The Role of Intraocular Pressure and Systemic Hypertension in the Progression of Glaucomatous Damage to the Macula

Abstract

Purpose:

To examine the relationships between intraocular pressure (IOP), systemic hypertension, and glaucoma progression using structural testing with optical coherence tomography (OCT) and functional testing with visual field (VF).

Patients and Methods:

191 eyes of 119 patients enrolled in a prospective, longitudinal study (Structural and Functional Progression of Glaucomatous Damage to the Macula study) with a diagnosis of glaucoma were analyzed. Patients were tested with 10-2 and 24-2 VF and spectral-domain OCT obtained at 4–6 month intervals. IOP from each visit was collected. Self-reported diagnoses of HTN were reported in 72 eyes (37%) in the patients included. Linear mixed effects regression was used to test the relationship between summary statistics from VF and OCT and HTN diagnosis. The goodness-of-fit of relationships was assessed with Bayesian Information Criterion.

Results:

Mean follow-up IOP was most associated with the following OCT parameters: global macula GCL, inferior macula GCL, mean MaVZ GCL, and mean LVZ macula GCL, and with the following VF parameters: 10-2 PSD and 10-2 MD. There was no significant difference in rates of progression between HTN and non-HTN patients for any OCT or VF parameter. Models with the best goodness-of-fit for the relationship between HTN and progression were the same as those observed for IOP.

Conclusion:

Macular structural and functional parameters are more sensitive to IOP in terms of glaucomatous progression when compared to more conventional parameters. While HTN was not significantly associated with progression using any parameter, macular structural and functional parameters had a better goodness-of-fit to model progression and may be useful as endpoints.

PRÉCIS

Macular structural and functional parameters were better correlated with pressure-dependent glaucomatous damage than conventional parameters. Self-reported systemic hypertension was not associated with structural or functional progression in this cohort.

INTRODUCTION

Glaucoma is the leading cause of irreversible blindness and the second leading cause of blindness in the United States.¹ It has a prevalence of 2.1% in the United States, and the incidence of glaucoma is highest in non-Hispanic blacks followed by Latinos then whites.^1–3 It is a progressive degenerative optic neuropathy with characteristic patterns of abnormalities of the optic nerve complex, which includes the optic nerve head, retinal nerve fiber layer (RNFL), parapapillary region, and macula.

Traditionally, glaucoma has been monitored using disc photography and 24-2 or 30-2 visual fields as the reference standard to determine functional loss. However, these tests miss damage within the central 10° of the visual field (VF), the region that corresponds to the macula.^4–6 The macula is the region of ±8° surrounding the fovea that contains the highest density of retinal ganglion cells (RGCs) and is critical for high-acuity vision.⁶ While macular damage was once thought to be only significant in the late stages of glaucoma, considerable evidence exists that macular damage occurs in the early stages of disease and can be missed with traditional staging methods.^4,6,7 One study showed that in patients with normal 24-2 tests, 10-2 tests revealed damage in 35% of ocular hypertensives, 39% of glaucoma suspects, and 61% of patients with early glaucomatous field loss.⁸

Preventing macular damage is of particular importance, because the macula is crucial in determining visual function, quality of life, and ability to perform activities of daily living.^4,9–14 Since physicians evaluate progression when deciding whether to escalate glaucoma treatment, if macular damage is missed using traditional staging systems, patients are likely not receiving sufficient medical intervention and treatment.

Both functional and structural tests can specifically assess changes to the macula. The 10-2 VF test is a functional test that assesses 68 points in the central 10° of the visual field and is more specific to changes in the central field. Additionally, optical coherence tomography (OCT) is a structural test that allows for visualization of the RNFL and retinal ganglion cell layer (GCL) thicknesses to diagnose and monitor glaucoma progression, including changes in the macula (macular cube). Regions of retinal GCL thinning can correspond to abnormal regions on the VF from glaucomatous damage, but the OCT is also sensitive to regions of thinning on patients who have VF determined to be within normal limits.^6,15

The most important risk factor for onset and progression of glaucoma is intraocular pressure (IOP). Reduction of IOP is the only evidence-based intervention to delay and prevent further disease progression.¹⁶ Hypertension (HTN) is another risk factor that may affect glaucoma progression.¹⁷ There is a weak positive correlation between blood pressure (BP) and IOP, and lower ocular perfusion is associated with greater glaucoma prevalence and progression.^17,18 Specifically, the interplay between systemic BP and IOP dictates perfusion of the optic nerve head and hypoperfusion of the optic nerve head can lead to disease progression. Since lowering BP is associated with decreased mortality from cardiovascular causes and lowering IOP is associated with slowing of glaucomatous progression, further elucidating the relationship between these frequent comorbidities can provide implications on treatment.

The goal of this study is to examine the relationship between IOP and progression in the global RNFL and the macula GCL+ using structural testing with OCT and functional testing with VF and to examine their relationship with systemic BP.

MATERIALS AND METHODS

Institutional Review Board approval was obtained for this study. The study adheres to the tenets of the Declaration of Helsinki. Written informed consent was obtained from all participants in the study. ClinicalTrials.gov Identifier: NCT02547740

191 eyes of 119 patients enrolled in a prospective, longitudinal study (Structural and Functional Progression of Glaucomatous Damage to the Macula study) were analyzed. The participants enrolled in this study were recruited at Columbia University Medical Center Harkness Eye Institute, enrolled between October, 2015 and September, 2019, between 20 and 80 years old, and of either European or African ancestry. Inclusion criteria for cases was glaucomatous optic neuropathy as defined in the American Academy of Ophthalmology Preferred Practice Pattern criteria. These patients have undergone the following functional tests of the macula: 10-2 and 24-2 standard automated perimetry (SAP) as well as the following structural tests of the macula: spectral-domain OCT. Each of these tests is obtained at every office visit following study enrollment at 4–6 month intervals. Patient charts were reviewed to collect all IOP measurements at follow-up visits. Patients included in this study had at least four visits with testing. The patients were asked during the study visits whether they had a diagnosis of systemic HTN.

The parameters tested with OCT specific to the macula included the MaVZ: macular vulnerability zone, MVZ: macular more vulnerable zone, LVZ: macular less vulnerable zone, and GCL: ganglion cell layer, while those not specific to the macular region include IVZ: Inferior vulnerability zone, SVZ: Superior vulnerability zone, and cpRNFL: circumpapillary retinal nerve fiber layer.^6,15,19 These regions are illustrated in Figure 1. For visual field tests, testing parameters included the PSD: pattern standard deviation and MD: mean deviation for both 10-2, specific to the macula, and 24-2 tests.

Figure 1.

A) The circumpapillary RNFL profile of a glaucomatous patient. The arrow with the green dot indicates a local minimum corresponding to the arcuate pattern, while the blue lines indicate the macular vulnerability zone (MVZ). B) A schematic of the optic disc, with the green dot and blue lines from A superimposed. C) A schematic model of the macula showing the superior (S) and inferior (I) quadrants of the disc, as well as the less (LVZ) and more (MVZ) vulnerable zones of the macula.⁶

Linear mixed effects regression was used to test the relationship between testing parameters and follow-up IOP. This approach was also used to test the relationship between summary statistics and HTN diagnosis. This trend-based approach measures rates of change (slopes) over time, which estimate the speed of progression for any given parameter. Mixed effects models are preferred in this type of analyses as it takes into account the longitudinal nature of the data – with its correlation over time – and the use of both eyes of the same patient when applicable. The goodness-of-fit of relationships was assessed with Bayesian Information Criterion (BIC). BIC is a method for model selection from a set of other models; models with lower BIC values correspond to better fit of the data between the predictors (ie.: IOP and HTN) and rates of change (OCT and VF). All statistical analyses were performed using Stata Version 16 (StataCorp LP, College Station, TX). Statistical significance was defined at P < 5%.

RESULTS

The demographic and clinical characteristics of the 191 eyes of 119 patients meeting eligibility criteria are shown in Table 1. Most patients were Caucasian women with early visual field loss based upon the 24-2 MD. The patients included in this study were on IOP-lowering treatment and had a mean (SD) follow-up IOP of 14.6 (3.5) mmHg. They underwent an average of 6.3 (3.1) tests spanning 2.2 (1.0) years. Self-reported diagnoses of HTN were reported in 72 eyes (37%) in the patients included in the study.

Table 1.

Demographic and clinical characteristics of the study sample.

Parameter	Estimate
Baseline age (years)	66.3 (10.3)
Sex (% Female)	52%
Race (% Caucasian)	88%
Systemic hypertension status (% hypertensive)	37%
Follow-up intraocular pressure (mmHg)	14.6 (3.5)
Peak intraocular pressure (mmHg)	17.4 (5.3)
Trough intraocular pressure (mmHg)	12.7 (3.7)
Intraocular Fluctuation (Peak – Trough, mmHg)	4.7 (4.9)
Central corneal thickness (microns)	532.8 (39.2)
Baseline 24-2 mean deviation (dB)	−2.3 (2.5)
Baseline global retinal nerve fiber layer thickness (microns)	72.7 (15.7)

All estimates are means and standard deviation (SD) unless otherwise specified.

The average (95% CI) 24-2 and 10-2 MD rate of progression was −0.31 dB/year (−0.43 to −0.19) and −0.36 dB/year (−0.48 to −0.24), respectively. The rate of progression for OCT was −1.14 microns/year (−1.53 to −0.75) for global cpRNFL and −0.89 microns/year (−1.30 to −0.48) for global macula GCL+.

As shown in Table 2, the speed of progression for all parameters tested were statistically associated with mean follow-up IOP except for the OCT parameters mean nasal and mean MVZ, although the latter barely missed the level of significance (p=0.059). Using goodness-of-fit testing, changes in IOP were most strongly associated with the following OCT parameters: global macula GCL, inferior macula GCL, mean MaVZ macula GCL, and mean LVZ macula GCL, and with the following VF parameters: 10-2 PSD and 10-2 MD.

Table 2:

Relationship between IOP and glaucomatous progression as measured by various OCT and VF Parameters. Macular parameters showed higher strength of association for both OCT and VF.

	Parameter	Bayesian Information Criterion (BIC)	Coefficient	P value
OCT (macula GCL)	Mean Global Macula	9925.016	−0.051	0.000
	Mean Inferior Macula	10069.51	−0.053	0.000
	Mean MaVZ	10321.38	−0.052	0.000
	Mean LVZ Macula	10399.86	−0.049	0.000
	Mean Superior Macula	10577.06	−0.073	0.000
OCT (disc cpRNFL)	Mean Temporal	10721.29	−0.026	0.047
	Mean Nasal	10852.9	−0.020	0.216
	Mean Global	10931.66	−0.075	0.000
	Mean Inferior	12665.43	−0.111	0.000
	Mean Superior	12884.78	−0.146	0.000
	Mean MVZ	13156.2	−0.045	0.059
	Mean IVZ	13279.72	−0.082	0.002
	Mean SVZ	13504.63	−0.150	0.000
VF	10-2 – PSD	2017.562	0.010	0.002
	10-2 – MD	2947.962	−0.024	0.000
	24-2 – PSD	4532.474	0.007	0.003
	24-2 – MD	5261.385	−0.022	0.000

Abbreviations – MaVZ: macular vulnerability zone, MVZ: macular more vulnerable zone, LVZ: macular less vulnerable zone, IVZ: Inferior vulnerability zone, SVZ: Superior vulnerability zone, cpRNFL: cirumpapillary retinal nerve fiber layer, GCL: ganglion cell layer, PSD: pattern standard deviation, MD: mean deviation

There was no significant difference in rates of progression between HTN and non-HTN patients with any OCT or VF parameter. Yet, when testing the relationship between HTN and progression, the models with better goodness-of-fit had the following OCT parameters: global macula GCL+, inferior macula GCL+, mean GCL+ of macular vulnerability zone (MaVZ), and mean macula GCL+ of less vulnerable zone (LVZ), and VF parameters: 10-2 PSD and 10-2 MD. These results are shown in Table 3.

Table 3:

Strength of association of OCT and VF parameters with progression in patients with HTN. Macular parameters showed higher strength of association for both OCT and VF.

	Parameter	Bayesian Information Criterion (BIC)
OCT (macula GCL)	Mean Global Macula	9782.799
	Mean Inferior Macula	9924.914
	Mean MaVZ	10172.49
	Mean LVZ Macula	10249.82
OCT (disc cpRNFL)	Mean Temporal	10412.26
	Mean Superior Macula	10424.86
	Mean Nasal	10660.41
	Mean Global	10750.59
	Mean Inferior	12463.65
	Mean Superior	12671.94
	Mean MVZ	12908.57
	Mean IVZ	13040.62
	Mean SVZ	13249.05
VF	10-2 - PSD	2006.507
	10-2 – MD	2917.868
	24-2 – PSD	4503.986
	24-2 – MD	5219.258

Abbreviations – MaVZ: macular vulnerability zone, MVZ: macular more vulnerable zone, LVZ: macular less vulnerable zone, IVZ: Inferior vulnerability zone, SVZ: Superior vulnerability zone, cpRNFL: cirumpapillary retinal nerve fiber layer, GCL: ganglion cell layer, PSD: pattern standard deviation, MD: mean deviation

DISCUSSION

Glaucomatous changes to the global, conventional parameters and macula were evaluated using both structural tests (OCT) and functional tests (24-2 and 10-2 VF). The OCT and VF parameters most significantly affected by changes in IOP corresponded to regions in the macula. For OCT, these parameters were the global macula GCL, inferior macula GCL, mean MaVZ GCL, and mean LVZ macula GCL. For VF testing, both the PSD and MD in 10-2 VF demonstrated better goodness-of-fit than the 24-2.

Note that regarding IOP, the BIC for the 24-2 MD was 5261.385 and decreased to 2947.962 for the 10-2 MD, while for the OCT RNFL, the BIC decreased from 10931.66 (disc cpRNFL) to 9925.016 (macular GCL). These observations suggest that while both metrics are associated with IOP, the macula-related parameters could better fit the relationship between IOP over time and VF/OCT longitudinal data.

Our results suggest that the macula may be more susceptible to pressure-dependent glaucomatous damage, even in early stages of disease, in terms of both structure and function. Structural changes may correlate with functional loss or represent early changes that may lead to functional loss. Functional loss in the macula, as indicated by changes in the 10-2 VF test, can negatively impact quality of life as evaluated by the National Eye Institute Visual Function Questionnaire, specifically with reading, mobility, and driving.^9,20 More stringent IOP control as well as structural and functional testing specific to the macula, may be necessary to prevent irreversible progressive loss in the central field due to glaucoma. Of note, the rates of progression were similar between the 24-2 and 10-2 MD, which has also been shown in other studies.^21,22 Despite that similarity when looking at the pooled data, some patients may experience more rapid progression on one test than the other which may have implications on how they should be more closely monitored.

It is known that IOP demonstrates diurnal-nocturnal fluctuation, with IOP highest at night or early morning.²³ The macula may also be sensitive to these fluctuations throughout the day, especially in the setting of a high baseline IOP. However, past studies have also shown that peak IOP is a better predictor of glaucomatous progression than mean IOP or fluctuation.²⁴ Nevertheless, the macula may be sensitive to fluctuations in IOP or prolonged peak IOP when the clinician is initiating or optimizing glaucoma treatment. Use of only traditional staging methods with 24-2 VF tests and peripapillary OCT tests can miss this type glaucomatous damage to the macula, as previous studies have highlighted.^7,8,25 Yet, clinicians should employ conventional testing parameters (global cpRNFL and 24-2 VF) in combination with macular parameters when monitoring progression.

Another factor affecting glaucoma progression is perfusion of the optic nerve head, which is dependent on the interplay between systemic blood pressure, IOP, and the local microcirculation. Both higher IOP and a lower systemic BP can lead to decreased perfusion of the optic nerve head. Adequate perfusion of the optic nerve head is necessary for metabolic and nutritional needs. Ischemia to the optic nerve head as a result of lower systemic BP or lower ocular perfusion pressure is associated with greater glaucoma prevalence and progression.^17,18 Decreases in systemic BP could stem from treatment of HTN. Previous studies have also shown that the type of systemic treatment used can impact glaucoma progression: β blockers may exhibit a protective effect on glaucoma progression while ACE inhibitors and calcium channel blockers may not affect underlying risk.²⁶

Adequate cerebral blood flow, a measure of optic nerve head perfusion, exists on a dynamic autoregulatory range. In patients with chronic hypertension, there is impairment of autoregulation retinal blood flow and a shift of the autoregulatory plateau to a higher pressure range.²⁷ Structural changes in the vascular endothelium also occur that impair vasodilation when there is a decrease in systemic blood pressure.²⁷ Thus in patients with chronic hypertension, normal or low systemic blood pressures may lead to inadequate perfusion to the optic nerve head.²⁷ Additionally, overtreatment of HTN, leading to low systemic BPs may result in glaucomatous progression.

While our results show that diagnosis of HTN was not significantly associated with progression using any OCT or VF parameter, based on ranked model fits, macular structural and functional parameters did best in fitting the progression data, suggesting their usefulness as endpoints. Thus, in glaucoma patients with comorbid HTN, monitoring changes in the macula may better assess disease progression, even in early stages of disease. Careful control of systemic BP and IOP may be necessary to prevent hypoperfusion of the optic nerve head and glaucomatous progression. A recent study examining IOP over 24 hours using a contact lens sensor showed that it was better correlated with glaucomatous progression than single IOP measurements.²⁸ Studies defining HTN based on 24-hour BP monitoring and including modalities of treatment may better elucidate whether this prevalent systemic disease is an independent risk factor for glaucoma progression.

Furthermore, our results that the macular region is more sensitive to changes in IOP may help explain in part why patients with normal tension glaucoma (NTG) require lower IOP and are more likely to have central damage and disease progression.²⁹ Additionally, one recent study showed that in patients with NTG, diurnal fluctuations in IOP and diastolic BP were risk factors for disease progression.³⁰ Our results also suggest that the macula may be sensitive to changes in systemic blood pressure. Thus, in patients with NTG and comorbid HTN, monitoring the macula for early glaucomatous damage may be warranted. Alternatively, these progressive changes may be more easily detected with macular parameters due to their dynamic ranges.

A limitation to this study is that patients included in this study had a minimum of four visits with testing. Differences in follow up periods may affect the precision on the calculated rates of change for both the standard and macular-based parameters. Additionally, the diagnosis of HTN was self-reported and only diagnosis of HTN was considered; treatment and degree of BP control was not assessed. The use of self-reported disease poses as a major limitation and should be considered when interpreting the lack of a significant association between systemic hypertension and glaucoma progression. Moreover, a longer follow-up period and more testing may reveal differences not seen in the current study design. Nonetheless, most studies examining the relationship between HTN and glaucoma onset and progression were also based on self-reported diagnoses and did not collect BP measurements. The present study allows for comparison with the existing literature and may be useful to ophthalmologists who often rely on self-reported information about HTN in their practices. These factors may explain why macular parameters demonstrated superior goodness-of-fit when considering HTN but were not found to be statistically significant. Nevertheless, our findings suggest that systemic blood pressure may play a role in glaucomatous damage to the macula.