March 2023
Volume 64, Issue 3
Open Access
Glaucoma  |   March 2023
Choroidal Microvasculature Dropout in the Absence of Parapapillary Atrophy in POAG
Author Affiliations & Notes
  • Eun Ji Lee
    Department of Ophthalmology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
  • Ji Eun Song
    Department of Ophthalmology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
  • Hye Seong Hwang
    Department of Ophthalmology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
  • Jeong-Ah Kim
    Department of Ophthalmology, Kangwon National University School of Medicine, Chuncheon, Korea
  • Seung Hyen Lee
    Department of Ophthalmology, Nowon Eulji Medical Center, Eulji University College of Medicine, Seoul, Korea
  • Tae-Woo Kim
    Department of Ophthalmology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
  • Correspondence: Tae-Woo Kim, Department of Ophthalmology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 82, Gumi-ro, 173 Beon-gil, Bundang-gu, Seongnam, Gyeonggi-do 13620, Republic of Korea; twkim7@snu.ac.kr
Investigative Ophthalmology & Visual Science March 2023, Vol.64, 21. doi:https://doi.org/10.1167/iovs.64.3.21
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      Eun Ji Lee, Ji Eun Song, Hye Seong Hwang, Jeong-Ah Kim, Seung Hyen Lee, Tae-Woo Kim; Choroidal Microvasculature Dropout in the Absence of Parapapillary Atrophy in POAG. Invest. Ophthalmol. Vis. Sci. 2023;64(3):21. https://doi.org/10.1167/iovs.64.3.21.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: To describe the parapapillary choroidal microvasculature dropout (CMvD) in glaucomatous eyes without β-zone parapapillary atrophy (β-PPA) and compare its characteristics with that of CMvD with β-PPA.

Methods: Peripapillary choroidal microvasculature was evaluated on en face images obtained using optical coherence tomography angiography. CMvD was defined as a focal sectoral capillary dropout with no visible microvascular network identified in the choroidal layer. Peripapillary and optic nerve head structures, including the presence of β-PPA, peripapillary choroidal thickness and lamina cribrosa curvature index were evaluated using the images obtained by enhanced depth-imaging optical coherence tomography.

Results: The study included 100 glaucomatous eyes with CMvD (25 without and 75 with β-PPA) and 97 eyes without CMvD (57 without and 40 with β-PPA). Regardless of the presence of β-PPA, eyes with CMvD tended to have a worse visual field at a given RNFL thickness than eyes without CMvD, with patients having eyes with CMvD having lower diastolic blood pressure and more frequent cold extremities than patients with eyes lacking CMvD. Peripapillary choroidal thickness was significantly smaller in eyes with than without CMvD, but was not affected by the presence of β-PPA. β-PPA without CMvD was not associated with vascular variables.

Conclusions: CMvD were found in the absence of β-PPA in glaucomatous eyes. CMvDs had similar characteristics in the presence and absence of β-PPA. Clinical and optic nerve head structural characteristics potentially relevant to compromised optic nerve head perfusion were dependent on the presence of CMvD, rather than the presence of β-PPA.

The juxtapapillary choroid contains multiple choroidal lobules, each consisting of densely packed microvessels supplied by feeding arterioles located in the center of the lobules.1 Optical coherence tomography (OCT) angiography (OCTA) has identified localized microvasculature dropout in the juxtapapillary choroid of patients with glaucoma.2,3 The choroidal microvasculature dropout (CMvD) detected by OCTA was found to correspond with a perfusion defect observed by indocyanine angiography,4 suggesting that CMvD is indicative of true perfusion compromise. Interestingly, CMvD has been reported in patients with compressive optic neuropathy in the choroid adjacent to the area of optic nerve axonal loss,5 suggesting that CMvD can develop secondary to decreased metabolic need from the damaged optic nerve. The juxtapapillary choroid may therefore be directly involved in the perfusion of the prelaminar tissue or at least closely associated with prelaminar blood flow. 
Decreased optic nerve head (ONH) perfusion is thought to play an important role in the pathogenesis of glaucoma.6 Because the juxtapapillary choroid is closely associated with ONH perfusion,7,8 vascular compromise in the juxtapapillary choroid (e.g., CMvD) may play a significant role in the development of optic nerve damage. CMvD was shown to be significantly associated with the location9 and severity2,10 of glaucomatous damage and to be an important predictor of glaucoma progression.1113 Although these findings suggest that CMvD has potential pathogenic importance in glaucomatous optic neuropathy, little is known about the pathophysiology or pathogenesis of CMvD. 
CMvD has been reported in areas with β-zone parapapillary atrophy (β-PPA). β-PPA has long been recognized as an area affected by ischemia, making it an indicator of vascular compromise in glaucoma.1417 The presence of β-PPA has been shown to be significantly associated with both the presence18,19 and progression20,21 of glaucoma. β-PPA has also been associated with decreased peripapillary choroidal thickness (CT),22,23 suggesting that the decreased choroidal perfusion in the parapapillary region is pathogenically associated with the development of β-PPA.23,24 In this regard, CMvD may be an extensive manifestation of β-PPA, with the β-zone preceding the formation of MvD in the choroid. Alternatively, atrophic retinal pigment epithelium in the β-zone may simply allow visualization of the choriocapillaris, such that CMvD has been described only in association with β-zone. Considering the crucial relationships of β-PPA and CMvD with glaucoma, it is important to determine the relationship between the pathogenesis of β-PPA and CMvD. 
Recently, we have found that clinically significant CMvD can be observed in areas without a β-zone, suggesting that CMvD and β-PPA may not necessarily share a common pathogenesis. The present study describes CMvDs in areas without β-zones. In addition, this study compares the clinical characteristics and ONH structure associated with CMvDs in glaucomatous eyes with and without β-zones. 
Methods
Participants
This study involved patients with POAG who were enrolled in the Investigating Glaucoma Progression Study, an ongoing prospective study of patients with glaucoma at the Glaucoma Clinic of Seoul National University Bundang Hospital. All subjects provided written informed consent to participate. The study protocol was approved by the Institutional Review Board of Seoul National University Bundang Hospital and followed the tenets of the Declaration of Helsinki. 
POAG was defined as the presence of an open iridocorneal angle, signs of glaucomatous optic nerve damage (i.e., neuroretinal rim thinning or notching, or a retinal nerve fiber layer [RNFL] defect), and a glaucomatous visual field (VF) defect. A glaucomatous VF defect was defined as a defect conforming to at least one of the following criteria: (1) results outside normal limits on glaucoma hemifield tests, (2) three abnormal points with a less than 5% probability of being normal and one abnormal point with a less than 1% probability of being normal by pattern deviation, or (3) a pattern standard deviation with a probability of less than 5% confirmed on two consecutive reliable tests. Reliability on these tests was defined as a fixation loss rate of 20% or lower, a false-positive error rate of 15% or lower, and a false-negative error rate of 25% or lower. 
For eyes to be included, a record was required of untreated IOP before the initiation of ocular hypotensive treatment or identified in the referral notes. In patients with an untreated IOP of 21 mm Hg or less, the diurnal variation was measured during office hours every 2 hours from 9 am to 5 pm, with the mean of the five measurements considered the untreated IOP for that patient. In patients with an untreated IOP of more than 21 mm Hg, the IOP was measured twice before starting IOP-lowering medication, with the mean of the two measurements considered the untreated IOP. In patients who were undergoing treatment with ocular hypotensive medication at the time of the initial visit, the diurnal variation was measured after a 4-week washout period. 
Eyes were excluded if they had a best-corrected visual acuity worse than 20/40, a spherical equivalent of less than −9.0 diopters (D) or more than +3.0 D, a cylinder correction of less than −3.0 D or more than +3.0 D, a history of intraocular surgery with the exception of uneventful cataract surgery, retinal diseases (e.g., diabetic retinopathy, retinal vessel occlusion, or retinoschisis) or neurological diseases (e.g., pituitary tumor). Eyes with γ-zone PPA25 were also excluded because the microstructures underlying CMvDs differ in PPA β- and γ-zones, with γ-zones consisting only of border tissue, not choroid, indicating different pathomechanisms.26 When both eyes of a subject were eligible, one eye was selected randomly for inclusion in the study. 
Clinical Examinations
All participants underwent comprehensive ophthalmic examinations, which included assessments of best-corrected visual acuity, Goldmann applanation tonometry, refraction tests, slit-lamp biomicroscopy, gonioscopy, stereo disc photography, red-free fundus photography (EOS D60 digital camera, Canon, Utsunomiyashi, Japan), measurement of peripapillary RNFL thickness, and scanning of the ONH by spectral-domain OCT (Spectralis, Heidelberg Engineering, Heidelberg, Germany), swept-source OCTA of the ONH area (DRI OCT Triton, Topcon, Tokyo, Japan), and standard automated perimetry (Humphrey Field Analyzer II 750, 24-2 Swedish interactive threshold algorithm, Carl Zeiss Meditec, Dublin, CA, USA). Other ophthalmic examinations included measurements of corneal curvature (KR-1800, Topcon), central corneal thickness (Orbscan II, Bausch & Lomb Surgical, Rochester, NY, USA), and axial length (IOLMaster version 5, Carl Zeiss Meditec). 
The clinical histories of all participants were recorded, including their demographic characteristics and the occurrence of migraine, cold extremities, and other systemic conditions. Systolic and diastolic blood pressures (BPs) were measured using a digital automatic BP monitor (Omron HEM-770A, Omron Matsusaka, Matsusaka, Japan) at the time of OCTA. 
All patients underwent a slit-lamp examination using a 78-D lens and/or fundus photography at regular follow-up visits. Disc hemorrhage was defined as an isolated hemorrhage seen at least once on the optic disc or in the peripapillary retina connected to the disc rim, as observed by slit-lamp examination or fundus photography. 
Assessment of β-PPA
The presence of β-PPA was based on the results of enhanced depth imaging OCT scanning of the optic disc and infrared fundus images obtained by Spectralis OCT (Fig. 1B). A potential magnification error was removed by entering the corneal curvature of each eye into the Spectralis OCT system before scanning. The PPA can be divided into areas with Bruch's membrane (BM) and underlying choroid (β-zone) and areas devoid of BM and choroidal tissue (γ-zone). This study only included eyes without any type of PPA (PPA- group) and those with a β-zone of horizontal width of more than 200 µm on at least one scan (PPA+ group).18 Eyes with PPA of longest horizontal width between 0 and 200 µm were not included in either group. When PPA+ group had a γ-zone of longest horizontal width of more than 100 µm, those eyes were excluded. In our experience, these criteria are best for differentiating β- and γ-zones, and characterizing the differences in clinical nature and rate of glaucoma progression between the groups.18,20 The horizontal width of the β-zone was manually measured using the built-in caliper tool of the Spectralis OCT system (Heidelberg Eye Explorer software version 1.7.0.0; Heidelberg Engineering). Only eyes with acceptable scans and good-quality images (i.e., quality score of ≥15) were included in the analysis. 
Figure 1.
 
Determination of the presence of β-PPA and CMvD and measurements of peripapillary CT. Color disc photographs (A, F), infrared images (B, G), en face OCTA images of the choroidal layer (C, H), cross-sectional OCTA images at locations indicated by arrows in C and H (D, I), and circumpapillary OCT B-scan images (E, J) of glaucomatous eyes without (upper) and with (lower) β-PPA. Green dashed circles indicate the optic disc margins (B, C, F, G). Red lines in C and G indicate margins of CMvD and the blue dotted circle in F indicates the margin of β-PPA. CT was measured based on the distance between BM (blue dotted lines) and the choroidoscleral interface (red dotted lines) in the OCT circumpapillary B-scan images (D, H).
Figure 1.
 
Determination of the presence of β-PPA and CMvD and measurements of peripapillary CT. Color disc photographs (A, F), infrared images (B, G), en face OCTA images of the choroidal layer (C, H), cross-sectional OCTA images at locations indicated by arrows in C and H (D, I), and circumpapillary OCT B-scan images (E, J) of glaucomatous eyes without (upper) and with (lower) β-PPA. Green dashed circles indicate the optic disc margins (B, C, F, G). Red lines in C and G indicate margins of CMvD and the blue dotted circle in F indicates the margin of β-PPA. CT was measured based on the distance between BM (blue dotted lines) and the choroidoscleral interface (red dotted lines) in the OCT circumpapillary B-scan images (D, H).
Assessment of CMvD
The ONH and peripapillary area were imaged using a commercially available swept-source OCTA device (DRI OCT Triton, Topcon), with a central wavelength of 1050 nm, an acquisition speed of 100,000 A-scans per second, and axial and transverse resolutions of 7 µm and 20 µm, respectively, in the tissue. Scans were taken from 4.5 mm × 4.5 mm × 4.5 mm cubes, with each cube consisting of 320 clusters of four repeated B-scans centered on the optic disc. En face projections of volumetric scans allowed visualization of the structural and vascular details within segmented layers. 
The choroidal microvasculature in the peripapillary area was evaluated in en face images of the peripapillary deep layer, which were generated based on the automated layer segmentation performed by the OCT instrument software. The en face images of the deep layer were derived from an en face slab that extended from the retinal pigment epithelium to 390 µm below the BM, which was sufficient to include the full thickness of the choroid and the inner scleral surface. 
CMvD was defined as a focal sectoral capillary dropout with no visible microvascular network in the deep layer en face images (Fig. 1C).2,4,27 A circumferential width of the area with capillary dropout exceeding one-half of a clock-hour of the disc circumference, which was consistent on two OCTA examinations with reliable image qualities, was considered a disruption of the microvascular network and was deemed a CMvD.4,27 Only the dropouts adjoining the disc margin were counted as CMvDs, because nonjuxtapapillary dropouts can be observed in healthy myopic eyes.28 The hemispheric location of each CMvD was based on the foveal–disc axis, and the area of the CMvD was manually measured using the built-in caliper tool of the ImageNet software. Two observers (J.E.S. and H.S.H.) independently identified CMvDs while masked to the clinical information of the subjects. Disagreements between these observers in the identification of CMvD were resolved by a third observer (E.J.L.). The mean of the two values from each observer was used as a CMvD area. All included OCT B-scan images had image quality scores of 30 or higher, in accordance with the manufacturer's recommendation. Eyes with poor quality OCTA images (e.g., blurred images that hampered the delineation of the CMvD) were excluded from the analysis. 
Measurements of the Curvature of the Lamina Cribrosa (LC) and Peripapillary CT
ONH structure was evaluated by measuring the LC curvature and peripapillary CT, using the ONH volume images obtained by enhanced depth imaging OCT and using the peripapillary circular scanning centered on the BM opening. The corneal curvature of each eye was entered into the Spectralis OCT system before OCT scanning to compensate for potential magnification error. 
The LC curvature is an index of the degree of posterior bowing or deformation of the LC, which is thought to represent the IOP-induced mechanical stress on the ONH.2931 The degree of LC deformation has been shown to decrease after reducing IOP,3234 with a greater degree of LC deformation being associated with more rapid glaucoma progression.29,35,36 
The LC curvature was evaluated using the LC curve index (LCCI), defined as the degree of inflection of the curve representing a section of the LC.31 The LCCI was determined by measuring the width of the anterior LC surface reference plane (W) and then by measuring the LC curve depth within the anterior LC surface plane in each B-scan, with LCCI calculated as follows: (LC curve depth/W) × 100. Because the curvature was normalized to the LC width, the LCCI is an indicator of the shape of the LC, independent of the actual size of the ONH. Only the LC within the W was considered, because the LC was often not clearly visible outside this region. In eyes with LC defects, the LCCI was measured using a presumed anterior LC surface that best fit the curvature of the remaining part of the LC or by excluding the area of the LC defect. The manual caliper tool in the Heidelberg Eye Explorer (version 1.10.4., Heidelberg, Germany) was used to measure W and LC curve depth in seven selected B-scan images spaced equidistantly across the vertical optic disc diameter except for those at superior and inferior poles, with the mean LCCI of each eye calculated using the measurements made from these seven B-scans. Superior, middle, and inferior LCCIs were determined from the mean of the values obtained from the two uppermost, three central and paracentral, and two lowermost B-scans, respectively. 
The peripapillary choroid is considered an important vascular structure that perfuses the ONH,7,37 with a thinner peripapillary choroid being regarded as indicative of decreased perfusion of the ONH.22,23,38 The peripapillary CT was measured on the 360° 3.5-mm diameter peripapillary circle scan centered on the BM opening using the manual segmentation function built into the Heidelberg Eye Explorer software. The posterior edge of the retinal pigment epithelium and the sclerochoroidal interface, representing the inner and outer boundaries of the choroid, respectively, were manually delineated (Fig. 1D). Using the circumpapillary RNFL thickness measurement algorithm, the peripapillary CT in the global area and in the six sectors based on the foveal–BM opening axis were automatically generated. 
The LCCI and peripapillary CT were measured by two experienced observers (J.A.K. and S.H.L.) who were masked to the clinical characteristics of the study subjects. The measurements by the two observers were averaged for analyses. 
Selection and Grouping of Patients
The study included four groups of eyes with POAG: eyes having CMvD but no β-PPA (MvD+PPA–; group 1), eyes having both CMvD and β-PPA (MvD+PPA+; group 2), eyes not having CMvD but having β-PPA (MvD–PPA+; group 3), and eyes having neither CMvD nor β-PPA (MvD–PPA–; group 4). Because of the relatively rare incidence of CMvD in POAG eyes without β-PPA, the eyes having MvD without β-PPA (group 1) were first identified, and the eyes in the other three groups were selected: The eyes in group 2 (MvD+PPA+) were selected by matching the area of the CMvD and global RNFL thickness with the eyes in group 1(MvD+PPA–) (1:3 matching). Subsequently, eyes in groups 3 (MvD–PPA+) and 4 (MvD–PPA–) were selected by matching the global RNFL thickness with those in groups 1 and 2. 
Data Analysis
Except where stated otherwise, all data are presented as mean ± standard deviation. Interobserver agreement regarding the presence of CMvD was assessed using kappa statistics (κ value). The interobserver reproducibility in the determination of the area of the CMvD, LCCI and the peripapillary CT were assessed by calculating intraclass correlation coefficients. Parametric data between or within groups were compared using independent- or paired-sample t-tests, whereas nonparametric data were compared using Mann–Whitney U tests or Wilcoxon signed rank tests. Factors associated with the rate of RNFL thinning were assessed by regression analysis, first with a univariate model and subsequently with a multivariate model that included variables in the univariate model with P values of less than 0.10. All statistical analyses were performed using the Statistical Package for the Social Sciences (version 22.0, SPSS, Chicago, IL, USA), with P values of less than 0.05 considered statistically significant. 
Results
Of the 422 POAG eyes that were initially enrolled, 27, 13, and 5 were excluded because of poor-quality OCTA images or B-scan images that did not allow clear delineation of MvD, the LC, or the choroid. Of the remaining 377 POAG eyes that initially met our inclusion criteria, 25 of 171 eyes without PPA and 134 of 206 eyes with PPA showed CMvD. Group 1 (MvD+PPA−) consisted of the 25 eyes with MvD and without PPA, whereas groups 2 (MvD+PPA+), 3 (MvD–PPA+) and 4 (MvD–PPA–) consisted of 75, 40, and 57 eyes, respectively. There was excellent interobserver agreement regarding the measured CMvD area (intraclass correlation coefficient = 0.965) and the detection of cMvD (κ = 0.958). The clinical characteristics of these participants are shown in Table 1. There were no significant differences among the four groups in gender distribution, IOP, baseline global RNFLT, incidence and recurrence of disc hemorrhage, axial length, and central corneal thickness. Patients with eyes having β-PPA were significantly older than patients with eyes lacking β-PPA (P < 0.001), and the VF mean deviation tended to be worse in eyes with than without CMvD (P = 0.042). Patients with eyes showing CMvD (groups 1 and 2) had lower diastolic BP than patients with eyes lacking both β-PPA and CMvD (group 4). The prevalence of migraine was significantly higher in patients with eyes having both β-PPA and CMvD (group 2) than in patients with eyes lacking both β-PPA and CMvD (group 4), and the prevalence of cold extremities was significantly higher in patients with eyes with (groups 1 and 2) than without (groups 3 and 4) CMvD, regardless of the presence of β-PPA. The rates of sleep apnea, diabetes mellitus, systemic hypertension, cardiac arrhythmia, asthma, and history of smoking did not differ among the four groups. 
Table 1.
 
Clinical Characteristics of Participants
Table 1.
 
Clinical Characteristics of Participants
The intraclass correlation coefficients for measuring the area of LCCI and peripapillary CT were 0.988 and 0.987, respectively. Table 2 shows comparisons of LCCI and peripapillary CT among the four groups. LCCI at all locations did not differ among these groups of eyes, although LCCI at a location corresponding with the hemisector of CMvD tended to be larger for group 2 (MvD+PPA+) than group 1 (MvD+PPA–) eyes (P = 0.051), although the difference did not attain statistical significance. Measurements of peripapillary CT showed that, although peripapillary CT was not affected by the presence of β-PPA, it was associated with the presence of CMvD. Peripapillary CT in all sectors but the nasal sector was significantly thinner in eyes with (groups 1 and 2) than without (groups 3 and 4) CMvD (P ≤ 0.001). In contrast, peripapillary CT did not differ significantly in groups 1 and 2 (eyes with CMvD) or in groups 3 and 4 (eyes lacking CMvD). The CT at the location corresponding to the CMvD hemisector did not differ between groups 1 (MvD+PPA–) and 2 (MvD+PPA+) (P = 0.166). Figure 2 illustrates differences in peripapillary CT profiles according to the presence or absence of CMvD and/or β-PPA. Eyes with CMvD were accompanied by thinning of the juxtapapillary choroid, regardless of the presence of β-PPA. 
Table 2.
 
Comparisons of Peripapillary CT and LCCI Among Groups
Table 2.
 
Comparisons of Peripapillary CT and LCCI Among Groups
Figure 2.
 
Peripapillary CT according to the presence of CMvD or β-PPA in glaucomatous eyes. (A, B) Eyes having CMvDs (arrowheads), without (A) and with (B) β-PPA. (C, D) Eyes lacking CMvDs, without (C) and with (D) β-PPA. (A-1 to D-1) Color disc photographs. (A-2 to D-2) En face OCTA images of the choroidal layer. (A-3 to D-3) Topographic images of the peripapillary CT. (A-4 to D-4) B-scan images obtained at the locations of glaucomatous damage (dashed light green lines in A-1 to D-1). Inset images are cross-sectional OCTA images of the area indicated with white square. (A-5 to D-5) Enlarged B-scan images corresponding to the white squares in A-1 to D-1, and in A-4 to D-4. Black and red dashed lines indicate BM and the choroidoscleral interface, respectively. Eyes having CMvD showed similar CT profiles, regardless of the presence of β-PPA (A-3, B-3), and these CT profiles were smaller than those of eyes not having CMvD (C-3, D-3). In contrast, CT was similar in eyes not having CMvD, regardless of the presence of β-PPA (C-3, D-3). In B-scan images, the choroid is notably thinned at the location of the CMvDs (arrows, A-4, B-4, A-5, B-5), as compared with the choroid in eyes without CMvDs (C-5, D-5).
Figure 2.
 
Peripapillary CT according to the presence of CMvD or β-PPA in glaucomatous eyes. (A, B) Eyes having CMvDs (arrowheads), without (A) and with (B) β-PPA. (C, D) Eyes lacking CMvDs, without (C) and with (D) β-PPA. (A-1 to D-1) Color disc photographs. (A-2 to D-2) En face OCTA images of the choroidal layer. (A-3 to D-3) Topographic images of the peripapillary CT. (A-4 to D-4) B-scan images obtained at the locations of glaucomatous damage (dashed light green lines in A-1 to D-1). Inset images are cross-sectional OCTA images of the area indicated with white square. (A-5 to D-5) Enlarged B-scan images corresponding to the white squares in A-1 to D-1, and in A-4 to D-4. Black and red dashed lines indicate BM and the choroidoscleral interface, respectively. Eyes having CMvD showed similar CT profiles, regardless of the presence of β-PPA (A-3, B-3), and these CT profiles were smaller than those of eyes not having CMvD (C-3, D-3). In contrast, CT was similar in eyes not having CMvD, regardless of the presence of β-PPA (C-3, D-3). In B-scan images, the choroid is notably thinned at the location of the CMvDs (arrows, A-4, B-4, A-5, B-5), as compared with the choroid in eyes without CMvDs (C-5, D-5).
Discussion
The present study described the CMvDS without β-PPA in POAG eyes. To our knowledge, CMvD not associated with PPA has never been described in the literature. Eyes having CMvDs shared similar ocular characteristics, such as worse VF mean deviation at a given RNFL thickness and thinner peripapillary CT, regardless of the presence of β-PPA. Patients with eyes having CMvDs also shared similar systemic characteristics, such as a lower diastolic BP and a higher rate of cold extremities, regardless of the presence of β-PPA. In the absence of CMvD, however, β-PPA was associated only with older age. 
CMvD was predominantly found in eyes having β-PPA. Thus, the number of eyes showing CMvD with PPA (MvD+PPA+) was matched in a 3:1 ratio with the number of eyes with CMvD but lacking PPA (MvD+PPA–), with the latter group consisting of 25 eyes. This finding suggested that β-PPA is not a prerequisite for CMvD. 
PPA has been associated with decreased CT.22,23 Decreased choroidal perfusion in the parapapillary region may be pathogenetically connected to the development of β-PPA.23,24 However, the present study found that peripapillary CT was dependent on the presence of CMvD, not on the presence of β-PPA, with eyes having CMvD showing significantly smaller CT at all locations than eyes lacking CMvD, regardless of the presence of β-PPA. In contrast, peripapillary CT was found to be comparable in eyes lacking CMvD with and without β-PPA. This finding suggested that peripapillary choroidal thinning plays a critical role in the development of CMvD, whereas the formation of β-PPA is not necessarily associated with choroidal thinning. Similarly, lower diastolic BP and cold extremities were associated with CMvD, not with β-PPA, further suggesting that CMvD but not β-PPA is pathogenically associated with vascular factors. 
The present study matched the number of eyes with and without β-PPA and CMvD, allowing a differential assessment of the characteristics associated individually with β-PPA and CMvD. Only older age was associated with β-PPA in the present study, whereas vascular factors, such as diastolic BP, cold extremities, and peripapillary CT, were not. These findings suggest that β-PPA is more likely a result of age-related atrophy rather than pathologically decreased peripapillary perfusion. Taken together, these findings suggest that β-PPA itself may not be a sufficient indicator of impaired perfusion. CMvD may be a more pathognomonic sign of decreased perfusion, playing a significant role in glaucomatous optic neuropathy. 
The association of CMvD with vascular factors observed in the present study was similar to previous findings.4,13,39 CMvD has been detected frequently in patients with glaucoma with a lower systemic BP,2,39 migraines, and cold extremities,4,39 factors that may be associated with vascular dysregulation. CMvD has also been associated with parafoveal VF defects,39,40 which are recognized as indicators of decreased ocular perfusion.41,42 CMvDs have also been found to be topographically associated with the location of decreased juxtapapillary CT.27,38 Systemic vascular impairment and consequent reduction of choroidal perfusion may result in decreased CT. Because peripapillary choroidal perfusion is closely associated with ONH perfusion, decreased CT may represent decreased perfusion in the ONH. Decreased ONH perfusion could induce ischemic optic nerve damage due to a reduction in nutrition to the parapapillary area and a consequent increase in vulnerability to glaucomatous damage.43,44 
β-PPA has been regarded as one of the important manifestations of glaucomatous optic neuropathy. Not only the presence of glaucoma,18,19 but also progression of the disease20,21 have been significantly associated with the presence of β-PPA. However, β-PPA is also found frequently in healthy eyes,45 and glaucomatous damage is not associated with the entire circumference of the β-PPA in glaucomatous eyes. Thus, the link between β-PPA and glaucoma is not highly robust. In contrast, CMvD is almost exclusively found in eyes with glaucoma.46 Further, there is a strong topographic association between CMvD and RNFL defects, both in location and extent,9 suggesting that CMvD is more strongly associated with glaucoma than is β-PPA. Previously reported associations between β-PPA and glaucoma1921 may be attributed to the relatively high prevalence of CMvD in the area of β-PPA in glaucoma.2,9,27 Although an overall association between β-PPA and glaucoma has been reported, this association may be absent when CMvD is not present along with β-PPA. 
Deformation of the LC is a powerful indicator of mechanical stress in glaucoma.4749 The LC deformation induced by stress related to IOP is thought to promote the death of retinal ganglion cells via various mechanisms, including blockade of axoplasmic flow and tissue remodeling by reactive astrocytes.4953 LCCI is a useful parameter to measure the degree of LC deformation and has been found to predict the development54 and progression29,55 of glaucoma. In the present study, neither LCCI at any locations nor IOP-related parameters differed among the groups. The lack of associations of both β-PPA and CMvD with either LCCI or IOP may suggest that it is less likely that β-PPA or CMvD are affected by mechanical stress. 
The main limitation of the present study was the small number of group 1 eyes (PPA–MvD+). The prevalence of CMvD was high in eyes having β-PPA, so the number of eyes in each group had to be matched based on the size of group 1. In addition, CMvD may have been undetected in some eyes under areas without β-PPA. Development of a device enabling better visualization of deeper choroidal vessels would provide more decisive determinations. 
In conclusion, the present study characterized the CMvDs in areas without β-PPA in POAG eyes. The CMvDs in eyes without β-PPA were associated with factors representing impaired perfusion, similar to those in eyes with β-PPA, although the presence of β-PPA alone was not associated with such factors. Although the clinical importance of CMvD in the absence of β-PPA requires long term validation, the presence of CMvD, rather than β-PPA, should be considered in evaluating the role/relevance of the compromised peripapillary vasculature in glaucoma. 
Acknowledgments
Supported by the Patient-Centered Clinical Research Coordinating Center, funded by the Ministry of Health & Welfare, Republic of Korea (grant no. HI19C0481, HC19C0276), and by Seoul National University Bundang Hospital Research Fund (no. 14-2022-0024). 
Disclosure: E.J. Lee, None; J.E. Song, None; H.S. Hwang, None; J.-A. Kim, None; S.H. Lee, None; T.-W. Kim, None 
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Figure 1.
 
Determination of the presence of β-PPA and CMvD and measurements of peripapillary CT. Color disc photographs (A, F), infrared images (B, G), en face OCTA images of the choroidal layer (C, H), cross-sectional OCTA images at locations indicated by arrows in C and H (D, I), and circumpapillary OCT B-scan images (E, J) of glaucomatous eyes without (upper) and with (lower) β-PPA. Green dashed circles indicate the optic disc margins (B, C, F, G). Red lines in C and G indicate margins of CMvD and the blue dotted circle in F indicates the margin of β-PPA. CT was measured based on the distance between BM (blue dotted lines) and the choroidoscleral interface (red dotted lines) in the OCT circumpapillary B-scan images (D, H).
Figure 1.
 
Determination of the presence of β-PPA and CMvD and measurements of peripapillary CT. Color disc photographs (A, F), infrared images (B, G), en face OCTA images of the choroidal layer (C, H), cross-sectional OCTA images at locations indicated by arrows in C and H (D, I), and circumpapillary OCT B-scan images (E, J) of glaucomatous eyes without (upper) and with (lower) β-PPA. Green dashed circles indicate the optic disc margins (B, C, F, G). Red lines in C and G indicate margins of CMvD and the blue dotted circle in F indicates the margin of β-PPA. CT was measured based on the distance between BM (blue dotted lines) and the choroidoscleral interface (red dotted lines) in the OCT circumpapillary B-scan images (D, H).
Figure 2.
 
Peripapillary CT according to the presence of CMvD or β-PPA in glaucomatous eyes. (A, B) Eyes having CMvDs (arrowheads), without (A) and with (B) β-PPA. (C, D) Eyes lacking CMvDs, without (C) and with (D) β-PPA. (A-1 to D-1) Color disc photographs. (A-2 to D-2) En face OCTA images of the choroidal layer. (A-3 to D-3) Topographic images of the peripapillary CT. (A-4 to D-4) B-scan images obtained at the locations of glaucomatous damage (dashed light green lines in A-1 to D-1). Inset images are cross-sectional OCTA images of the area indicated with white square. (A-5 to D-5) Enlarged B-scan images corresponding to the white squares in A-1 to D-1, and in A-4 to D-4. Black and red dashed lines indicate BM and the choroidoscleral interface, respectively. Eyes having CMvD showed similar CT profiles, regardless of the presence of β-PPA (A-3, B-3), and these CT profiles were smaller than those of eyes not having CMvD (C-3, D-3). In contrast, CT was similar in eyes not having CMvD, regardless of the presence of β-PPA (C-3, D-3). In B-scan images, the choroid is notably thinned at the location of the CMvDs (arrows, A-4, B-4, A-5, B-5), as compared with the choroid in eyes without CMvDs (C-5, D-5).
Figure 2.
 
Peripapillary CT according to the presence of CMvD or β-PPA in glaucomatous eyes. (A, B) Eyes having CMvDs (arrowheads), without (A) and with (B) β-PPA. (C, D) Eyes lacking CMvDs, without (C) and with (D) β-PPA. (A-1 to D-1) Color disc photographs. (A-2 to D-2) En face OCTA images of the choroidal layer. (A-3 to D-3) Topographic images of the peripapillary CT. (A-4 to D-4) B-scan images obtained at the locations of glaucomatous damage (dashed light green lines in A-1 to D-1). Inset images are cross-sectional OCTA images of the area indicated with white square. (A-5 to D-5) Enlarged B-scan images corresponding to the white squares in A-1 to D-1, and in A-4 to D-4. Black and red dashed lines indicate BM and the choroidoscleral interface, respectively. Eyes having CMvD showed similar CT profiles, regardless of the presence of β-PPA (A-3, B-3), and these CT profiles were smaller than those of eyes not having CMvD (C-3, D-3). In contrast, CT was similar in eyes not having CMvD, regardless of the presence of β-PPA (C-3, D-3). In B-scan images, the choroid is notably thinned at the location of the CMvDs (arrows, A-4, B-4, A-5, B-5), as compared with the choroid in eyes without CMvDs (C-5, D-5).
Table 1.
 
Clinical Characteristics of Participants
Table 1.
 
Clinical Characteristics of Participants
Table 2.
 
Comparisons of Peripapillary CT and LCCI Among Groups
Table 2.
 
Comparisons of Peripapillary CT and LCCI Among Groups
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