Introduction: This study investigated the clinical characteristics of and risk factors for microcystic macular edema (MME) in patients with chronic primary angle-closure glaucoma (CPACG) and primary open-angle glaucoma (POAG). Methods: This retrospective observational study included 1,588 eyes from 926 glaucoma inpatients and analyzed the patients’ basic demographic information, visual field parameters, macular scans, and peripapillary retinal nerve fiber layer thickness. Results: Our findings were that the incidence rate of MME was 3.97% (34/857) in CPACG and 5.88% (43/731) in POAG. MME was predominantly diagnosed at an advanced stage in CPACG (almost 100%) compared to POAG (93.02%). MME was most frequently involved in the inferior (83.12%) quadrant of the peri-macular region in both CPACG and POAG. Risk factors for MME occurrence in CPACG and POAG included lower visual field mean deviation (OR = 1.14, 95%: CI 1.05-1.24, p = 0.003; OR = 1.14, 95% CI: 1.06–1.21, p < 0.001) and younger age (OR = 0.92, 95% CI: 0.88-0.96, p < 0.001; OR = 0.96, 95% CI: 0.93–0.99, p = 0.003), while female sex (OR = 0.30, 95% CI: 0.11–0.84, p = 0.022) reduced the MME occurrence in POAG. Conclusion: MME could develop in both CPACG and POAG patients, occurring earlier in POAG. The inferior peri-macular region is commonly affected. Younger age and poorer visual field are risk factors for MME in glaucoma patients.

Microcystic macular edema (MME) has been defined as a small hyporeflective lesion that is often located in the thickening inner nuclear layer (INL) [1]. Gelfand et al. [2] first provided a description of MME in multiple sclerosis (MS) patients and reported that this lesion was correlated with the severity of MS in 2012. As research progressed, researchers found that MME can be observed in various optic neuropathies that are nonspecific in MS [1, 3]. Currently, researchers are still mainly focused on MS [4, 5] and neuromyelitis optica [5, 6]. They believed that the presence of MME may indicate inflammation of the retina and disruption of the blood-retinal barrier, which is linked to greater disability and visual impairment [4].

Glaucoma has been recognized as a leading cause of irreversible blindness worldwide [7]. For the diagnosis and follow-up observation of glaucoma, optical coherence tomography (OCT) examination is indispensable. OCT has previously focused on the optic disc, retinal ganglion cell layer, and retinal nerve fiber layer (RNFL) in glaucoma patients [8]. In 2013, Wolff et al. [9] first reported that MME occurs in glaucoma patients with optic nerve atrophy. Hasegawa et al. [10] observed MME in OCT images in 6.0% of eyes in primary open-angle glaucoma (POAG) patients. Murata et al. [11] reported that MME was observed only in open-angle glaucoma patients. They did not find MME in their study of a limited sample of primary angle-closure glaucoma patients. To date, Kessel et al. [12] reported the only case of bilateral MME in a chronic primary angle-closure glaucoma (CPACG) patient.

In this study, we analyzed and compared MME between CPACG and POAG patients and compared clinical characteristics between MME and non-MME eyes to reveal the incidence rate and clinical characteristics of MME in Chinese primary glaucoma patients and to identify the risk factors for MME.

Patients and Examinations

This was a cross-sectional, retrospective, hospital-based study approved by the Independent Institute Research Ethics Committee of the Zhongshan Ophthalmic Center (ZOC), Guangzhou, China, and adhered to the tenets of the Declaration of Helsinki. Patients diagnosed with CPACG and POAG were consecutively enrolled from January 2019 to December 2021 at the ZOC. The inclusion criteria included the following: (1) individuals were diagnosed with CPACG or POAG by a glaucoma expert. CPACG was defined as eyes with having at least 180 degrees of synechial closure on indentation/manipulative gonioscopy and a chronically elevated intraocular pressure (IOP) >21 mm Hg but without symptoms or suffering acute attack. CPACG eyes had glaucomatous optic neuropathy or visual field (VF) defects. POAG was defined as eyes with open-angle, VF defects, glaucomatous optic neuropathy and a history of elevated IOP >21 mm Hg. (2) Individuals had OCT scan images with completion of vertical and horizontal tomography in the macular area. The exclusion criteria included the following: (1) patients with damage from other retinal diseases (retinal vein occlusion, epiretinal membrane, etc.) or any disease associated with macular lesions (age-related macular degeneration, diabetic macular edema, etc.); (2) patients with secondary retinoschisis caused by congenital factors and diseases such as high myopia or epiretinal membrane traction; (3) patients with optic nerve abnormalities other than glaucoma, such as neurological complications (MS, neuromyelitis optica, etc.); (4) blurred OCT images, which could lead to unclear retinal stratification and interrupted scanning signals; (5) patients with underlying conditions that can cause retinopathy, such as diabetes and hypertension; and (6) patients with a history of internal eye surgery within 6 months. The stages of glaucomatous eyes were classified by visual field mean deviation (VF MD), which included mild (>−6 dB), moderate (−6 to −12 dB), and advanced (<−12 dB).

All included patients had a comprehensive record of ocular examination, including the assessment of best-corrected visual acuity (BCVA) by using Snellen chart, slit-lamp biomicroscopy (BQ-900, Haag-Streit, Switzerland), gonioscopy (Single Mirror Gonioscope, Ocular Instruments, Bellevue, WA, USA), fundus examination with Volk lens (VOLK90D, FOLEE, USA), tonometry using a Goldmann applanation tonometer (Haag-Streit, Koniz, Switzerland), axial length measured with A-scan ultrasonography (CineScan; Quantel Corporation Ltd., Clermont-Ferrand, France, UK), Humphrey 30-2 visual field testing (Humphrey Visual Field Analyzer; Carl Zeiss Meditec Inc., Dublin, CA, USA), and spectral-domain OCT (Spectralis, Heidelberg Engineering, Heidelberg, Germany, UK).

Optical Coherence Tomography

The peripapillary RNFL thickness was scanned by a circle scanning protocol with a 3.4-mm diameter. Macular images were obtained by horizontal and vertical linear scanning centered at the fovea with a scan angle of 30°. Infrared images with a 30° angle were acquired simultaneously during OCT scanning. MME was defined as [1] small hyporeflective round to elliptical cystoid spaces perpendicular to the retinal surface in the INL layer, with no fusion between the individual microcysts (Fig. 1). The relatively hyporeflective areas in the IR image were considered to correspond with the MME on the OCT image, which was used to observe the MME location [9], and the peri-macular region was divided into four quadrants (Fig. 1).

Fig. 1.

OCT image of MME patients and the macular area divided into superior (S), inferior (I), nasal (N), and temporal (T). a-c IR image of the peri-macular region can be seen that only had an arc-shaped relative dark area in the inferior region, the horizontal scanning tomography without MME, the vertical tomography through the dark area of the IR image shows the reflex of INL reduction with MME occurring at the corresponding position (white arrows), and temporal peripapillary RNFL thickness shows thinning significantly. d-f Ring-shaped relative dark area can be seen around the IR image of the peri-macular region, involving almost four quadrants, and the OCT horizontal and vertical tomography scans in the dark area show that the reflex of INL reduction with the presence of MME (white arrows); peripapillary RNFL thickness shows significant extensive thinning.

Fig. 1.

OCT image of MME patients and the macular area divided into superior (S), inferior (I), nasal (N), and temporal (T). a-c IR image of the peri-macular region can be seen that only had an arc-shaped relative dark area in the inferior region, the horizontal scanning tomography without MME, the vertical tomography through the dark area of the IR image shows the reflex of INL reduction with MME occurring at the corresponding position (white arrows), and temporal peripapillary RNFL thickness shows thinning significantly. d-f Ring-shaped relative dark area can be seen around the IR image of the peri-macular region, involving almost four quadrants, and the OCT horizontal and vertical tomography scans in the dark area show that the reflex of INL reduction with the presence of MME (white arrows); peripapillary RNFL thickness shows significant extensive thinning.

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Statistical Analysis

This study was analyzed by using Statistical Package for the Social Sciences (SPSS) software version 24.0 (SPSS Incorporation, Chicago, IL, USA). The mean and standard deviation (SD) were used to describe the continuous variables of demographic and clinical data, and frequencies (percentages) were calculated for categorical variables. Differences between groups in age and sex were analyzed by utilizing the independent two-sample t test and the χ2 test, respectively. The generalized estimating equation model was used for comparisons with binocular data to adjust for intracorrelation between eyes within the same subject. Univariate and multivariate regression analyses were conducted to determine the association between glaucoma and the presence of MME with adjustment for the correlation between eyes. For multiple comparisons, p < 0.017 was statistically significant adjusted by Bonferroni correction. When comparing two groups, p < 0.05 was defined as statistically significant.

A total of 1,588 eyes (926 patients) were included from glaucoma inpatients, including 857 eyes (500 patients) from CPACG and 731 eyes (426 patients) from POAG (Fig. 2). Table 1 shows the demographic characteristics of these included patients.

Fig. 2.

Study design and patient flow.

Fig. 2.

Study design and patient flow.

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Table 1.

Clinical characteristics of CPACG and POAG groups

VariablesCPACGPOAGp value*
N (eyes/patients) 857/500 731/426 / 
Age, mean ± SD, years 58.06±11.70 52.51±15.55 <0.001 
Female, n (%) 271 (54.20) 196 (46.01) 0.013 
BCVA (LogMAR), mean ± SD 0.28±0.46 0.38±0.50 0.001 
IOP, mean ± SD, mm Hg 19.33±8.60 18.99±7.95 0.468 
Average RNFL thickness, mean ± SD, μm 73.19±28.11 60.57±20.96 <0.001 
AL, mean ± SD, mm 22.54±0.80 23.77±1.16 <0.001 
VF MD value, mean ± SD, dB −15.87±11.57 −18.23±10.64 <0.001 
Stage of glaucoma, n (%) 
 Mild and moderate 390 (45.51) 246 (33.65) <0.001 
 Advanced 467 (54.49) 485 (66.35) 
VariablesCPACGPOAGp value*
N (eyes/patients) 857/500 731/426 / 
Age, mean ± SD, years 58.06±11.70 52.51±15.55 <0.001 
Female, n (%) 271 (54.20) 196 (46.01) 0.013 
BCVA (LogMAR), mean ± SD 0.28±0.46 0.38±0.50 0.001 
IOP, mean ± SD, mm Hg 19.33±8.60 18.99±7.95 0.468 
Average RNFL thickness, mean ± SD, μm 73.19±28.11 60.57±20.96 <0.001 
AL, mean ± SD, mm 22.54±0.80 23.77±1.16 <0.001 
VF MD value, mean ± SD, dB −15.87±11.57 −18.23±10.64 <0.001 
Stage of glaucoma, n (%) 
 Mild and moderate 390 (45.51) 246 (33.65) <0.001 
 Advanced 467 (54.49) 485 (66.35) 

CPACG, chronic primary angle-closure glaucoma; POAG, primary open-angle glaucoma; SD, standard deviation; BCVA, best-corrected visual acuity; LogMAR, logarithm of the minimal angle of resolution; IOP, intraocular pressure; RNFL, retinal nerve fiber layer; AL, axial length; VF, visual field; MD, mean deviation; GEE, generalized estimating equation.

*Independent two-sample t test for age, Pearson’s χ2 test for sex, and the GEE model for others with adjustment of intracorrelation between eyes within the same subject. p values with statistical significance (<0.05) were bold.

MME was identified in 77 out of 1,588 eyes (4.85%). The incidence rate of MME was 3.97% (34/857) in CPACG and 5.88% (43/731) in POAG patients. The results show no significant differences in age, BCVA, IOP, mean RNFL thickness, or VF MD values (p > 0.017 in all, Bonferroni correction) in CPACG with the MME group compared with POAG with the MME group. All the CPACG eyes with MME were in advanced stages, while only 93.02% of the POAG eyes had MME in advanced stages (Table 2).

Table 2.

Clinical characteristics of CPACG/POAG with MME and without MME

VariablesCPACG with MME (34 eyes of 29 patients) (1)CPACG without MME (823 eyes of 471 patients) (2)POAG with MME (43 eyes of 30 patients) (3)POAG without MME (688 eyes of 396 patients) (4)p value* (1) versus (3)p value* (1) versus (2)p value* (3) versus (4)
N (eyes/patients) 34/29 823/471 43/30 688/396 / / 
Prevalence of MME, n (%) 3.97 5.88 0.144 / / 
Age, mean ± SD, years 43.41±14.52 58.96±10.89 41.77±14.58 53.32±15.34 0.665 <0.001 <0.001 
Female, n (%) 19 (65.52) 252 (53.50) 6 (20.00) 190 (47.98) <0.001 0.208 0.003 
BCVA (LogMAR), mean ± SD 0.78±0.96 0.26±0.42 0.56±0.71 0.37±0.48 0.413 <0.001 0.049 
IOP, mean ± SD, mm Hg 22.10±8.62 19.22±8.58 18.04±6.49 19.05±8.03 0.155 0.035 0.666 
Average RNFL thickness, mean ± SD, μm 48.03±15.77 74.25±28.03 56.21±12.88 60.84±21.34 0.198 <0.001 0.003 
AL, mean ± SD, mm 21.91±0.82 22.57±0.80 24.01±0.87 23.76±1.17 <0.001 <0.001 0.217 
VF MD value, mean ± SD, dB −28.59±5.24 −15.47±11.49 −26.00±7.01 −17.77±10.64 0.142 <0.001 <0.001 
Stage of glaucoma, n (%) 
 Mild and moderate 0 (0) 3 (6.98) / 
 Advanced 34 (100) 40 (93.02) / 
VariablesCPACG with MME (34 eyes of 29 patients) (1)CPACG without MME (823 eyes of 471 patients) (2)POAG with MME (43 eyes of 30 patients) (3)POAG without MME (688 eyes of 396 patients) (4)p value* (1) versus (3)p value* (1) versus (2)p value* (3) versus (4)
N (eyes/patients) 34/29 823/471 43/30 688/396 / / 
Prevalence of MME, n (%) 3.97 5.88 0.144 / / 
Age, mean ± SD, years 43.41±14.52 58.96±10.89 41.77±14.58 53.32±15.34 0.665 <0.001 <0.001 
Female, n (%) 19 (65.52) 252 (53.50) 6 (20.00) 190 (47.98) <0.001 0.208 0.003 
BCVA (LogMAR), mean ± SD 0.78±0.96 0.26±0.42 0.56±0.71 0.37±0.48 0.413 <0.001 0.049 
IOP, mean ± SD, mm Hg 22.10±8.62 19.22±8.58 18.04±6.49 19.05±8.03 0.155 0.035 0.666 
Average RNFL thickness, mean ± SD, μm 48.03±15.77 74.25±28.03 56.21±12.88 60.84±21.34 0.198 <0.001 0.003 
AL, mean ± SD, mm 21.91±0.82 22.57±0.80 24.01±0.87 23.76±1.17 <0.001 <0.001 0.217 
VF MD value, mean ± SD, dB −28.59±5.24 −15.47±11.49 −26.00±7.01 −17.77±10.64 0.142 <0.001 <0.001 
Stage of glaucoma, n (%) 
 Mild and moderate 0 (0) 3 (6.98) / 
 Advanced 34 (100) 40 (93.02) / 

CPACG, chronic primary angle-closure glaucoma; POAG, primary open-angle glaucoma; MME, microcystic macular edema; SD, standard deviation; BCVA, best-corrected visual acuity; LogMAR, logarithm of the minimal angle of resolution; IOP, intraocular pressure; RNFL, retinal nerve fiber layer; AL, axial length; VF, visual field; MD, mean deviation; GEE, generalized estimating equation.

*Independent two-sample t test for age, Pearson’s χ2 test for sex, and the GEE model for others with adjustment of intracorrelation between eyes within the same subject. The adjusted significant level with Bonferroni correction was 0.05/3 = 0.017 due to multiple tests. p values with statistical significance based on the adjusted significant level were bold.

In the CPACG group, patients with MME had a younger age, worse BCVA, thinner mean RNFL thickness, lower VF MD values, and shorter axial length than those without MME (p < 0.017 in all, Bonferroni correction) (Table 2). In the POAG group, patients with MME changes had a younger age, a lower proportion of females, thinner mean RNFL thickness, and lower VF MD values than those without MME (p < 0.017 in all, Bonferroni correction) (Table 2).

There were no significant differences in the distribution of MME between the CPACG and POAG groups (p > 0.05 in all). The inferior peri-macular region was the most easily affected region (83.12%) in both the CPACG and POAG groups (Table 3). The RNFL thickness among different ranges of MME was not significantly different (p = 0.783) (Fig. 1; Table 4). The VF MD values were better in eyes with a single quadrant of MME than in those with multiple quadrants of MME (p < 0.001) (Table 4).

Table 3.

Distribution of MME at difference peri-macular regions

Total (n = 77 eyes)CPACG (n = 34 eyes)POAG (n = 43 eyes)p value*
Macular quadrant number, n (%) 
 Single quadrant 27 (35.06) 12 (35.29) 15 (34.88) 0.916 
 Two quadrants 18 (23.38) 9 (26.47) 9 (20.93) 0.470 
 Three quadrants 23 (29.87) 10 (29.41) 13 (30.23) 0.699 
Four quadrants 9 (11.69) 3 (8.82) 6 (13.95) 0.285 
Peri-macular region orientation, n (%) 
 Superior 50 (64.94) 20 (58.82) 30 (69.77) 0.515 
 Inferior 64 (83.12) 27 (79.41) 37 (86.05) 0.390 
 Nasal 43 (55.84) 20 (58.82) 23 (53.49) 0.981 
 Temporal 11 (14.29) 5 (14.71) 6 (13.95) 0.534 
Total (n = 77 eyes)CPACG (n = 34 eyes)POAG (n = 43 eyes)p value*
Macular quadrant number, n (%) 
 Single quadrant 27 (35.06) 12 (35.29) 15 (34.88) 0.916 
 Two quadrants 18 (23.38) 9 (26.47) 9 (20.93) 0.470 
 Three quadrants 23 (29.87) 10 (29.41) 13 (30.23) 0.699 
Four quadrants 9 (11.69) 3 (8.82) 6 (13.95) 0.285 
Peri-macular region orientation, n (%) 
 Superior 50 (64.94) 20 (58.82) 30 (69.77) 0.515 
 Inferior 64 (83.12) 27 (79.41) 37 (86.05) 0.390 
 Nasal 43 (55.84) 20 (58.82) 23 (53.49) 0.981 
 Temporal 11 (14.29) 5 (14.71) 6 (13.95) 0.534 

MME, microcystic macular edema; CPACG, chronic primary angle-closure glaucoma; POAG, primary open-angle glaucoma; GEE, generalized estimating equation.

*Using the GEE model to adjust intracorrelation between eyes within the same subject.

Table 4.

Correlation analysis of MME involved quadrant ranges with RNFL and VF MD values

Single quadrant (n = 27 eyes)Two quadrants (n = 18 eyes)Three quadrants (n = 23 eyes)Four quadrants (n = 9 eyes)p value*
Average RNFL thickness, mean ± SD, μm 53.00±13.23 52.94±14.85 51.87±16.52 52.13±16.69 0.783 
VF MD, mean ± SD, dB −23.24±7.76 −30.40±3.88 −27.72±4.86 −30.44±2.08 0.000 
Single quadrant (n = 27 eyes)Two quadrants (n = 18 eyes)Three quadrants (n = 23 eyes)Four quadrants (n = 9 eyes)p value*
Average RNFL thickness, mean ± SD, μm 53.00±13.23 52.94±14.85 51.87±16.52 52.13±16.69 0.783 
VF MD, mean ± SD, dB −23.24±7.76 −30.40±3.88 −27.72±4.86 −30.44±2.08 0.000 

MME, microcystic macular edema; RNFL, retinal nerve fiber layer; VF, visual field; MD, mean deviation; SD, standard deviation; GEE, generalized estimating equation.

*Using the GEE model to adjust intracorrelation between eyes within the same subject.

Univariate and multivariate regression analyses were performed by the generalized estimating equation model to identify the risk factors for MME among CPACG and POAG patients, and the group without MME was used as the reference group (Table 5). For multivariate regression analysis, age (OR = 0.92, 95% CI: 0.88–0.96, p < 0.001) and VF MD absolute values (OR = 1.14, 95%: CI: 1.05–1.24, p = 0.003) significantly influenced MME occurrence in the CPACG group, and age (OR = 0.96, 95% CI: 0.93–0.99, p = 0.003), VF MD absolute values (OR = 1.14, 95% CI: 1.06–1.21, p < 0.001), and sex (OR = 0.30, 95% CI: 0.11–0.84, p = 0.022) significantly influenced MME occurrence in the POAG group.

Table 5.

Generalized estimating equation (GEE) model to determine the association between glaucoma and MME occurrence with adjusted intracorrelation between eyes within the same subject

VariableRisk estimate for MME among CPACGRisk estimate for MME among POAG
univariate analysismultivariate analysis*univariate analysismultivariate analysis*
odds ratio (95% CI)p valueodds ratio (95% CI)p valueodds ratio (95% CI)p valueodds ratio (95% CI)p value
Age (per 1 year increase) 0.91 (0.88, 0.94) <0.001 0.92 (0.88, 0.96) <0.001 0.95 (0.93, 0.98) <0.001 0.96 (0.93, 0.99) 0.003 
Gender (male = 1, female = 2; reference: male) 1.65 (0.75, 3.63) 0.212 0.27 (0.11, 0.68) 0.005 0.30 (0.11, 0.84) 0.022 
BCVA (per 1 LogMAR increase) 2.45 (1.68, 3.57) <0.001 0.62 (0.26, 1.48) 0.280 1.29 (1.00, 1.65) 0.049 0.68 (0.32, 1.43) 0.305 
IOP (per 1 mm Hg increase) 1.03 (1.00, 1.05) 0.035 0.96 (0.90, 1.02) 0.157 1.00 (0.98, 1.01) 0.666 
Average RNFL thickness (per 1 μm increase) 0.96 (0.95, 0.98) <0.001 0.98 (0.96, 1.01) 0.176 0.99 (0.99, 1.00) 0.003 1.02 (0.99, 1.05) 0.137 
VF MD absolute value (per 1 dB increase) 1.14 (1.09, 1.20) <0.001 1.14 (1.05, 1.24) 0.003 1.04 (1.03, 1.06) <0.001 1.14 (1.06, 1.21) <0.001 
AL (per 1 mm increase) 0.35 (0.21, 0.57) <0.001 0.66 (0.38, 1.13) 0.130 1.18 (0.91, 1.54) 0.217 
VariableRisk estimate for MME among CPACGRisk estimate for MME among POAG
univariate analysismultivariate analysis*univariate analysismultivariate analysis*
odds ratio (95% CI)p valueodds ratio (95% CI)p valueodds ratio (95% CI)p valueodds ratio (95% CI)p value
Age (per 1 year increase) 0.91 (0.88, 0.94) <0.001 0.92 (0.88, 0.96) <0.001 0.95 (0.93, 0.98) <0.001 0.96 (0.93, 0.99) 0.003 
Gender (male = 1, female = 2; reference: male) 1.65 (0.75, 3.63) 0.212 0.27 (0.11, 0.68) 0.005 0.30 (0.11, 0.84) 0.022 
BCVA (per 1 LogMAR increase) 2.45 (1.68, 3.57) <0.001 0.62 (0.26, 1.48) 0.280 1.29 (1.00, 1.65) 0.049 0.68 (0.32, 1.43) 0.305 
IOP (per 1 mm Hg increase) 1.03 (1.00, 1.05) 0.035 0.96 (0.90, 1.02) 0.157 1.00 (0.98, 1.01) 0.666 
Average RNFL thickness (per 1 μm increase) 0.96 (0.95, 0.98) <0.001 0.98 (0.96, 1.01) 0.176 0.99 (0.99, 1.00) 0.003 1.02 (0.99, 1.05) 0.137 
VF MD absolute value (per 1 dB increase) 1.14 (1.09, 1.20) <0.001 1.14 (1.05, 1.24) 0.003 1.04 (1.03, 1.06) <0.001 1.14 (1.06, 1.21) <0.001 
AL (per 1 mm increase) 0.35 (0.21, 0.57) <0.001 0.66 (0.38, 1.13) 0.130 1.18 (0.91, 1.54) 0.217 

p values with statistical significance were bold.

MME, microcystic macular edema; CPACG, chronic primary angle-closure glaucoma; POAG, primary open-angle glaucoma; BCVA, best-corrected visual acuity; LogMAR, logarithm of the minimal angle of resolution; IOP, intraocular pressure; RNFL, retinal nerve fiber layer; VF, visual field; MD, mean deviation; AL, axial length.

*Variables with p < 0.05 in the univariate analysis were included in the multivariate analysis.

The current study revealed that the occurrence of MME in POAG (5.88%) was slightly higher than that in CPACG (3.97%), and MME occurred at an earlier stage in POAG than CPACG. Both CPACG and POAG patients most frequently demonstrated MME in the inferior peri-macular region. Younger age and lower VF MD values are risk factors for MME occurrence in both CPACG and POAG, and female sex may be a protective factor against MME occurrence in POAG.

Previous studies have suggested that MME is a kind of macular lesion. It has been reported in various optic neuropathies [1, 3] and was found in 6–7.9% of POAG patients [11, 13, 14]. In this study, the incidence rate of MME in POAG patients was similar to that in previous studies. To our knowledge, there have been few reports concerning the occurrence of MME in CPACG. The present study revealed that MME could occur not only in POAG but also in CPACG, while the incidence rate of MME in CPACG was slightly lower than that in POAG. The present study also revealed that MME was found only in advanced stages of CPACG, while a small proportion of mild- and moderate-stage POAG patients could also develop MME in addition to advanced POAG. Moreover, POAG complicated with the MME group had a thicker RNFL and higher VF MD values than the CPACG group, although the difference was not statistically significant. These results suggested that MME might occur slightly earlier in POAG than CPACG. Müller cell dysfunction is a part of the pathophysiology of MME in previous studies [10]. The Müller cell body is located only in the INL, which is closely related by contact with neighboring retinal neurons, blood vessels, and synapses [15]. Elevated IOP may trigger Müller cells to become overactive, damaging the retina [16]. The reduced expression of potassium channel Kir4.1 in Müller cell membranes has been observed in animal models of various retinopathies, which results in the damage of rapid water transport and the swelling of cells [17]. It is well known that the development of glaucomatous optic neuropathy in CPACG is mainly due to mechanical compression caused by pathologically elevated IOP [18]. In addition to mechanical compression, capillary loss in the macular area and peripapillary region has also been reported in early POAG, and ischemia and hypoxia have been considered to play a role in POAG optic nerve damage [19, 20]. Retinal ischemia and hypoxia in POAG may aggravate Müller cell dysfunction, which may lead to the earlier appearance of MME in POAG.

MME was often observed in the temporal (49.6%) and nasal (48.1%) peri-macular areas in MS and optic neuropathies [1]. These areas were consistent with the papillomacular bundle zone, which is more likely to be involved in MS and other optic neuropathies [21]. In this study, MME predominantly occurred in the inferior peri-macular region of the retina. This result was consistent with previous studies [13, 14], which corresponded with areas of ganglion cell loss in glaucoma [22]. As the inferior-temporal macular area is the most vulnerable area of ganglion cells in glaucoma, this region may be the most easily affected area in glaucoma [23].

Patients with MME were younger, with worse BCVA, thinner mean RNFL thickness, and lower VF MD values in both the CPACG group and POAG group than in non-MME glaucomatous eyes. Younger age and poorer visual field were also found to be risk factors for MME occurrence in both CPACG and POAG patients. This finding was consistent with those of previous studies of MME in glaucoma [13]. Leung et al. believed that younger patients had thicker neural and glial tissue [24], which may easily result in the identification of MME. A previous study revealed that younger rats showed surprisingly slower and worse ocular blood flow recovery during IOP elevation than older rats [25]. In addition, younger patients have higher oxygen consumption [26]. Thus, RGCs and Müller cells may be more easily damaged during IOP elevation in younger patients. Further studies are required to understand the detailed mechanism. Poorer visual field was another risk factor for MME in this study. A higher incidence rate of MME has been reported in advanced glaucoma [10, 13, 27]. A poorer visual field means more severe glaucomatous nerve damage [28]. This result suggested that the more severe the nerve damage, the more severe the Müller cell damage and the easier the MME occurrence. Otherwise, in the POAG group, sex was associated with MME occurrence, and female sex was a protective factor against MME occurrence. Previous studies have shown that estrogen exposure could increase retinal, retrobulbar, and choroidal blood flow and provide protection for nerves in the retina [29], which can protect against ischemic damage seen in POAG [30].

This study had several limitations, such as its retrospective, cross-sectional, and hospital-based design. A longitudinal study may help us obtain the development process of MME. Although we combined spectral-domain OCT and IR images to observe MME, MME will be better identified with other multimodal images, such as en face SS-OCT.

In summary, our study revealed the clinical characteristics and risk factors for MME in glaucoma patients. Both CPACG and POAG demonstrated MME, but they had different incidence rates and stages. This may be related to the different mechanisms of these two diseases. The occurrence of MME in glaucoma has unique characteristics compared to other optic nerve diseases. Further longitudinal observation may help to better understand the pathomechanism of MME and its impact on visual function in glaucoma.

The authors would like to thank the nonmedical staff from the Zhongshan Ophthalmic Center of Sun Yat-sen University for their support during the study.

This study protocol was reviewed and approved by the Independent Institute Research Ethics Committee of the Zhongshan Ophthalmic Center (ZOC), approval number [2022KYPJ249]. The need for informed consent was waived by the Independent Institute Research Ethics Committee of the ZOC.

The authors have no conflicts of interest to declare.

This study was supported by the National Natural Science Foundation of China (Grant No. 81970808) and the Natural Science Foundation of Guangdong Province (Grant No. 2022A1515011469).

Chengguo Zuo contributed to the study concept. Xing Liu and Chengguo Zuo contributed to the study design. Yuan Liu, Ni Guo, Shufen Lin, Yixiu Lin, Shaoyang Zheng, Yuheng Tan, and Nachuan Luo collected the patient data and medical records. Ling Jin and Zhenyu Wang contributed to the data interpretation. Hui Xiao and Yuan Liu wrote the manuscript. All the authors contributed to the critical revision of the manuscript and final approval for its submission.

Additional Information

Hui Xiao and Yuan Liu contributed equally as first authors.

Data are not available due to ethical reasons. Further inquiries can be directed to the corresponding author.

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