Glaucoma•

Characteristics of beta parapapillary atrophy in primary angle-closure suspect

Abstract

Objective To investigate the characteristics of beta parapapillary atrophy (β-PPA) in patients with primary angle-closure suspect (PACS).

Methods and analysis In total, 215 and 259 eyes with PACS and non-PACS (NPACS), respectively, were enrolled in this observational, cross-sectional study. Stereoscopic fundus and optical coherence tomography images were used to characterise β-PPA; the former was also used to measure the major β-PPA parameters. Univariate and multiple logistic regression analyses were used to identify the factors correlated with the presence of β-PPA and with β-PPA parameters.

Results The β-PPA occurrence rates were 48.80% and 44.40% in the PACS and NPACS groups, respectively, with no significant difference between groups. Compared with that in the NPACS group, the β-PPA area was significantly larger (p=0.005) in the PACS group, but the angular extent and maximum radial length did not differ between groups (p=0.110 and 0.657, respectively) after adjusting for age and axial length. The presence of β-PPA was associated with older age (OR 1.057, 95% CI 1.028 to 1.088, p<0.001) and larger disc area (OR 1.716, 95% CI 1.170 to 2.517, p=0.006). A larger β-PPA area was associated with older age (p=0.014), greater vertical cup-to-disc ratio (p=0.028), larger disc area (p<0.001) and PACS diagnosis (p=0.035).

Conclusion 48.80% of participants with PACS had β-PPA, which is slightly larger than NPACS. The area of β-PPA was larger in PACS, while the angular extent and maximum radial length did not differ between groups.

What is already known on this topic

  • A finding of beta parapapillary atrophy (β-PPA) is specific to primary open-angle glaucoma (POAG). A larger β-PPA area is associated with a diagnosis of POAG and helps distinguish affected eyes from healthy eyes. However, few studies have focused on the characteristics of β-PPA in primary angle-closure glaucoma (PACG) and none in primary angle-closure suspect (PACS).

What this study adds

  • β-PPA was present in 48.80% of participants with PACS. The β-PPA was larger in area in participants with PACS compared with those without. PACS was independently associated with the area of β-PPA.

How this study might affect research, practice or policy

  • This study provides baseline information on the characteristics of β-PPA in PACS and its differences between PACS and non-PACS. A longitudinal study is needed to provide information on differences in characteristics of β-PPA between eyes with PACS and PAC/PACG to see if any characteristic of β-PPA might be a possible predictor for the progression of primary angle-closure disease.

Introduction

Glaucoma is the leading cause of irreversible blindness worldwide.1 It is estimated that the number of patients with glaucoma worldwide will increase to 111.8 million by 2040, and that 32.04 million of these patients will have primary angle-closure glaucoma (PACG), which can cause severe visual impairment.2 It has been estimated that patients with PACG in China account for 48% of patients worldwide,3 and that 91% of bilateral glaucoma blindness cases in China are attributed to PACG.4

Primary angle-closure disease (PACD) is a group of diseases that can be divided into three stages according to the definition of the International Society of Geographic and Epidemiologic Ophthalmology, namely, primary angle-closure suspect (PACS), primary angle closure (PAC) and PACG.5 PACS is considered to be in the early stage of PACG and is generally associated with normal intraocular pressure (IOP), no glaucomatous optic neuropathy (GON) and a high PACG risk.6 Some cases of PACS progress to PAC or PACG during the follow-up, whereas others do not. A narrow anterior chamber angle (ACA) and shallow anterior chamber are anatomical risk factors for angle closure. Hence, previous studies of PACS focused on anterior segment morphology, such as the ACA, anterior chamber, iris, lens and ciliary body, aiming to identify those who will develop PAC or PACG during follow-up; however, to date, such prognosis remains unclear.5 7–10

Beta parapapillary atrophy (β-PPA) is defined as the thinning and degeneration of the chorioretinal tissue adjusted to the optic disc.11 12 Studies have reported that β-PPA is associated with glaucomatous eyes and is also a risk factor for the development of primary open-angle glaucoma (POAG).13–17 β-PPA occurs more often (59.5% vs 17.4%) and affects a larger area in eyes with POAG than in normal eyes.15 Nevertheless, few studies have investigated PACG. β-PPA was hypothesised to be the result of a slippery retinal pigment epithelium (RPE) due to increasing IOP.18 In PACG, the increasing IOP is the only factor of damage to the optic nerve. Hence, β-PPA in PACS, PAC and PACG, as well as other changes in the optic nerve, should be considered important phenomena.

To our knowledge, no study has investigated the characteristics of β-PPA in eyes with PACS. Therefore, this study aimed to describe the characteristics of β-PPA and its associated factors in eyes with PACS.

Materials and methods

Study design and population

This observational, cross-sectional study recruited participants aged 50 years or more residing in Daxing District, Beijing, from October 2018 to November 2018. The inclusion criteria of patients with PACS were as follows: pigmented trabecular meshwork invisible for ≥180° in the primary position under static and dynamic gonioscopy, the absence of peripheral anterior synechiae (PAS), IOP≤21 mm Hg, absence of GON, gonioscopy and optic disc image reading performed by two experienced glaucoma specialists (SL and YZ). The exclusion criteria were the presence of suspectable GON (defined as a vertical cup/disc ratio (VCDR) ≥0.7 and VCDR>0.2 between the eyes, optic disc haemorrhages, optic nerve rim loss or notch and retinal nerve fibre layer defects on spectral-domain ocular coherence tomography), prior iris laser treatment or intraocular surgery, history of intraocular inflammation, trauma, congenital malformation, secondary angle closure, prior episode of acute PAC in either eye or refractive error <−6.00 dioptres.6 Poor-quality images in which identifying the β-PPA border was difficult were also excluded. Control participants (non-PACS (NPACS)) had normal eye examination results and open-angle structures on gonioscopy and also met the aforementioned exclusion criteria. Only eyes that met the inclusion criteria were included for each participant. If both eyes met the inclusion criteria, the right eye was selected for inclusion in the study.

Clinical examinations

All participants underwent eye examinations including visual acuity, optometry (Topcon Corporation, Tokyo, Japan), non-contact tonometry (Topcon Corporation), slit lamp examination (Haag Streit, Bern, Switzerland), gonioscopy (Ocular, Bellevue, Washington, USA), fundus photography (Kowa Nonmyd WX, Tokyo, Japan), ocular biometry measurements (Lenstar LS900; Haag Streit) and optical coherence tomography (OCT) (Optovue, Fremont, California, USA). Age, sex, best-corrected visual acuity (BCVA), IOP, spherical equivalence (SE), axial length (AL), corneal curvature radius (CCR), VCDR, rim area, disc area, mean cup depth and maximum cup depth of all participants were collected. The IOP was measured three times, and the average value was used in statistical analysis.

Evaluation of optic disc images

Stereoscopic fundus images were obtained and saved without pupil dilation. The available field angle was 34° (20° and 27° in the horizontal and vertical directions, respectively) with a square mask. After tracing the disc and cup contour lines and entering the SE data, the CCR of the examined eye, parameters of the optic disc and cup including the VCDR, rim, disk area, mean cup, maximum cup depth were automatically reported by the built-in software of Kowa Nonmyd WX (KOWA VK-2 WX).

Evaluation and measurement of β-PPA

β-PPA was defined based on the stereoscopic fundus and OCT images. Zone ß was characterised by a small grey field adjusted to the disc margin with the visibility of the sclera and the large choroidal vessels on fundus images.11 19 Occasionally, it is difficult to identify zones ß and γ on fundus images. Hence, OCT images were also used for evaluation. The region between the outer border of the disc and the end of the RPE with Bruch’s membrane was zone β, whereas the region without Bruch’s membrane was zone γ, as described in figure 1.

Figure 1
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Figure 1

Representative images used for the evaluation of beta and gamma parapapillary atrophy. (A) Stereoscopic fundus image. (B) Scanning laser ophthalmoscopy image. (C) Optical coherence tomography horizontal B-scan. Green lines: position of the horizontal B-scan; red lines: optic disc border; white arrow: direction of the horizontal B-scan; green arrows: temporal Bruch’s membrane opening; blue arrows: beginning of the retinal pigment epithelium. Beta parapapillary atrophy: between the green and blue arrows, gamma parapapillary atrophy: between the green arrows and red lines.

The measurement of β-PPA included area, angular extent and maximum radial length, as described in figure 2. The contour line of β-PPA was drawn directly on the fundus image. To calculate the exact area, angular extent and maximum radial length of β-PPA, SE and AL should be adjusted, for which we used the built-in software Kowa Nonmyd WX and the parameters of β-PPA were automatically reported. The parameters were measured three times for each eye, and the average values were used for the analysis.

Figure 2
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Figure 2

Illustration of measurement of β-PPA parameters. (A) Stereoscopic fundus image of a participant’s eye. (B) The same stereoscopic fundus image as in (A) with the β-PPA parameters illustrated (green line: disc margin; red line: PPA margin; red shadow with a: area of β-PPA; b: angular extent of β-PPA; c: maximum radial length of β-PPA). (C) Schematic diagram showing the β-PPA parameters of a: β-PPA area; b: angular extent of β-PPA; c: maximum radial length of β-PPA. β-PPA, beta parapapillary atrophy.

All images were evaluated and measured independently by two well-trained examiners (FX and MZ) who were masked to the categorisation of the subject to the PACS or NPACS groups. To assess the interobserver reproducibility of the measurements, 20 fundus images were randomly chosen from this study and measured independently by two examiners. The intraclass correlation coefficients (ICCs) were calculated. The respective ICCs of the β-PPA area, angular extent and maximum radial length between the two examiners were 0.99 (95% CI 0.97 to 0.99), 0.89 (95% CI 0.52 to 0.98) and 0.97 (95% CI 0.79 to 0.99), which suggested an excellent consistency of measurements.

Statistical analysis

The Shapiro-Wilk test was used to verify the normality of the distribution of quantitative variables. All characteristics were compared between the two groups using the independent samples t-test or Mann-Whitney U test for quantitative variables and χ2 test for qualitative variables as appropriate. Confounding factors were adjusted when the major parameters of β-PPA were compared between the groups. Univariate and multiple logistic regression analyses were used to identify factors that correlated with the presence of β-PPA. Variables with a p<0.10 in the univariate analyses were entered into a multivariate model, and ORs with 95% CIs were calculated. Multiple linear regression analysis was performed to identify the factors correlated with the β-PPA parameters. All multivariate models were obtained using a stepwise elimination approach, and multicollinearity among the variables was confirmed before multivariate analysis.

Data analysis was performed by using SPSS for Windows, V.25.0 (IBM). Statistical significance was set at p<0.05.

Results

In total, 549 eyes that met the eligibility criteria were screened. Of these, 75 eyes were excluded because of poor fundus image quality. Therefore, a total of 474 eyes were finally included in the study (online supplemental material S1). Overall, 215 and 259 patients were diagnosed with PACS and NPACS, respectively. Eyes with PACS were older, had more hypermetropia, had a shorter AL, had a larger VCDR, had a smaller rim disc area ratio, had a deeper mean cup depth and had a deeper maximum cup depth than eyes with NPACS. The demographic and clinical characteristics are shown in table 1.

Table 1
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Comparison of demographic, ocular characteristics and the major parameters of beta parapapillary atrophy between primary angle closure suspect and non-primary angle closure suspect

Table 1 also lists the major parameters of β-PPA after adjusting for age and AL. The area was significantly larger in the eyes with PACS than in those with NPACS (median, 1.34 vs 1.26; p=0.005). Although the occurrence of β-PPA was not significantly higher, the angular extent and maximum radial length were not significantly larger in eyes with PACS than in those with NPACS (48.80% vs 44.40%; median, 0.35 vs 0.33, 154 vs 139; p=0.341, 0.110 and 0.657, respectively).

Furthermore, we analysed the differences in demographic and clinical characteristics between participants with and without β-PPA (online supplemental material S2). Eyes with β-PPA were older and had a larger disc area than those without β-PPA (median, 62 vs 59 and 2.55 vs 2.49, respectively; p<0.001 and p=0.013, respectively).

We then analysed the differences between PACS subjects with and without β-PPA. Eyes with β-PPA were older (63.51 vs 61.12, p=0.007) and had a higher AL than those without β-PPA (median, 2.55 vs 2.49 mm; p=0.033) (online supplemental material S3).

Factors associated with the presence of β-PPA in all participants were analysed using univariate and multivariate analyses. Two factors were found to be significantly associated with the presence of β-PPA: older age (OR 1.057, 95% CI 1.028 to 1.088, p<0.001) and larger disc area (OR 1.716, 95% CI 1.170 to 2.517, p=0.006) (table 2).

Table 2
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Factors associated with the presence of beta parapapillary atrophy in included subjects (N=474)

In multiple linear regression analysis (table 3), a larger β-PPA area was associated with older age (p=0.014), larger VCDR (p=0.028), larger disc area (p<0.001) and diagnosis of PACS (p=0.035).

Table 3
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Factors associated with the area of beta parapapillary atrophy in included subjects (N=220)

Discussion

To our knowledge, this is the first study to describe the characteristics of β-PPA in patients with PACS. Our study showed that the occurrence rates of β-PPA were 48.80% and 44.40% in PACS and NPACS, respectively. Despite a similar occurrence rate, the size of β-PPA was different between the two groups. The average area of β-PPA in PACS was significantly larger than that in NPACS.

β-PPA can be commonly found in glaucomatous eyes, and normal eyes as well. However, It has been found that β-PPA occurs more often in glaucomatous eyes compared with normal eyes, significantly larger as well.15 Moreover, previous studies have underscored the pathogenic significance of β-PPA in POAG.14 20 Investigators pointed out that the formation of β-PPA may be a pathogenic mechanism in glaucomatous optic nerve damage.20 In addition, β-PPA plays an important role in the diagnosis and progression of POAG.21–23 A larger β-PPA area was associated with the diagnosis of POAG and contributed to distinguishing healthy eyes from eyes with POAG.24 Furthermore, increased β-PPA parameters, including area, angular extent, radial extent and margin regularity, have been reported to be associated with the progressions of POAG and glaucomatous visual field.16 25 However, the role of β-PPA is unclear in eyes with PACG, despite a few studies reporting the prevalence and characteristics of β-PPA in PACG.26

In contrast to POAG, the elevation of the IOP was the only cause of GON in PACG. Wang et al observed that parapapillary RPE folding or centrifugal sliding after an acute elevation of IOP.18 On the basis of this finding, they suggested that the presence and development of β-PPA, which was characterised by the loss of RPE cells, might be associated with the mechanical stress applied to the RPE layer on the parapapillary Bruch’s membrane due to increased IOP.27 The model used by Wang et al was a provocative test for PACG (the dark room prone provocative test), and it provides a good model to infer that the presence and development of β-PPA are associated with progression in PACG.

Our study showed that the area of β-PPA in eyes with PACS was significantly larger than that in eyes with NPACS after adjusting for age and the AL. PACS is the early stage of PACD, and in some cases, progresses to PAC/PACG. During the progression period, appositional angle closure or PAS may occur, which results in inconsistent or sustained increases in the IOP. The dark room prone provocative test simulates a kind of appositional angle closure in PACS, which is reversible and will generally reopen the angle after relaxation or medication.28 29 This might explain the large area of β-PPA in PACS due to appositional angle closure.

We further evaluated the factors associated with the presence and size of β-PPA in all participants and demonstrated that the presence of β-PPA was associated with older age and a larger disc area. A larger β-PPA area was associated with older age, a larger VCDR, a larger disc area and diagnosis of PACS, as well as several factors associated with β-PPA. Mataki et al’s study demonstrated that the presence of β-PPA was related to older age, myopic refraction, a greater disc area and lower IOP.30 Vianna et al found that the area of β-PPA was larger in eyes with POAG than in normal eyes.31 Several studies have reported that the area of β-PPA was also related to BCVA and glaucomatous optic nerve damage, which was, to some extent, similar to our study’s results.26 32 33

The finding that the presence and area of β-PPA are associated with older age could be explained by age-related degeneration.34 Panda-Jonas et al reported that approximately 0.3% of retinal photoreceptors and RPE cells are lost per year throughout one’s life and choriocapillary atrophy occurs.35 The positive correlation between the presence and area of β-PPA with a larger disc area might also be explained by the long perfusion distance.36 Previous studies assumed that the laminar and prelaminar regions of larger discs would be more vulnerable than other regions to localised hypoperfusion, which might cause degeneration of RPE and photoreceptors.36

The area of β-PPA was also positively correlated with the VCDR in our study, which was similar to the findings reported by Uhm et al and Jonas and Naumann.11 15 In those two studies, the area of β-PPA was correlated with the VCDR in normal and glaucomatous eyes.11 15 This study’s results, to some extent, indicated that β-PPA area increased positively with the tendency of optic disc cup enlargement, although damage due to glaucoma did not occur in participants with PACS. Therefore, in the future study, we will further investigate the differences in characteristics of β-PPA between eyes with PACS and PAC/PACG to see if any characteristic of β-PPA might be a possible predictor for the progression of PACD.

Our study has a few limitations. First, the study only enrolled patients with PACS and NPACS; the inclusion of β-PPA in patients with PAC/PACG may provide more information in a future study. Second, this study was a cross-sectional design; follow-up of the changes in β-PPA and the progression from PACS to PAC or PACG will offer strong evidence. Third, standard automated perimetry was not performed in all participants. So, there might be some possibility that PACG is being mistaken for PACS. However, IOP, readable fundus images and OCT examination were taken and all the GON or suspectable GON were excluded. Further follow-up investigations on the associations between β-PPA and GON in eyes are needed.

Conclusion

In conclusion, we found that 48.80% of participants with PACS had β-PPA, which is slightly larger than NPACS. The area of β-PPA was larger in PACS while the angular extent and maximum radial length did not differ between groups. Moreover, PACS was independently associated with β-PPA area.

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