 2016	≥5	Glaucoma	240	Cirrus SD-OCT	VF	RNFL	Progressive RNFL thinning determined by GPA and TPA is predictive of detectable functional decline in glaucoma.
		Healthy	25
Shin et al 2017	5.0	Glaucoma	196	Cirrus SD-OCT	VF	RNFL GCIPL	Ganglion cell–inner plexiform layer GPA provides a new approach for evaluating glaucoma progression. It may be more useful for detecting progression in the advanced stages of glaucoma than RNFL GPA.
Seth et al 2018	6.6	Glaucoma suspect	63	Cirrus SD-OCT	VF	RNFL	Structural change appears to be more useful to detect progression in glaucoma suspects, while functional change is a better indicator as the disease progresses. Percentage change from baseline RNFL thickness was a better measure than absolute change in RNFL.
		Glaucoma	59
Shin et al 2018	6.0	Glaucoma	292	Cirrus SD-OCT	VF	GCIPL	Progression of GCIPL thinning occurred before apparent progression on SAP in most glaucomatous eyes.
Hou et al 2018	≥5	Glaucoma	231	Cirrus SD-OCT	VF	RNFL GCIPL	Progressive macular GCIPL thinning and progressive RNFL thinning are mutually predictive. Progressive RNFL thinning and progressive GCIPL thinning are both indicative of VF progression but not vice versa.
		Healthy	93

GCIPL = ganglion cell inner plexiform layer; GPA = Guided Progression Analysis; RGC = retinal ganglion cell; RNFL = retinal nerve fiber layer; SAP = standard automated perimetry; SD-OCT = spectral domain OCT; TD-OCT = time domain OCT; TPA = Trend-based Progression Analysis; VF = visual field.

In another study, Kuang et al⁶ followed a cohort of 75 glaucoma suspects until they showed evidence of repeatable VF defects. The authors studied the ability of SD-OCT to detect structural damage at the point of earliest confirmed functional loss. Ocular Hypertension Treatment Study criteria were used to define VF progression.^23,24 The subjects were followed for a median of 6.3 years with SAP, time-domain OCT (Stratus OCT, Carl Zeiss Meditec), and SD-OCT (Cirrus SD-OCT, Carl Zeiss Meditec). Because measurements from time domain OCT and SD-OCT instruments are not directly interchangeable, a conversion factor was obtained from a subgroup of 63 eyes of 63 subjects who had testing with both instruments on the same day during the transition period using a Passing-Bablock regression.²⁵ At the time of development of the earliest VF defect, mean average RNFL thickness was 75 μm in glaucomatous eyes compared with 90 μm from the age-matched healthy group (P < 0.001). Of note, this value is almost identical to the threshold for RNFL thickness loss where VF defects become detectable as estimated by Wollstein et al⁵ in a cross-sectional study (75.3 μm). Significant differences between glaucomatous and healthy eyes were still seen as early as 8 years before the date of VF conversion with mean RNFL thicknesses of 86.3 μm and 91.4 μm, respectively. At a specificity of 95%, up to 44% of subjects had abnormal average RNFL thickness 2 years before the development of a field defect. This number decreased to 35% at 4 years and to 19% at 8 years. Although 19% may seem to be a small proportion, it is important to consider that 8 years is a relatively large amount of time, and such lead-time could have significant management implications to a significant group of patients. In fact, the results suggest that OCT could detect damage in approximately one-third of patients with glaucoma up to 5 years before the appearance of the earliest field defects. Although OCT was able to detect the damage before functional loss, only half of the patients had abnormal OCT results at the time of earliest development of field defects using a 95% specificity cutoff. The authors did not report on glaucoma structural and functional spatial relationship.

The ability of structural progression detected by SD-OCT (Cirrus HD-OCT; Carl Zeiss Meditec) to predict functional progression was evaluated by Yu and colleagues.²⁶ A total of 139 patients with primary open-angle glaucoma (240 eyes) were followed for >5 years. Some 52.5% (126 eyes) had mild VF loss (mean deviation [MD] > –6 decibels [dB]), 16.7% (40 eyes) had moderate VF loss (MD –6 dB to –12 dB), and 30.8% (74 eyes) had advanced VF loss (MD < –12 dB). Progressive RNFL thinning was determined by event analysis (Guided Progression Analysis [GPA]) and trend analysis (Trend-based Progression Analysis [TPA]) of serial registered RNFL thickness maps. Progression of VF was detected according to the Early Manifest Glaucoma Trial and pointwise linear regression criteria. Guided Progression Analysis detected 65 eyes (27.1%) and TPA detected 117 eyes (48.8%) with progressive RNFL thinning during the study follow-up. A total of 30 eyes (12.5%) showed “likely” VF progression by the Early Manifest Glaucoma Trial criteria, and 39 eyes (16.3%) showed VF progression by the pointwise linear regression criteria. Eyes with progressive RNFL thinning had lower VF survival estimates compared with eyes without progressive RNFL thinning. Progressive RNFL thinning analyzed by TPA and GPA was strongly predictive of subsequent development of VF progression. Specifically, eyes with progressive RNFL thinning detected by TPA or GPA had more than 8-fold and 3-fold increases in risk, respectively, in developing “likely” VF progression compared with eyes without progressive RNFL thinning after controlling for the baseline measures.

With the use of OCT (Cirrus HD-OCT; Carl Zeiss Meditec), Hou and colleagues²⁷ studied the temporal relationship among progressive macular ganglion cell inner plexiform layer (GCIPL) thinning, progressive parapapillary RNFL thinning, and VF progression in patients with primary open-angle glaucoma. A total of 136 patients with glaucoma (231 eyes) had been followed for an average of 5.8 years. At the baseline examination, 51.1% of eyes showed mild VF defects (MD≥–6.0 dB) and 48.9% showed moderate to advanced VF defects (MD <–6.0 dB). Twenty-eight eyes (12.1%) demonstrated likely VF progression, and 43 eyes (18.6%) demonstrated possible VF progression by the Early Manifest Glaucoma Trial criteria during the study follow-up. OCT RNFL-guided progression analysis detected 57 eyes (24.7%) with progressive GCIPL thinning and 66 eyes (28.6%) with progressive RNFL thinning; 35 eyes showed both progressive RNFL and GCIPL thinning. The agreement between progressive RNFL thinning and progressive GCIPL thinning was moderate (κ, 0.41; 95% confidence interval, 0.28–0.55). Among the 35 eyes detected to have progressive RNFL and GCIPL thinning during the study follow-up, 54.3% showed progressive GCIPL thinning detected before progressive RNFL thinning, 37.1% showed progressive RNFL thinning detected before progressive GCIPL thinning, and 3 eyes showed RNFL and GCIPL thinning detected at the same time; 74.3% of the 35 eyes showed spatial correspondence. Of 67 healthy eyes, only 6 (9.0%) demonstrated progressive RNFL thinning and 3 (4.5%) demonstrated progressive GCIPL thinning over a mean follow-up period of 7.8 years, which suggests that most eyes detected with progressive RNFL or GCIPL thinning by GPA in the glaucoma group represent disease-related thinning. Eighteen eyes demonstrated progressive structural thinning and VF progression, among which 77.8% showed spatial correspondence. Both progressive GCIPL thinning and progressive RNFL thinning were connected to an increased risk of VF progression; furthermore, both measurements had similar hazard ratios for functional progression. Progressive RNFL thinning and progressive GCIPL thinning were mutually predictive, yet VF progression was not indicative of the progressive RNFL or GCIPL thinning. Progressive RNFL thinning conferred a 2.99-fold increase in the risk of progressive GCIPL thinning, whereas progressive GCIPL thinning conferred a 5.27-fold increase in risk of progressive RNFL thinning after adjusting for baseline covariates.

Progressive thinning of the GCIPL and RNFL (Cirrus HD-OCT; Carl Zeiss Meditec) in glaucoma subjects over a 5-year period was studied by Shin et al.²⁸ The reference standard of glaucoma progression was determined by VF progression based on the Early Manifest Glaucoma Trial criteria or linear regression analysis of the VF index. Of 196 eyes, 117 were classified as mild and 79 were classified as moderate to severe based on baseline VF defects. Seventy-six eyes (38.8%) and 43 eyes (21.9%) demonstrated progressive GCIPL and RNFL thinning, respectively, and 48 eyes (24.5%) were classified as progressors by reference standard. Among the 38 eyes with progressive GCIPL and VF change, progressive GCIPL thinning preceded in 50% of eyes or occurred concomitantly with VF progression in 28.9% eyes. Among the 20 eyes with progressive RNFL and VF change, progressive RNFL thinning preceded VF progression in 60% and occurred concomitantly with VF progression in 10%. For the eyes with progressive GCIPL or RNFL thinning before VF progression, the average delay was 14.4 ± 11.7 months and 16.9 ± 11.3 months, respectively. Assessment of disease progression in the advanced stages of glaucoma is extremely difficult in terms of both the functional and structural aspects of the disease. The GCIPL analysis was able to identify progressors regardless of glaucoma severity; however, RNFL analysis was not able to separate progressors in moderate to severe glaucoma subjects. Although VF examination commonly is used to detect disease progression in eyes with advanced glaucoma, VF results tend to fluctuate greatly with increasing glaucoma severity.^29,30 In advanced glaucoma, RNFL measurements are not useful for monitoring glaucoma progression because of the floor effect, which stops the detection of further RNFL thinning.^17,31,32 The study suggests that GCIPL GPA may be a useful alternative method for detecting disease progression in advanced stages of glaucoma.

Seth et al³³ studied OCT (Cirrus HD-OCT; Carl Zeiss Meditec) structural and VF functional progression in 63 glaucoma suspects and 59 glaucoma subjects with a mean follow-up period of 6.6 years. The authors estimated that structural change appears to be more useful in detection of progression in early disease states, whereas functional change is a better indicator as the disease progresses. The study showed poor agreement between OCT GPA and SAP GPA in both early and advanced stages. The subjects who demonstrated progression by SAP had a similar percentage change from baseline RNFL thickness (–9.9% vs. –8.6% P = 0.46), although the absolute change was significantly greater in glaucoma suspects (–8.75 μ vs. –6.4 μ, P = 0.03). In a glaucoma suspect cohort, of 20 eyes that showed structural or functional progression, only 2 eyes progressed by both OCT and SAP, and in both cases structural progression predated functional by 11 and 17 months, respectively. In the more advanced stage, more patients demonstrated functional than structural progression (10 vs. 6 subjects), yet only 2 subjects showed progression by both OCT and SAP. The authors used a novel method for determining RNFL attenuation that included a percentage decline from baseline RNFL thickness measurements. Because the RNFL thickness in patients with glaucoma is already attenuated at baseline, it is possible that the absolute decrease is not so apparent even though they progress functionally. However, when estimating the percentage change from baseline, they found that it was similar in both glaucoma suspects and glaucoma patients. At least in glaucoma patients, OCT-GPA has a higher negative predictive value, and if a patient appears stable on OCT but shows progression on VF, it could be a subjective error, and it may be prudent to repeat the VF and not consider that as progression straightaway.

Shin et al³⁴ studied the spatial characteristics and patterns of progressive macular GCIPL thinning (Cirrus HD-OCT; Carl Zeiss Meditec) in glaucomatous eyes. They included 292 eyes of 192 patients with primary open-angle glaucoma with a mean follow-up of 6.0 years. The pattern of progressive GCIPL thinning was evaluated by comparing the baseline GCIPL thickness deviation map and the final GCIPL thickness change map. Visual field progression was determined by Early Manifest Glaucoma Trial criteria and linear regression of the VF index. A total of 72 eyes (24.7%) showed progressive GCIPL thinning, and 41 of 72 eyes also showed VF progression. In the majority of cases, progressive GCIPL thinning preceded VF progression. Of the eyes with progressive GCIPL thinning, 58 (80.6%) showed mild, 7 (9.7%) showed moderate, and 7 (9.7%) showed advanced VF defects at the baseline examination. The progressive GCIPL thinning preceded (61.0%) or occurred concomitantly (21.9%) with VF progression in 34 of the 41 eyes (82.9%). In the 25 eyes with progressive GCIPL thinning before VF progression, GCIPL GPA detected the progressive change 17.3 ± 11.9 months earlier than the progressive VF change. Among the 41 eyes with both progressive GCIPL and VF deterioration, the mean duration of follow-up until the first detection of progressive GCIPL thinning was significantly earlier (6.3 ± 17.8 months). The eyes with progressive GCIPL thinning showed a higher likelihood of VF progression than the eyes with progressive RNFL thinning (56.9% in the present study vs. 46.4% in the study of Leung et al³⁵), although direct comparisons are limited because of the different participant characteristics, follow-up duration, and progression criteria. This could be explained because GCIPL is measured in the macular area that falls within the 24–2 VF testing area, whereas the peripapillary RNFL supplies the entire retina, some of which falls outside the VF testing area, which may result in a weak correlation. From the progressive changes of the GCIPL, it can be postulated that macular damage begins with focal GCIPL defects and spreads to a nearby area to form diffuse defects as the disease progresses; meanwhile, more severe damage accumulates inside preexisting defects.

Discussion

This article was intended to describe the glaucomatous structure–function relationship as we measure it and provide clinical guidance for patient care. We have previously presented longitudinal data demonstrating the glaucomatous structure–function progression relationship and the concept of the tipping point. Although the tipping point was derived experimentally from cross-sectional data, our clinical observations based on long-term data support the hypothesis that the tipping point curve represents the average trajectory for individuals longitudinally. Structure and function seem to change simultaneously past the tipping point and before the floor effect. The regions of disconnect are likely an artifact of how we measure structure and function. The tipping point and floor effect do not represent the true relationship between optic nerve structure and function, which we posit is more linear and highly correlated. Before discussing the clinical implications of these findings, we will discuss the challenge of age-related changes and elaborate on the apparent discordance between structure and function.

The detection of glaucoma structural progression is also challenging given the difficulty to discriminate between glaucomatous damage and measurement variability or age-related structural loss. Several cross-sectional and prospective studies demonstrated a significant negative correlation between age and average RNFL thickness of 0.16 to 0.52 μm/year.^36,37 Age-related structural loss varies as a function of baseline RNFL where a higher baseline thickness is subject to higher rates of decline.^38–40 Highly myopic eyes have a significantly greater age-related decrease in RNFL than normal eyes.⁴¹

Although OCT structural measurements of RNFL thickness and SAP functional measurements of VF sensitivity provide complementary assessments of glaucomatous neuropathy, comparisons of these methods in randomized controlled trials have reported discrepancies in the time course of structural and functional defects.^1,6,42,43 Because the loss of RNFL thickness and VF sensitivity are both caused by the underlying loss of RGCs, the discordance is likely related to several factors that confound the comparison: measurement scale and relative variation of baseline parameters.

OCT and SAP have different dynamic ranges of measurements: RNFL thickness is measured by OCT over a linear range of approximately 50 to 200 μm,^44,45 whereas VF sensitivity is measured by SAP over a 5.1 log unit (51 dB) range.⁴⁶ It is critical to take into account the unit of measurement when comparing the relationship between structural and functional measurements in glaucoma.^17,47 Although OCT measures structure in linear units, SAP measures function in logarithmic decibel units. The logarithmic scale compresses the range of losses in the early stages of glaucoma while expanding the range in later stages.⁴⁸ As such, significant RGC and RNFL losses are likely to correspond to relatively small changes in VF sensitivity at early stages of glaucoma compared with relatively larger changes in the later stages of glaucoma. Furthermore, baseline RNFL thickness and VF sensitivity affect the rates of structural and functional change. Glaucomatous eyes in early stages of disease with larger baseline RNFL thickness are associated with a higher rate of structural loss, suggesting more rapid progression in early than in advanced disease.⁴⁹ This is in contrast with studies showing that advanced glaucomatous eyes with more severe VF sensitivity loss are associated with higher risks of progression.^50,51 Detecting glaucoma progression varies considerably between structural OCT and functional SAP assessment depending on the stage of disease and measurement variability of OCT and SAP.¹⁷ These differences in scale and baseline parameters introduce an artifactual relationship between glaucomatous structural and functional measurements. Because of the high variability and low sensitivity to abnormality with SAP early in the glaucomatous process, there is a poor relationship with OCT-measured RNFL and GCL/IPL thickness when the layers are thick and normal.

To date, studies on glaucoma progression have been limited to cross-sectional and short longitudinal investigations (<6.5 years).^{6,26,33,34,49,52–55} The length of studies is limited primarily by the rapid evolution of OCT devices. Given what is known about the discordance of structural and functional progression in glaucoma, it is not surprising that all these studies have shown poor agreement. The short duration of these longitudinal studies further compounds the discordance because of the slowly progressive natural history of glaucoma that makes it challenging to detect progression with limited follow-up. It is important to keep in context that the tipping point and floor effect are artifacts that reflect an artifactual construct of the measurement devices; however, this framework is clinically applicable and serves as the best available evidence for diagnosis and treatment decisions to prevent glaucomatous vision loss. On the basis of this longitudinal framework, we present considerations and recommendations for practical management of glaucoma across mild, moderate, and severe disease stages.

The early glaucoma stage occurs before the tipping point and is defined as structural optic nerve abnormalities consistent with glaucoma without functional SAP deficits or with abnormalities detected present only on short wavelength automated perimetry or frequency-doubling technology. At this stage, change in structure by OCT and function by event GPA on SAP in a pattern and location consistent with the ocular structure–function relationship should confirm a suspicious glaucoma diagnosis and serve as an indication to start treatment. This should not only confirm the detection of glaucoma but also confirm that the disease is actively progressing. The diagnosis of glaucoma can be made on structural or functional abnormality alone, but early identification of progression by the strategic use of both devices may result in an opportunity to intervene as early as possible in the glaucoma disease course to avoid preventable progressive vision loss. Medications and laser trabeculoplasty are reasonable starting interventions; however, in a high-risk patient with a high likelihood of going blind over his/her lifetime, surgical intervention may be warranted.

If there is uncertainty in early glaucomatous disease, corroboratory internal OCT structural parameters can be used to detect additional abnormal structure loss in a pattern and location corresponding with a glaucomatous structure–structure relationship. Structural loss of macular GCL + IPL by OCT that is in agreement with RNFL loss increases the certainty of a glaucoma diagnosis (before detectable SAP abnormality) based on confirmation of a structure–structure relationship. Although a change analysis protocol does not yet exist for macular GCL + IPL, it can still be used to corroborate RNFL loss suspicious for a glaucoma process and support a decision to diagnose and start treatment with medications or laser trabeculoplasty. Likewise, macular GCL + IPL by OCT can indicate normal structure when RNFL analysis is equivocal. These imaging results in a patient with no glaucomatous risk factors support a decision to observe. Last, structural change in ONH parameters by OCT can be used to corroborate RNFL change and progression indicating the need to intervene, starting therapy with medications and laser trabeculoplasty, or advancing therapy to surgical options in the appropriate high-risk patient.

The moderate glaucoma stage occurs after the tipping point and is defined as structural optic nerve abnormalities consistent with glaucoma and glaucomatous SAP abnormalities in 1 hemifield and not within 5 degrees of fixation. Beyond the tipping point, glaucomatous structure–function loss should be detected and followed as the basis for escalating interventions to halt progression and prevent vision loss. If structure–function changes do not correlate after the tipping point, repeat testing or consideration of an alternative nonglaucomatous process is indicated. It is worth noting that if a higher-sensitivity VF protocol (HVF 10–2, short wavelength automated perimetry, frequency-doubling technology) is used, then the tipping point may be detected earlier in the glaucoma disease process.

The severe glaucoma stage occurs after the floor effect and is defined as structural optic nerve abnormalities consistent with glaucoma and glaucomatous SAP abnormalities in both hemifields and within 5 degrees of fixation. On the spectrum of the glaucomatous disease course, after reaching the floor effect in advanced glaucoma, interventions to halt progression should be based on change by SAP only.

The floor effect results in an inability to reliably segment the RNFL, preventing further detection of RNFL loss. Despite this limitation, OCT imaging should be continued because changes in ONH parameters can still be monitored. Further, there may be areas of relatively thicker RNFL in a severely glaucomatous eye in which change may still be locally measurable.

Visual field test–retest variability worsens with disease severity. Detection of glaucoma progression with VF changes can be difficult because of variability, and local changes can sometimes be corroborated with changes in OCT ONH parameters, or even changes in remaining RNFL in some circumstances, even beyond the floor effect.

Conclusions

The way we understand the glaucoma structure–function relationship has evolved with the innovation of technology that allows for more sensitive measures of change. The concept of structural damage preceding functional loss is an artifact of the devices used to measure such events and trends. The current ophthalmic clinical testing methods limit our ability to detect functional change early in glaucoma and measure structural change late in the disease process. We propose that structure and function change concordantly, and any discordance is an artifactual limitation of our current clinical tools. We hope our description of structure–function interactions will allow clinicians to make more judicious decisions when evaluating a patient with suspected glaucoma progression.

Abbreviations and Acronyms:

dB

decibels

GCIPL

ganglion cell inner plexiform layer

GPA

Guided Progression Analysis

MD

mean deviation

ONH

optic nerve head

RGC

retinal ganglion cell

RNFL

retinal nerve fiber layer

SAP

standard automated perimetry

SD-OCT

spectral domain OCT

TPA

Trend-based Progression Analysis

VF

visual field