Asymmetric Patterns of Visual Field Loss in Primary Angle Closure Glaucoma, High Tension Glaucoma, and Normal Tension Glaucoma

The data directly comparing the spatial pattern of VF defects between primary angle-closure glaucoma (PACG), high-tension glaucoma (HTG) and normal-tension glaucoma (NTG) is not available. We aim to compare the asymmetric patterns of VF defects in patients with PACG, NTG and HTG across different severity levels. A total of 162 eyes of 114 patients with PACG, 111 eyes of 74 patients with HTG and 148 eyes of 102 patients with NTG were included. VF examinations were performed with standard automated perimetry (HFA, SITA-standard strategy, 24-2), and defects were categorized into 3 stages (early, moderate, and advanced) and each hemield was divided into 5 regions according to Glaucoma Hemield Test (GHT). The mean total deviation (TD) of each GHT region was calculated. The relationship between the values of pattern standard deviation (PSD) and mean TD was assessed. In the early stage, nasal region of PACG, central region of HTG and all ve regions of NTG in the superior hemield had signicantly worse mean TD than their counterparts in the inferior hemield. In the moderate stage, three regions of NTG in the superior hemield had signicantly worse mean TD than their inferior counterparts. In the advanced stage, central region of PACG, and central and paracentral regions of HTG in the superior hemield had signicantly worse mean TD than their inferior counterparts. When participants were matched by age, sex and mean deviation, in PACG and HTG eyes, all 5 GHT regions in the superior hemield had worse mean TD than that that of their inferior-hemield counterparts; however, the differences were not statistically signicant. In NTG eyes, the paracentral, nasal, arcuate 1 and arcuate 2 regions in the superior hemield had signicantly worse mean TDs than their inferior counterparts. The superior hemield is affected more severely than the inferior hemield in all 3 subtypes of primary glaucoma. This asymmetric tendency was more pronounced in NTG compared to PACG and HTG.


Introduction
Glaucoma is the leading global cause of irreversible blindness, affecting 79.6 million people worldwide in 2020. 1 It is a progressive optic neuropathy with characteristic structural changes and corresponding visual eld (VF) defects. 2 Primary glaucoma is divided into primary angle-closure glaucoma (PACG) and primary open-angle glaucoma (POAG) based on the status of the iridocorneal angle. 3 And POAG is subdivided into high-tension glaucoma (HTG) and normal-tension glaucoma (NTG). PACG, with a crowded anterior segment and narrow anterior chamber angle, is characterized by elevated IOP secondary to the mechanical obstruction of the aqueous out ow by apposition of the iris to the trabecular meshwork. 4 Pressure-dependent damage is considered to be the major pathogenesis of glaucomatous optic neuropathy in PACG. 4 By comparison, the mechanism of optic nerve damage in HTG is thought to be a mixture of pressure-dependent and pressure-independent causes. Besides IOP, there are other factors believed to be involved in the development and worsening of HTG, such as choroidal blood ow, vascular dysregulation, and low cerebrospinal uid pressure. [5][6][7] The pressure-independent vasogenic risk factors are considered to be more important in the development and progression of NTG as compared to HTG. 6,8,9 The difference between PACG, HTG and NTG also re ects genetic associations, and glaucomatous structural and functional damage. The genetic associations differ between PACG, HTG and NTG. The MYOC 10 and CAV1/CAV2 11 loci have been found to be associated with HTG, and the OPTN gene with NTG, 12 while COL11A1, PCMTD1 and ST18 13 are associated with PACG. The morphometric features of glaucomatous optic nerve head (ONH) damage also differ between PACG, HTG and NTG. Eyes with NTG tend to have a greater degree of rim thinning, larger cup areas and cup/disc ratios and smaller rim area than eyes with HTG 14,15 and PACG 16 . Smaller optic discs with smaller cup areas and larger rim area are presented in PACG than in HTG eyes. 17 The characteristics of the visual eld damage in POAG have been previously reported by several studies using Goldmann perimetry: visual eld defects in NTG were found to be more central, 18,19 more localized, [20][21][22] steeper 18,19,23 and more commonly in the superior hemi eld than in HTG. 24 In comparison, published data on VF damage in PACG is relatively limited. 25 The differences between VF defect in PACG, NTG and HTG have been reported by several studies utilizing automated perimetry: in both PACG and HTG, the superior hemi eld is more severely affected than the inferior hemi eld, 26,27 and the VF defects in HTG as compared to PACG tend to be more localized. 26,28 However, each of these studies included only one or two types of glaucoma, only one prior small study has directly compared the interocular asymmetry of the VF defects between eyes with NTG, PACG and HTG, 29 and one study has compared the VF progression rates among these 3 glaucoma subtypes. 30 The data directly comparing the spatial pattern of VF defects between PACG, HTG and NTG is not available. We therefore compared the asymmetric patterns of VF defects in patients with PACG, NTG and HTG across different severity levels.

Participants
In this cross-sectional study, patients diagnosed with HTG and PACG by a glaucoma specialist (Y.B.L.) were recruited from the glaucoma clinic of the Eye Hospital of Wenzhou Medical University from January 2017 to December 2019. Patients with NTG were recruited from the Wenzhou Glaucoma Progression Study (WGPS), a longitudinal community-based study providing free glaucoma screenings in the Wenzhou area. 31,32 Written informed consent was obtained from all participants. The current study was approved by the Ethics Committee of the Eye hospital of Wenzhou Medical University, and adhered to the tenets of the Declaration of Helsinki.
All participants in the current study had PACG, NTG or HTG. PACG was defined as the presence of angle closure together with evidence of glaucomatous optic neuropathy and corresponding VF defect, while angle closure was the inability to visualize the posterior trabecular meshwork for >= 180° on gonioscopy. HTG was defined as the presence of an open anterior chamber angle as assessed by gonioscopy, a single intraocular pressure (IOP) measurement > 24 mmHg, and evidence of glaucomatous optic neuropathy and a corresponding VF defect. NTG included an open anterior chamber angle as assessed by gonioscopy, the presence of glaucomatous optic neuropathy with corresponding VF defect, six median untreated IOP measurements consistently < 21 mmHg, with no single measurement > 24 mmHg and no more than one reading equal to 23 or 24 mmHg. 8,33 Glaucomatous optic neuropathy was defined as the presence of any of the following: optic disc hemorrhage, retinal nerve ber layer (RNFL) defect, vertical cup-to disc ratio > 0.7 and/or CDR asymmetry > 0.2 or neuroretinal rim width <0. 1. 3 Additional inclusion criteria were as follows: age >= 18 years, presenting visual acuity >= 6/18, and spherical equivalent (SE) refractive error between -6.0 and +3.0 diopter (D). Patients were excluded if they had secondary glaucoma, previous laser or incisional surgery of the retina, and/or other conditions potentially affecting the visual eld.
Each potential participant underwent a comprehensive ophthalmic examination by a certi ed ophthalmic technician, including assessment of presenting visual acuity, refraction, IOP, slit-lamp biomicroscopy, gonioscopy, fundus photography (Visucam 200; Carl Zeiss Meditec, Inc., Dublin, CA, USA), and standard automated perimetry (Humphrey Field Analyzer [HFA] II; Carl-Zeiss Meditec, Inc.). IOPs were measured between 8:00 AM and 5:00 PM on one day and the median of two readings was used.
Visual eld (VF) examinations were performed with the white-on-white 24-2 Swedish Interactive Threshold Algorithm (SITA) program. VF tests with fixation loss rates < 20% or false-positive and false negative error rates < 15% were considered reliable and eligible for analysis; the rst VFs test for each participant was excluded from analysis.
VF severity was categorized into 3 stages based on the mean deviation (MD): early glaucoma (>= -6 dB), moderate glaucoma (< -6 dB and > -12 dB), advanced glaucoma (<= -12 dB). 34 To evaluate the pattern of VF defects, the probability plot was divided into 5 sub eld regions in each of the superior and inferior hemi elds: central, paracentral, nasal, and two peripheral (arcuate 1 and arcuate 2), derived from the Glaucoma Hemi eld Test (GHT). 27,35,36 When recording pointwise data and dividing regions, VF tests of left eyes were inverted to resemble a right eye for ease of comparison. The mean total deviation (TD) values and mean pattern deviation (PD) values of the 10 visual eld regions were calculated, including both superior and inferior hemi elds.

Statistical Analysis
Generalized estimating equation (GEE) models were used to adjust for correlations between the two eyes of a participant and clustering within study groups in comparing demographic characteristics. For the pointwise analysis, the mean TD value of each VF test point in the superior hemi eld was compared with its corresponding point in the inferior hemi eld at each severity level for the three glaucoma groups using GEE model, accounting for mean TD. For the region-wise analysis, the mean TDs and mean PDs of the 5 GHT regions in the superior hemi eld were compared with their counterparts in the inferior hemi eld at each severity level for the three groups using the GEE model, adjusting for mean TD/PD and sex. The relationship between TD and PSD was compared in the three groups analyzed using GEE models. Statistical signi cance was set at P<0.05, and all analyses were performed using SPSS software version 21.0 (IBM., Chicago, IL) and "R" software (R version 4.0.2).

Comparisons Between Glaucoma Sub-type
One hundred and sixty-two eyes of 114 participants with PACG, 111 eyes of 74 participants with HTG and 148 eyes of 102 participants with NTG were enrolled in this study. (Table 1) Participants with HTG were signi cantly younger than those with NTG and PACG (HTG vs. NTG, P =0.012; HTG vs. PACG, P <0.001). There were more women than men in the PACG and NTG groups, while there were more men in the HTG group. The mean SE refraction in the PACG group was signi cantly more hyperopic (positive) than that in the NTG and HTG groups (both P <0.001). The mean IOP in the NTG group was signi cantly lower than that for the HTG groups (P <0.001). LogMAR VA in the PACG group was signi cantly better than that for the NTG group (P<0.001).
In the early and moderate stages, there was no signi cant difference in the MD and mean TD among PACG, NTG and HTG eyes.
In the advanced stage, the MD and mean TD of HTG and PACG group were signi cantly worse than that for the NTG group (all P <0.05). There were no signi cant differences in age and gender across early, moderate, and advanced severity levels among PACG, HTG and NTG group (Table 1). In the PACG group, VA was worst and IOP was highest in the advanced stage (all P <0.05); SE was similar across the severity levels. In the HTG and NTG groups, VA, IOP and SE was similar across the severity levels.
A total of 48 triplets were eyes included in each glaucoma subtype matched based on their age, sex, MD. There was no signi cant difference in age, sex, MD or degree of VF loss between the PACG, HTG and NTG groups (P = 0.154, 0.310, 0.272, 0.644, respectively, Table 2).

Comparisons Between Hemi elds
In the early stage, the mean TD of the superior nasal region in the PACG group was signi cantly worse than its counterpart in the inferior hemi eld (P =0.032, Table 3, Fig. 1-A). However, there was no signi cant difference between the hemi elds in the remaining four regions. In the early stage of the HTG group ( Fig. 1-D), the central region in the superior hemi eld had signi cantly worse mean TD than its inferior counterpart (P =0.022); the remaining four regions showed no signi cant difference between the hemi elds. In the early stage of the NTG group, all ve GHT regions in the superior hemi eld had signi cantly worse mean TD than their inferior counterparts ( Fig. 1-G). In the moderate stage, three superior hemi eld regions (nasal, central, and peripheral arcuate 2) of the NTG group also had signi cantly worse mean TD than their corresponding regions in the inferior hemi eld (all P <0.05, Fig. 1-H). There was no signi cant difference in these mean TD of the ve regions between the hemi elds in both the moderate stage of the HTG and PACG groups (all P >0.05, Fig. 1-B, E). In the advanced stage, the superior hemi eld central region of the PACG group had signi cantly worse mean TD than its inferior counterpart (P <0.001, Fig. 1-C); in the advanced stage of the HTG group, both central and paracentral regions in the superior hemi eld had signi cantly worse mean TD than those in inferior hemi eld (P =0.015 and P =0.045, respectively, Fig. 1-F). There was no signi cant difference in the mean TD for any of the ve regions between the hemi elds in the advanced stage of the NTG group ( Fig. 1-I). The mean TD was signi cantly worse in the superior hemi eld for early and moderate stages in the NTG group (all P <0.05), while there was no signi cant difference between the hemi elds across the severity levels in either the PACG or HTG groups.
In the early stage, one point of the paracentral region, one point of the peripheral (arcuate 1) region and one point of the nasal region in superior hemi eld had signi cantly worse TD than their inferior counterparts in the PACG group. (Figure 2) In the early stage of the HTG group, one point of the nasal region, one point of the central region and a point in the region adjacent to the blind spot had signi cantly worse mean TD than one in the inferior hemi eld. In the early stage of the NTG group, several points clustering in the nasal, paracentral, peripheral (arcuate 1) and peripheral (arcuate 2) regions had signi cantly worse TD than their inferior counterparts. In the moderate stage, one point in the nasal, paracentral and peripheral (arcuate 1) region, and a point in the region adjacent to the blind spot in superior hemi eld had signi cantly worse mean TD when compared with their counterparts in the inferior hemi eld in the PACG group. In the moderate stage of the NTG group, several points clustering in the nasal, central, peripheral (arcuate 1) and peripheral (arcuate 2) regions in superior hemi eld had signi cantly worse mean TD than their inferior counterparts. In the advanced stage, several points clustering in the central and paracentral regions in the superior hemi eld had signi cantly worse mean TD than their inferior counterparts in the PACG group. In the advanced stage of the HTG group, several points clustering in the nasal, central, and paracentral regions had signi cantly worse mean TD than their inferior counterparts. Figure 3 shows the comparisons between the superior and inferior hemi elds for the matched subjects. The mean TD of the superior hemi eld, as a whole, was worse than that of the inferior hemi eld, and this difference was more signi cant in the NTG eyes (P = 0.243, 0.250 and 0.002 for PACG, HTG and NTG, respectively). In PACG and HTG eyes, all 5 GHT regions in the superior hemi eld had worse mean TD than that that of their inferior-hemi eld counterparts; however, the differences were not statistically signi cant (all P > 0.05, Fig. 3-A, B). In NTG eyes, the paracentral, nasal, arcuate 1 and arcuate 2 regions in the superior hemi eld had signi cantly worse mean TDs than their inferior counterparts (P = 0.045, 0.003, 0.007 and 0.001, respectively, Fig. 3-C).
In PACG eyes, a point in the region adjacent to the blind spot had signi cantly worse TD than its counterpart in the inferior hemi eld (TD and P-values are shown in Fig. 3-D). In HTG eyes, 1 point of the nasal region, 1 point of the arcuate 2 region and 1 point in the region adjacent to the blind spot in the superior hemi eld had signi cantly worse TD values than their inferior counterparts (Figure 3-E). In NTG eyes, 1 point of the central region and several points clustering in the nasal, arcuate 1 and arcuate 2 regions had signi cantly worse TDs than their inferior-hemi eld counterparts (Fig. 3-F).
When the comparisons were conducted using PD values, the superior hemi eld was also affected more severely than the inferior hemi eld ( Figure S1 and S2).

Relationship Between PSD and mean TD
The relationship between PSD and mean TD in the three groups followed an inverted-U shape, demonstrating that PSD worsens as mean TD worsens until the damage is so extensive that the PSD begins to decline again. (Figure 4) The best-t quadratic curves for the NTG, HTG, and PACG groups demonstrated that the NTG group had greater PSD values and the PACG group had lower PSD values for a given mean TD. After controlling for mean TD and (mean TD) 2 , the PACG group had signi cantly lower PSD values for a given mean TD than either the NTG or HTG group (all P <0.001).

Discussion
In early stage PACG eyes in the current study, the nasal region in the superior hemi eld had signi cantly worse VF damage than in the inferior counterpart region. These results are consistent with reports by Bonomi et al 37  In HTG eyes in the current study, the central region in the early stage, and the central and paracentral regions in the advanced stage had signi cantly greater damage in the superior compared to the inferior hemi eld. This is similar to the report from Gazzard and associates, 27 who compared the characteristics of VF defect between HTG and PACG eyes. Their early HTG eyes had signi cantly lower mean pattern deviation in the paracentral region of the superior hemi eld than in the inferior hemi eld; advanced HTG eyes had signi cantly lower mean pattern deviation in the superior central region. In the early and advanced HTG eyes in both Gazzard et al 27 and the current study, only the central and paracentral region in the superior hemi eld was more damaged than the corresponding inferior region. Whereas, in a previous study conducted by Youse et al 36 , almost all superior GHT regions had signi cantly worse VF damage than the corresponding inferior regions in Japanese POAG patients. The main reason for this disagreement in the asymmetric VF defect patterns among these studies is likely the different criteria used in de ning POAG. In the Youse 36 study, POAG was de ned as the presence of glaucomatous optic neuropathy with open anterior chamber angle, while IOP was not a diagnostic criterion. The proportion of NTG among POAG cases in the Japanese population is as high as 92%, 39 and thus a number of NTG cases may be included in the POAG group in the Youse study, which may have in uenced the VF defect patterns in POAG eyes.
In NTG eyes, ve regions at the early stage and three regions at the moderate stage had signi cantly greater damage in the superior compared to the inferior hemi eld. Park et al 40 evaluated the patterns of VF defects in 34 NTG eyes by dividing probability plots into 2 sub elds in each of the hemi elds. They found that the depth of VF defects in the superior paracentral area was greater than in the corresponding inferior area, which is consistent with our study. As described above, Youse et al 36 assessed VF damage among Japanese patients with POAG, among whom many cases were likely NTG. They observed that three GHT regions in the early stage, and ve GHT regions in the moderate and advanced stages had signi cantly worse VF damage than the corresponding inferior regions. This is in agreement with our ndings, to a certain extent. Huang et al 29 compared VF loss in NTG, POAG, and PACG patients, however, their comparison mainly focused on interocular asymmetry.
In the current study, PACG patients were more likely to be female than patients with HTG. This is consistent with previous studies suggesting that women are at greater risk of PACG than men. [41][42][43] PACG patients were signi cantly older than HTG patients, also consistent with previous population-based studies suggesting that older age is a strong risk factor for PACG. 42,[44][45][46] Patients with NTG in this study were recruited from a community screening for subjects aged 50 years or older. 31 This may partly explain the nding that NTG patients were signi cantly older than HTG patients. A more hyperopic SE refraction was observed in PACG than in NTG and HTG, which is in agreement with previous reports describing the strong association between hyperopia and PACG, whereas myopia is reported to be associated with POAG. 36,47,48 Patients with NTG recruited from community screening had signi cantly better VF parameters, and were more likely to be in the early or moderate stages of glaucoma than patients with HTG and NTG. This nding is in accord with prior reports, including our own on this screening cohort, that glaucoma patients detected by screening had signi cantly milder VF damage than those diagnosed initially in clinic. 31,49 The MD of regions in the superior hemi eld were worse than their inferior counterpart regions in the 3 subtypes of primary glaucoma; this result is in accordance with previously studies. Caprioli et al 19  The different patterns of superior-inferior asymmetry in VF defects in the 3 glaucoma subtypes may be associated with their different pathogenic mechanisms. PACG is principally an IOP-dependent glaucoma, due to elevated IOP secondary to angle closure. 4 The mechanism of HTG is thought to be mixed, but with visual eld damage most closely linked to the level of IOP. 55 IOP-independent mechanism including vasogenic risk factors are likely to play a more signi cant role in the pathogenesis of glaucomatous optic neuropathy in NTG, compared to HTG. 6,8,9 Mechanisms of visual eld damage caused by IOP-dependent factors may different from those caused by IOP-independent factors, and this may underlie the observed differences in the patterns of VF defects between NTG, PACG or HTG patients in the current and other studies. Furthermore, studies of the morphologic characteristics of the optic nerve head have also found difference between the 3 subtypes glaucoma: NTG eyes have a larger cup and smaller rim than those with HTG 14, 15, 56, 57 and PACG 16 . These different patterns of glaucomatous optic neuropathy may be a further indication of different pathogenic mechanisms of glaucoma damage in patients with PACG, HTG and NTG.
In the current study, PACG eyes had a lower PSD than those with NTG and HTG. This nding agrees with previous studies reporting that VF loss in PACG eyes is more diffuse than in POAG eyes at the same level of overall eld damage. [26][27][28]36 NTG eyes in the current study had higher PSD than those with HTG for a given mean TD, which is consistent with previous reports that POAG with lower IOP tends to have more localized eld defects compared to cases with higher pressure. 20 Strengths of our study include the fact that it is one of the rst to compare the patterns of VF defects between patients with PACG and POAG in China. Over the last two decades, data on this important topic from China are limited to only a few small studies, 27,29,35 only one of which included patients with NTG, focusing only on inter-ocular asymmetry and including few patients (42 NTG, 38 POAG, and 37 CACG). 29 NTG patients in the current report were recruited from a longitudinal, community-based study, which may strengthen the generalizability of ndings.
Limitations of this study must also be acknowledged. Firstly, the HTG and PACG patients were recruited from clinical settings, which tended to include more severely-affected patients compared to the NTG patients identi ed in the community. Secondly, although we excluded patients with vision impairment or blindness, prevalent cataract may still have affected the pattern of observed VF defects. Finally, the study was cross-sectional, while a longitudinal design would be needed to determine the pattern of progression in the different sub-types of primary glaucoma.
In summary, we found that the superior hemi eld is affected more severely than the inferior hemi eld in all three subtypes of primary glaucoma, and this tendency is more pronounced in NTG compared to PACG and HTG. Moreover, the VF damage in NTG and HTG is more localized than that in PACG.   Data represent mean ± standard deviation.