(PDF) Deep-Layer Microvasculature Dropout by Optical Coherence Tomography Angiography and Microstructure of Parapapillary Atroph

Glaucoma Deep-Layer Microvasculature Dropout by Optical Coherence Tomography Angiography and Microstructure of Parapapillary Atrophy Min Hee Suh,1 Linda M. Zangwill,2 Patricia Isabel C. Manalastas,2 Akram Belghith,2 Adeleh Yarmohammadi,2 Tadamichi Akagi,2,3 Alberto Diniz-Filho,2 Luke Saunders,2 and Robert N. Weinreb2 1 Department of Ophthalmology, Haeundae Paik Hospital, Inje University College of Medicine, Busan, South Korea 2 Hamilton Glaucoma Center, Shiley Eye Institute, the Department of Ophthalmology, University of California San Diego, La Jolla, California, United States 3 Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan Correspondence: Robert N. Wein- PURPOSE. To investigate the association between the microstructure of b-zone parapapillary reb, University of California San atrophy (bPPA) and parapapillary deep-layer microvasculature dropout assessed by optical Diego, 9500 Gilman Drive, MC 0946, coherence tomography angiography (OCT-A). La Jolla, CA 92093, USA;

. METHODS. Thirty-seven eyes with bPPA devoid of the Bruch’s membrane (BM) (cPPA) ranging Submitted: September 25, 2017 between completely absent and discontinuous BM were matched by severity of the visual Accepted: March 19, 2018 field (VF) damage with 37 eyes with fully intact BM (bPPAþBM) based on the spectral-domain (SD) OCT imaging. Parapapillary deep-layer microvasculature dropout was defined as a Citation: Suh MH, Zangwill LM, Man- dropout of the microvasculature within choroid or scleral flange in the bPPA on the OCT-A. alastas PIC, et al. Deep-layer micro- vasculature dropout by optical The widths of bPPA, cPPA, and bPPAþBM were measured on six radial SD-OCT images. coherence tomography angiography Prevalence of the dropout was compared between eyes with and without cPPA. Logistic and microstructure of parapapillary regression was performed for evaluating association of the dropout with the width of bPPA, atrophy. Invest Ophthalmol Vis Sci. cPPA, and bPPAþBM, and the cPPA presence. 2018;59:1996–2005. https://doi.org/ RESULTS. Eyes with cPPA had significantly higher prevalence of the dropout than did those 10.1167/iovs.17-23046 without cPPA (75.7% versus 40.8%; P ¼ 0.004). In logistic regression, presence and longer width of the cPPA, worse VF mean deviation, and presence of focal lamina cribrosa defects were significantly associated with the dropout (P < 0.05), whereas width of the bPPA and bPPAþBM, axial length, and choroidal thickness were not (P > 0.10). CONCLUSIONS. Parapapillary deep-layer microvasculature dropout was associated with the presence and larger width of cPPA, but not with the bPPAþBM width. Presence and width of the exposed scleral flange, rather than the retinal pigmented epithelium atrophy, may be associated with deep-layer microvasculature dropout. Keywords: deep-layer microvasculature dropout, parapapillary atrophy, optical coherence tomography angiography b -Zone parapapillary atrophy (bPPA), a feature of the glaucomatous eye,1 is characterized by atrophy of the retinal pigment epithelium (RPE) and choriocapillaris adjacent angiography (OCT-A). OCT-A enables visualization of both deep- layer and superficial microvasculature.6,12–17 The objective of the present study is to elucidate the to the optic disc.1–3 It has been suggested that reduced blood association between the microstructure of the bPPA and the supply to the optic nerve head (ONH) due to closure of the deep-layer microvasculature dropout in primary open-angle choriocapillaris may be a mechanism that accounts for the glaucoma (POAG) patients. relationship between the bPPA and glaucoma.1–5 Specifically, characteristics of the deep-layer microvasculature contained within the bPPA may differ according to whether Bruch’s membrane (BM) is present (bPPAþBM), or discontinuous or MATERIALS AND METHODS absent (c-zone PPA [cPPA]).3,6–12 In cPPA areas devoid of the POAG patients were included from the Diagnostic Innovations BM, parapapillary deep-layer microvasculature is composed of in Glaucoma Study (DIGS) (ClinicalTrials.gov identifier: the microvasculature located within the elongated scleral flange.3,12 In contrast, in bPPAþBM areas, deep-layer microvas- NCT00221897).12,15,16,18 Details of the DIGS protocol and culature is only composed of the choriocapillaris.6,12 However, eligibility have been described previously.18 This study was little is known about this issue since noninvasive visualization approved by the institutional review boards at the University of of the deep-layer microvasculature has not been possible until California, San Diego, and conformed to the tenets of the the recent development of optical coherence tomography Declaration of Helsinki and the Health Insurance Portability and Copyright 2018 The Authors iovs.arvojournals.org j ISSN: 1552-5783 1996 This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. Deep-Layer Microvasculature Dropout and PPA IOVS j April 2018 j Vol. 59 j No. 5 j 1997 Accountability Act. Informed consent was obtained from all extending equidistant from the fovea-BMO axis were selected participants.12 and included in the analysis (Fig. 1A1).8 Study Subjects Analysis of b-Zone Parapapillary Atrophy Established POAG patients who had good-quality OCT-A images The PPA region was evaluated using the Spectralis software (Angiovue; Optovue, Inc., Fremont, CA, USA) and radial ONH feature that facilitated synchronous viewing of the color- images using both spectral-domain OCT (SD-OCT) (Spectralis; converted infrared fundus image and the selected location on Heidelberg Engineering GmbH, Heidelberg, Germany) and the OCT scan.6–8 The presence of the bPPA was defined as an swept-source OCT (SS-OCT) images (DRI-OCT; Topcon, Tokyo, area without the RPE. cPPA was defined as an area with the Japan) were enrolled. All subjects completed an ophthalmo- exposed Elschnig’s ring between the optic disc boundary and logic examination, including assessment of best corrected the BM tips. Both bPPA and cPPA were required to have a visual acuity, refractive error, slit-lamp biomicroscopy, intraoc- temporal width ‡100 lm on at least one radial OCT scan image ular pressure (IOP) measurement with Goldmann applanation as measured by the built-in caliper of the Spectralis OCT (Fig. tonometry, gonioscopy, central corneal thickness (CCT) 1A1, B1).8,9 The presence of bPPA and cPPA was determined measured with ultrasound pachymetry (DGH Technology independently by two experienced observers (MHS and PICM) Inc., Exton, PA, USA), axial length measured by the IOL Master who were masked to patients’ clinical information.8,9 Dis- (Carl Zeiss Meditec, Dublin, CA, USA), dilated fundus agreements were resolved by consensus between the two examination, simultaneous stereophotography of the optic observers. If consensus could not be reached, the subject was disc, standard automated perimetry (Humphrey Field Analyzer, excluded from the analysis. 24-2 Swedish interactive threshold algorithm; Carl Zeiss Eyes with bPPA were divided into two groups according to Meditec), SD-OCT, OCT-A, and SS-OCT. Perimetry and all the presence of cPPA (eyes with and without cPPA). The two imaging tests were conducted within a 6-month period.12 groups were matched for the VF mean deviation (MD) to Systolic and diastolic blood pressure (BP) was measured at the minimize the influence of glaucoma severity on the deep-layer height of the heart with an Omron Automatic BP instrument microvasculature dropout.12,21 Specifically, patients with cPPA (Model BP791IT; Omron Healthcare, Inc., Lake Forest, IL, were matched to patients without cPPA into three groups USA). Mean ocular perfusion pressure (MOPP) was calculated based on the severity of their VF damage, (18 early POAG [MD according to the following formula: MOPP ¼ 2 3 (mean arterial = > 6 dB], 12 moderate POAG [12 dB MD 6 dB], and pressure IOP), where mean arterial pressure (MAP) = DBP þ seven advanced POAG [MD < 12 dB]) by using a frequency- matching method. For specific analyses, eyes with cPPA were 3 (SBP DBP). Presence of an optic disc hemorrhage (DH) was = 1 defined as an isolated splinter or flame-shaped hemorrhage on further classified into two subgroups: (1) those with discon- tinuous BM (PPA with some BM present) and (2) those lacking the ONH based on standardized review of annually acquired BM (PPA in which BM was absent throughout the entire optic disc stereophotographs.12 area).6,8–10 In addition, focal cPPA was defined as cPPA To be included in the current study, POAG patients were localized to the superior or inferior hemiretina and not required to have visible bPPA on fundus imaging with a involving the fovea-BMO axis (Fig. 1A1). temporal width ‡100 lm on at least one radial scan measured The bPPA and cPPA width were measured by the two by the built-in caliper of the SD-OCT, BVCA ‡20/40, and open observers (MHS and PICM) as the distance between the angles by gonioscopy.12 Subjects with a history of ocular temporal optic disc boundary and the temporal margin of the intervention (except for uncomplicated cataract or glaucoma RPE and BM tips, respectively, using the built-in caliper tool of surgery), intraocular diseases (e.g., diabetic retinopathy or the Spectralis SD-OCT. The average of bPPA and cPPA width nonglaucomatous optic neuropathy), or systemic diseases measured by the two observers at six radial scans, for which (e.g., stroke or pituitary tumor) that could influence the study the center was located at the fovea-BMO axis, was calculated results were excluded. Those with systemic hypertension (HT) (Fig. 1A1, B1).8 If the temporal margin of the ONH or bPPA was and diabetes mellitus (DM) were included unless they were not well visualized, adjacent radial scans 158 apart were used diagnosed to have diabetic or hypertensive retinopathy. for the measurement. bPPAþBM width was calculated as the Subjects with unreliable visual field (VF) or poor-quality difference between the bPPA and cPPA width. imaging tests were also excluded.12 POAG was defined as the presence of glaucomatous optic nerve damage (i.e., the presence of focal thinning, notching, OCT-A Imaging localized or diffuse atrophy of retinal nerve fiber layer) and The Angiovue incorporated in the Avanti SD-OCT system compatible repeated VF damage. Glaucomatous VF damage provides noninvasive visualization of the vasculature of various was defined as a VF outside normal limits on Glaucoma user-defined retinal layers by using the motion contrast Hemifield Test or pattern standard deviation (PSD) outside 95% technique and split-spectrum amplitude-decorrelation angiog- normal limits confirmed on two consecutive, reliable (20% raphy method. Details have been described in else- fixation losses, 15% false positives and false negatives) tests.12 where.12,13,15–17,22–24 Based on the quality review according to a standard protocol established by the Imaging Data SD-OCT Imaging of b-Zone Parapapillary Area Evaluation and Analysis (IDEA) Reading Center, OCT-A images with poor image quality, as defined by the following criteria, Spectralis SD-OCT software (Glaucoma Module Premium were excluded: (1) a signal strength index <48 (1 ¼ minimum, Edition, version 1.7.0.0; Heidelberg Engineering GmbH) was 100 ¼ maximum), (2) poor clarity, (3) residual motion artifacts used to visualize the ONH, including the PPA area, using a 939- visible as irregular vessel pattern or disc boundary on the mm-sized rectangle centered on the ONH (Fig. 1A1, B1). enface angiogram, (4) local weak signal, (5) segmentation Details were described elsewhere.19,20 Briefly, 24 consecutive errors of the retinal nerve fiber layer (RNFL) and choroidal radial equidistant B-scans were acquired. Each B-scan, sub- layer. The delineation of disc margin was reviewed for accuracy tending 158, starting from the fovea-BM opening (BMO) axis and adjusted manually as necessary according to standard was automatically determined by the device. From the 24 radial protocols.12 Vessel density (%) of the microvasculature located scans, six good-quality radial scans (quality score > 15) in the RNFL was calculated as the proportion of measured area Deep-Layer Microvasculature Dropout and PPA IOVS j April 2018 j Vol. 59 j No. 5 j 1998 FIGURE 1. OCT-A–derived deep-layer microvasculature dropout according to the microstructure of bPPA. (A) Right eye of 70-year-old POAG patient with bPPA devoid of the BM (cPPA) and (B) right eye of 87-year-old POAG patient with bPPA with bPPAþBM, but without cPPA. (A1, B1) Right images are B-scans obtained at locations indicated by a white vertical arrow of the color-converted fundus images. Six radial B-scans (white arrows) of the SD-OCT centered on the fovea-BM opening (BMO) axis (white horizontal arrow) were selected, and temporal margins of the bPPAþBM indicating RPE tips (red dots and black arrowheads), cPPA indicating BM termination (sky blue dots and blue arrows), and optic disc (white arrowheads) were delineated. Note that inferior localized cPPA not involving the fovea-BMO axis was present in (A1), while bPPAþBM with intact BM occupied the entire bPPA area in (B1). (A2, B2) En face (upper) and horizontal (lower) B-scans of choroidal layer vessel density maps of the OCT-A. Green solid lines indicate locations of B-scans. Well demarcated deep-layer microvasculature dropout (yellow arrowheads) within the cPPA was observed in (A2), whereas deep-layer microvasculature was relatively preserved (green arrowheads) in (B2). (A3) The two eyes did not show notable difference in the degree of VF damage. occupied by flowing blood vessels on the ONH 4.5 3 4.5-mm were aligned by registering images to large vessels (Fig. 1A1, field of view images centered on the optic disc.12,15,16 A2). Circumpapillary vessel density (cpVD) was calculated in a region defined as a 750-lm-wide elliptical annulus extending SS-OCT Imaging from the optic disc boundary based on 3608 global area.12,15,16 The optic disc was imaged with the Topcon DRI SS-OCT device to determine the presence of focal lamina cribrosa (LC) defects Dropout of the Deep-Layer Microvasculature in the and to measure choroidal thickness. Details have been Parapapillary Atrophy described elsewhere.12,25–27 Both en face and horizontal SS- OCT images covering a 12 3 9-mm cube centered on the Details for determining the presence of deep-layer microvas- posterior pole were obtained using a three-dimensional raster culature dropout within the bPPA is described elsewhere.12 scan (wide-field protocol) consisting of 256 serial horizontal B- Briefly, two independent observers (MHS and PICM) masked to scans.12,25–27 the patients’ baseline characteristics and optic disc features Poor-quality images with motion artifacts, quality score qualitatively analyzed the bPPA area on 4.5 3 4.5-mm-sized <50, clipped or poorly focused scans, poorly visible LC, or the choroidal layer vessel density map and the infrared fundus segmentation failure of the choroidal layer were exclud- images acquired at the same positions. Discrepancies between ed.12,25–27 Poor visibility of the LC was defined as <70% the two observers were resolved by consensus, or if consensus visibility of the anterior laminar surface within the BM could not be reached, the subject was excluded from the opening12,16 and segmentation failure of choroid as >25% analysis.12 A parapapillary deep-layer microvasculature drop- discordance between the visual inspection and the automated out was defined as a complete loss of the choriocapillaris or identification of the BM and the chorioscleral interface.12,25,26 the microvasculature within the scleral flange on both Based on the horizontal and enface SS-OCT images, horizontal and enface choroidal layer vessel density maps presence of focal LC defects was determined as laminar holes (Fig. 1A2).12 To avoid false positives, dropout was required to or laminar disinsertions violating the normal U- or W-shaped be present in at least four consecutive horizontal scans and also contour of the anterior laminar surface by the two observers to be ‡200 lm in diameter on at least one scan.12 To avoid (MHS and PICM) masked to the patients’ clinical informa- false negatives, reflectance or shadowing of the large vessels tion.12,16,28–34 The subject was excluded from the analysis if on the horizontal and en face images were excluded from the consensus between the two observers could not be reached. qualitative review.12 For determining the presence of deep- To be classified as a LC defect, the size of the focal LC defect layer microvasculature dropout within the cPPA in eyes with was required to be ‡100 lm in diameter and >30 lm in depth both dropout and cPPA, Spectralis SD-OCT and OCT-A images in at least two consecutive scans.12,16,28–32 These criteria were Deep-Layer Microvasculature Dropout and PPA IOVS j April 2018 j Vol. 59 j No. 5 j 1999 used to reduce the possibility that the LC defects were (54.1% 6 6.1% versus 50.2% 6 9.3% for upper nasal cpVD and identified due to the hyporeflective vascular shadowing on the 55.4% 6 10.1% versus 50.2% 6 9.3% for inferonasal cpVD; P < en face SS-OCT images and the disc photographs.12,16,34 0.05) in eyes with cPPA compared to eyes without cPPA. For all Total choroidal thickness was derived from the average other RNFL and cpVD variables, the two groups were not choroidal thickness values from each of 108 locations from a 1- different (all P > 0.10). mm2-sized grid on the 12 3 9-mm wide-field SS-OCT images using standard SS-OCT software.12,26 Interobserver Agreement for the Measurement Data Analysis Interobserver agreement for determining the cPPA, cPPA with discontinuous BM, focal cPPA, deep-layer microvasculature Clinical characteristics, ONH morphologic parameters, and dropout, and focal LC defect were excellent (j ¼ 0.86, 95% OCT-A–derived parameters were compared between eyes confidence interval [CI] 0.75–0.98, P < 0.001 for cPPA; j ¼ with and without cPPA. For continuous variables, Student’s t- 0.89, 95% CI 0.69–1.00, P < 0.001 for cPPA with discontin- test and Mann-Whitney U test were used, depending on the uous BM; j ¼ 0.87, 95% CI 0.63–1.00, P < 0.001 for focal cPPA; normality test results. For categorical variables, the v2 test j ¼ 0.86, 95% CI 0.74–0.98, P < 0.001 for dropout; and j ¼ was performed.12 Univariable and multivariable logistic 0.82, 95% CI 0.70–0.94, P < 0.001 for focal LC defect).36 Based regression analyses were performed to determine the on the Bland-Altman plot, there was good agreement between association between the parapapillary deep-layer microvascu- the two observers in the bPPA and cPPA width as follows: the lature dropout and the bPPA microstructure. Variables with a mean differences between the two observers were 21.5 lm P value of <0.10 in the univariable analyses were included in (95% CI, 4.4–38.6 lm) for bPPA width and 42.3 lm (95% CI, the multivariable logistic regression to adjust potential 21.2–63.4 lm) for cPPA width, respectively; the 95% CI of the confounding factors in evaluating association between the limits of agreement for bPPA width was 123.3 to 166.3 lm deep-layer microvasculature dropout and bPPA microstruc- (95% CI of the upper limits, 136.9–195.6 lm; lower limits, ture. Interobserver agreement in determining the presence of 152.6 to 93.9 lm), and for cPPA width was 81.6 to 166.2 the bPPA and cPPA, microvasculature dropout, and focal LC lm (95% CI of the upper limits, 129.9–202.6 lm; lower limits, defects were assessed using the j coefficient.35,36 Interob- 118.0 to 45.3 lm) (Fig. 2). server agreement in measuring the bPPA and cPPA width was assessed using Bland-Altman analysis. Statistical software (MedCalc; Med-Calc, Inc., Mariakerke, Belgium) was used Deep-Layer Microvasculature Dropout and ONH for statistical analyses, and the a level (type I error) was set at Morphologic Parameters in Eyes With and Without 0.05. cPPA The ONH morphologic parameters measured by Spectralis SD- RESULTS OCT and presence of the parapapillary deep-layer microvascu- lature dropout were compared between eyes with and without Study Population cPPA (Table 2). Eyes with cPPA had a significantly higher prevalence of the deep-layer microvasculature dropout (75.7% One hundred forty eyes of 140 consecutive POAG DIGS versus 40.8%; P ¼ 0.004), larger bPPA width (411.4 6 211.5 vs. patients who were evaluated for eligibility were included in 277.4 6 97.8 lm; P < 0.001), and smaller bPPAþBM width this report. Of these 140 eyes, 27 were excluded for the (180.3 6 120.1 vs. 277.4 6 97.8 lm; P < 0.001). The two following reasons: (1) poor-quality SD-OCT images (n ¼ 9), (2) groups were not significantly different with respect to the an absence of bPPA (n ¼ 11), and (3) temporal bPPA width BMO area (P ¼ 0.947) and fovea-BMO angle (P ¼ 0.900). Among <100 mm (n ¼ 7). Among the remaining 113 eyes of 113 28 eyes with both cPPA and deep-layer microvasculature patients, 11 eyes were excluded due to poor OCT-A, nine eyes dropout, 26 eyes (92.9%) had cPPA areas containing dropouts due to poor SS-OCT images, and one eye due to failure to reach the consensus between observers for the determination of the (Fig. 1A1). deep-layer microvasculature dropout. A final sample of 92 eyes was available for analysis; from this sample, 37 eyes with cPPA bPPA Microstructure and Deep-Layer were matched for severity of VF damage by the frequency- Microvasculature Dropout matching method with 37 eyes without cPPA. Six of 37 eyes (16.2%) had cPPA lacking BM, whereas the remaining 31 eyes Univariable and multivariable logistic regression analyses (83.8%) had discontinuous BM. were used to evaluate the association between the width of Clinical characteristics and presence of the deep-layer bPPA, cPPA, and bPPAþBM and presence of the cPPA and microvasculature dropout of the POAG patients (37 with and parapapillary deep-layer microvasculature dropout (Tables 37 without cPPA) were compared (Table 1). Eyes with and 3–6). without cPPA were not significantly different with respect to In the univariable analysis (Table 3), parapapillary deep- sex; CCT; ethnicity; presence of diabetes and systemic layer microvasculature dropout was significantly associated hypertension; antihypertensive and diabetes medication; num- with the longer bPPA width (odds ratio [OR], 1.01; P ¼ ber of glaucoma medications; IOP; systolic and diastolic BP 0.0008), cPPA presence (OR, 4.08; P ¼ 0.004), longer cPPA MOPP; presence of the DH, VF MD, VF PSD; presence of the width (OR, 1.01; P ¼ 0.0052), lower cpVD (OR, 1.16; P < focal LC defect; and total choroidal thickness (all P > 0.10). 0.001), worse VF MD (OR, 1.24; P < 0.001), presence of the Eyes with cPPA were more myopic and had longer axial lengths focal LC defect (OR, 3.18; P ¼ 0.017), thinner total choroidal than those without cPPA (2.4 6 2.5 vs. 0.5 6 1.6 diopter thickness (OR, 1.01; P ¼ 0.025), and longer axial length (OR, [D] for spherical equivalent and 25.2 6 1.4 vs. 24.0 6 1.0 mm 1.49; P ¼ 0.036). Age; sex; race; CCT; IOP; systolic and for axial length; P < 0.05). Subjects who had eyes with cPPA diastolic BP; MOPP; prevalence of the DM, HT, and DH; BMO were younger than those without cPPA with marginal opening area; fovea-BMO angle; and bPPAþBM width were not significance (70.0 6 10.9 vs. 74.8 6 11.9 years; P ¼ 0.073). significantly associated with microvasculature dropout (all P > Upper nasal and inferonasal cpVD were significantly higher 0.10). Deep-Layer Microvasculature Dropout and PPA IOVS j April 2018 j Vol. 59 j No. 5 j 2000 TABLE 1. Comparison of the Demographics and Test Results Between POAG Patients According to the Presence of the bPPA Devoid of the BM (cPPA) Eyes With cPPA, 37 Eyes, Eyes Without cPPA, 37 Eyes, Variables 37 Patients 37 Patients P Value Age, y 70.0 6 10.9 74.8 6 11.9 0.073* Sex, male/female 18/19 20/17 0.816† Spherical equivalent, D 2.4 6 2.5 0.5 6 1.6 <0.001* Axial length, mm 25.2 6 1.3 24.0 6 1.0 <0.001* CCT, lm 534.8 6 55.4 530.7 6 40.9 0.720* Ethnicity, Asian/European/African descent 6/28/3 4/24/9 0.157† Self-reported history of diabetes, n (%) 0 (0) 4 (10.8) 0.123† Self-reported history of hypertension, n (%) 12 (32.4) 18 (48.6) 0.163† Antihypertensive medication, n (%) 10 (27.0) 14 (37.8) 0.456† Diabetes medication, n (%) 0 (0) 3 (8.1) 0.239† Topical glaucoma medications, n 0.225† 0 8 14 1 17 16 >1 12 7 Topical medications, n 0.360† Prostaglandin analogues 23 20 b-antagonists 10 3 Carbonic anhydrase inhibitors 10 4 a-1 agonist 6 5 IOP, mm Hg 14.5 6 4.5 13.3 6 5.0 0.179‡ Systolic BP, mm Hg 122.0 6 15.0 130.2 6 12.5 0.027‡ Diastolic BP, mm Hg 75.9 6 9.8 77.4 6 11.2 0.546* MOPP, mm Hg 61.5 6 13.1 59.6 6 11.2 0.499‡ DH, n (%) 9 (24.3) 3 (8.1) 0.115† VF MD, dB 7.47 6 5.97 7.92 6 7.00 0.974‡ VF PSD, dB 7.95 6 4.23 6.45 6 4.02 0.144‡ cpRNFL thickness, lm Global area 69.8 6 11.0 69.3 6 11.6 0.828* Upper temporal 58.4 6 15.6 57.3 6 13.4 0.746* Upper nasal 64.3 6 11.3 60.3 6 13.4 0.164* Lower nasal 59.1 6 9.9 57.0 6 10.3 0.380* Lower temporal 51.3 6 11.7 53.4 6 9.4 0.393* Superotemporal 93.4 6 22.7 88.8 6 18.4 0.341* Superonasal 82.7 6 16.9 77.2 6 17.2 0.167* Inferonasal 75.1 6 17.5 77.7 6 20.9 0.566* Inferotemporal 74.7 6 23.3 82.5 6 24.0 0.163* Whole-image vessel density, % 46.5 6 5.3 45.0 6 5.5 0.226* Circumpapillary vessel density, % Global area 54.0 6 6.2 53.0 6 6.6 0.514* Upper temporal 58.8 6 9.7 58.1 6 8.3 0.556‡ Upper nasal 54.1 6 6.1 50.2 6 9.3 0.013* Lower nasal 52.1 6 6.7 51.6 6 7.4 0.756* Lower temporal 55.9 6 8.4 55.5 6 7.2 0.810* Superotemporal 55.6 6 9.6 53.6 6 8.8 0.365* Superonasal 54.8 6 6.1 52.3 6 7.3 0.107* Inferonasal 55.4 6 10.1 50.2 6 9.3 0.024* Inferotemporal 48.6 6 10.5 52.4 6 11.1 0.133* Focal LC defect, n (%) 18 (48.6) 19 (51.4) 0.829* Total choroidal thickness, lm 137.1 6 45.9 159.9 6 64.7 0.158‡ Values are shown in mean 6 standard deviation. Statistically significant values are shown in bold. D, diopter; cpRNFL, circumpapillary retinal nerve fiber layer. * The comparison was performed using independent samples t-test. † The comparison was performed using v2 test. ‡ The comparison was performed using Mann-Whitney U test. In order to avoid issues of multicollinearity in the cPPA Presence and Deep-Layer Microvasculature multivariable analysis, we evaluated the correlations between Dropout covariates. We found that VF MD, cpVD, and presence of the focal LC defects were significantly associated with one another. Multivariable logistic regression analysis demonstrated that For this reason, the correlated variables were included in the cPPA presence remained as a significant factor associated with multivariable model separately to avoid issues of multicolli- the presence of dropout after adjusting for axial length, total nearity. choroidal thickness, and VF MD (OR, 5.34; P ¼ 0.012) (Table Deep-Layer Microvasculature Dropout and PPA IOVS j April 2018 j Vol. 59 j No. 5 j 2001 FIGURE 2. Bland-Altman plots showing the width of bPPA (A) and cPPA (B) of the two observers. The solid lines represent the mean difference, and the dashed lines represent the 95% limits of agreement (LOA). 4). Similarly, cPPA presence remained as a significant factor Eyes with focal cPPA had significantly shorter axial length than associated with deep-layer microvasculature dropout in models the remaining 32 eyes with cPPA involving the fovea-BMO axis when focal LC defects (OR, 3.75; P ¼ 0.030) and cpVD (OR, (23.7 6 0.80 vs. 25.5 6 1.3 mm, P ¼ 0.005; independent t- 5.67; P ¼ 0.009) each were included in the multivariable test). models instead of VF MD (Table 4). bPPA Width and Deep-Layer Microvasculature cPPA Width and Deep-Layer Microvasculature Dropout Dropout bPPA width was not significantly associated with the deep-layer Longer cPPA width also remained as a significant factor microvasculature dropout after adjusting for axial length, total associated with deep-layer microvasculature dropout after choroidal thickness, and VF MD (P ¼ 0.176) (Table 6). Similar adjusting axial length, total choroidal thickness, and VF MD patterns were observed in the multivariable analysis when (OR, 1.01; P ¼ 0.039) (Table 5). Similar patterns were observed focal LC defect (P ¼ 0.112) and cpVD (P ¼ 0.166) were in the multivariable analysis when cpVD was included instead included instead of VF MD (Table 6). In all multivariable logistic of VF MD (OR, 1.01; P ¼ 0.048). When focal LC defect was regression analyses, worse VF MD was significantly associated with the deep-layer microvasculature dropout (all P < 0.05), included instead of VF MD, cPPA width was marginally while axial length and total choroidal thickness were not significant (OR, 1.01; P ¼ 0.073) (Table 5). significantly associated with the dropout (all P > 0.10) (Tables 4–6). Focal cPPA and Deep-Layer Microvasculature Dropout DISCUSSION Five of 37 eyes (13.5%) with cPPA had focal cPPA not involving the fovea-BMO axis, and all of them had deep-layer microvas- This study found that glaucomatous eyes with cPPA had a culature dropout located within the cPPA region (Fig. 1A1). significantly higher prevalence of parapapillary deep-layer microvasculature dropout than those with bPPAþBM (75.7% versus 40.8%, P ¼ 0.004; v2 test). Furthermore, parapapillary TABLE 2. Comparison of the ONH Morphologic Parameters Measured deep-layer microvasculature dropout was positively associated by Spectralis SD-OCT and Presence of the Parapapillary Deep-Layer Microvasculature Dropout Measured by OCT-A Between Eyes With and with the presence and longer width of the cPPA even after Without cPPA According to the Presence of the bPPA Devoid of the BM adjusting for other potentially confounding factors such as axial length, choroidal thickness, glaucoma severity, and Eyes Eyes presence of focal LC defects.12 However, width of the bPPAþBM With cPPA, Without cPPA, was not associated with deep-layer microvasculature dropout. 37 Eyes, 37 Eyes, P These findings suggest that parapapillary deep-layer microvas- Variables 37 Patients 37 Patients Value culature dropout may be associated with a continuum of cPPA with exposed scleral flange ranging from completely present to BMO area, mm2 2.1 6 0.6 2.1 6 0.5 0.947* completely absent but not with the area of bPPAþBM with Fovea-BMO angle, deg 7.6 6 3.9 7.7 6 4.6 0.900* atrophic change of the RPE. bPPA width, lm 411.4 6 211.5 277.4 6 97.8 <0.001† Our previous study12 showed that deep-layer microvascu- bPPAþBM width, lm 180.3 6 120.1 277.4 6 97.8 <0.001† lature dropout within the bPPA was associated with more Presence of the deep- 28 (75.7) 15 (40.8) 0.004‡ advanced disease status, presence of a focal LC defect, reduced layer microvasculature superficial microvasculature, thinner choroidal thickness, and dropout, % lower diastolic BP. However, in the previous study, the * The comparison was performed by using independent samples t- association between the dropout and microstructure of bPPA test. was not evaluated.12 The current study demonstrated that † The comparison was performed by using Mann-Whitney U test. cPPA area was significantly associated with the presence of ‡ The comparison was performed by using v2 test. deep-layer microvasculature dropout. These results are consis- Deep-Layer Microvasculature Dropout and PPA IOVS j April 2018 j Vol. 59 j No. 5 j 2002 TABLE 3. Univariate Logistic Regression Evaluating Factors Associated presence and width of the cPPA may be associated with slower With the Presence of Parapapillary Deep-Layer Microvasculature progression of glaucoma9,10 and with studies suggesting that Dropout (n ¼ 74) deep-layer microvasculature dropout is associated with a more Univariate Model advanced disease status.11,12 Also, the presence and width of the cPPA is known to be associated with axial elongation of the Odds Ratio, P eye globe.6,7 Therefore, as axial globe elongation is halted with Variables 95% CI Value aging, the mechanical stress due to scleral stretching may also be relieved. Possible explanations for the discrepancies among Age, per 1 y older 1.02, 0.98–1.06 0.418 studies may be attributed to differences of the study Female vs. male 2.17, 0.84–5.58 0.106 population and definition regarding the microstructure of the Non-white race vs. white 1.33, 0.49–3.65 0.577 PPA.6,7 In the current study, glaucomatous eyes with cPPA had CCT, per 1 lm thinner 1.01, 1.00–1.02 0.260 significantly longer axial lengths, larger bPPA width, and IOP, per 1 mm Hg lower 1.09, 0.98–1.20 0.109 smaller BMO area than those without cPPA. In a univariable Systolic BP, per 1 mm Hg higher 1.00, 0.97–1.04 0.782 regression for determining factors associated with the deep- Diastolic BP, per 1 mm Hg lower 1.04, 0.99–1.09 0.113 layer microvasculature dropout, axial length and bPPA width MOPP, per 1 mm Hg higher 1.02, 0.98–1.06 0.375 remained as associated factors as well as the presence and Diabetes, absence 1.50, 0.19–0.20 0.695 width of cPPA. However, in multivariable regression, only the Hypertension, absence 1.21, 0.47–3.12 0.687 width and presence of the cPPA were significantly associated DH, absence 1.06, 0.30–3.71 0.931 with deep-layer microvasculature dropout; axial length and Circumpapillary vessel density, 1.16, 1.05–1.28 <0.001 bPPA width, therefore, were excluded in most models. One per 1% lower possible explanation for these results is a relatively small VF MD, per 1 dB worse 1.24, 1.09–1.42 <0.001 number of eyes with high myopia (axial length ‡ 26.5 mm or Focal LC defect, detection 3.18, 1.22–8.39 0.017 spherical equivalent ‡ 6.0 D) (n ¼ 7) and older patients with Total choroidal thickness, 1.01, 1.00–1.02 0.025 cPPA (72.4 years) than those of previous studies (age ranging per 1 lm thinner between 42.9 and 58.9 years).6,9,10 Therefore, there were Axial length, per 1 mm longer 1.49, 1.00–2.21 0.036 proportionately fewer cPPA eyes that completely lacked BM BMO opening area, per 1 1.53, 0.54–4.29 0.421 (16.2%, n ¼ 6) than in previous studies (percentage of cPPA mm2 larger completely lacking BM ranging between 18.8% and Fovea-BMO angle 0.99, 0.89–1.11 0.898 35.6%).6,9,10 Second, a pathogenic process other than axial bPPA width, per 1 lm larger 1.01, 1.00–1.01 <0.001 elongation may contribute to the development of a certain type bPPAþBM width, per 1lm larger 1.00, 1.00–1.00 0.714 of bPPA devoid of BM and vascular disruption. In this study, cPPA, presence 4.08, 1.51–11.03 0.004 five (13.5%) of 37 eyes with cPPA had focal cPPA that does not cPPA width, per 1 lm larger 1.01, 1.00–1.01 0.005 involve the fovea-BMO axis, and their axial length was shorter Statistically significant values are shown in bold. bPPAþBM, cPPA. than that of the remaining 32 eyes with cPPA involving the fovea-BMO axis (23.7 vs. 25.5 mm, P ¼ 0.005; independent t- test). In addition, eyes with focal cPPA in our study have tent with previous studies suggesting that penetrating branch- relatively shorter axial lengths (mean ¼ 23.7 mm) than those es of the short posterior ciliary artery passing through the with cPPA in previous studies (mean axial length ranging scleral flange may be subject to increased mechanical stress between 25.74 and 26.42 mm).6,9,10 It is interesting that all and strain.37,38 Therefore, cPPA with exposed scleral flange eyes with focal cPPA had deep-layer microvasculature dropout. may be a sign of increased IOP-related scleral tension that leads Given that axial growth of the globe leads to the temporal to disruption of the deep-layer microvasculature. Further dragging of the ONH,39 it is less likely that cPPA induced by measurement of the IOP-related stress or strain and subsequent axial elongation does not involve the fovea-BMO axis, a central vascular changes according to the presence and continuum of horizontal axis of the ONH. Therefore, focal cPPA not involving the exposed scleral flange are warranted to elucidate this the fovea-BMO axis may reflect a local alteration of the BM and speculation. loss of an adjacent deep-layer microvasculature derived by However, how the relationship between the cPPA and mechanisms other than those from axial elongation. However, parapapillary deep-layer microvasculature dropout relates to the role of focal cPPA and its relationship with the deep-layer the pathophysiology of glaucoma is still unclear. The current microvasculature disruption in the pathophysiology of glauco- results do not concur with other studies suggesting that the ma can only be confirmed by future studies with a larger TABLE 4. Multivariate Logistic Regression Testing the Association Between the Parapapillary Deep-Layer Microvasculature Dropout and the Presence of bPPA Devoid of the BM (cPPA) (n ¼ 74) Multivariate Model 1 Multivariate Model 2 Multivariate Model With VF MD, AXL, With Focal LC Defect, 3 With cpVD, AXL, and CT Included AXL, and CT Included and CT Included Odds Ratio, Odds Ratio, Odds Ratio, Variables 95% CI P Value 95% CI P Value 95% CI P Value cPPA, presence 5.34, 1.46–19.57 0.012 3.75, 1.14–12.33 0.030 5.67, 1.53–20.98 0.009 AXL, per 1 mm longer 1.04, 0.61–1.80 0.877 1.17, 0.70–1.94 0.544 1.09, 0.64–1.85 0.752 CT, per 1 lm thinner 1.01, 1.00–1.02 0.175 1.01, 1.00–1.02 0.228 1.01, 1.00–1.02 0.218 VF MD, per 1 dB worse 1.28, 1.10–1.49 0.001 Focal LC defect, presence 3.67, 1.23–10.96 0.020 cpVD, per 1% lower 1.20, 1.08–1.35 0.001 Statistically significant values are shown in bold. AXL, axial length; CT, total choroidal thickness. Deep-Layer Microvasculature Dropout and PPA IOVS j April 2018 j Vol. 59 j No. 5 j 2003 TABLE 5. Multivariate Logistic Regression Testing the Association Between the Parapapillary Deep-Layer Microvasculature Dropout and the Width of bPPA Devoid of the BM (cPPA) (n ¼ 74) Multivariate Model 2 Multivariate Model 1 With With Focal LC Defect, Multivariate Model 3 With cpVD, VF MD, AXL, and CT Included AXL, and CT Included AXL, and CT Included Odds Ratio, Odds Ratio, Odds Ratio, Variables 95% CI P Value 95% CI P Value 95%CI P Value cPPA width, 1 lm larger 1.01, 1.00–1.01 0.039 1.01, 1.00–1.01 0.073 1.01, 1.00–1.01 0.048 AXL, per 1 mm longer 0.97, 0.55–1.72 0.923 1.10, 0.64–1.88 0.741 1.04, 0.55–1.67 0.878 CT, per 1 lm thinner 1.01, 1.00–1.02 0.150 1.01, 1.00–1.02 0.202 1.01, 1.00–1.02 0.154 VF MD, per 1 dB worse 1.29, 1.10–1.49 0.002 Focal LC defect, presence 3.34, 1.15–9.73 0.027 cpVD, per 1% lower 1.18, 1.06–1.32 0.003 Statistically significant values are shown in bold. number of study subjects with focal cPPA. Further longitudinal vasculature and the adjacent choroidal structure outside the studies with larger numbers of normal and glaucomatous eyes PPA. with high myopia are required to determine whether the rate The present study has several limitations. First, eyes with of glaucoma progression differs according to the axial length, and without cPPA were matched by the severity of glaucoma to type of cPPA, and the presence of deep-layer microvasculature minimize the possibility of selection bias that more severe dropout. glaucoma eyes are more likely to have deep-layer microvascu- The current finding that bPPA width was associated with lature dropout. Therefore, caution is needed in interpreting the the deep-layer microvasculature dropout in univariable regres- study results that cPPA was associated with microvasculature sion analysis, but not in multivariable regression analysis, dropout. However, matching did have an advantage as it made concurs with our previous results.12 Furthermore, bPPAþBM for a more controlled experiment since both deep-layer width was not associated with dropout in univariable microvasculature dropout and presence of the cPPA were regression analysis. However, these results do not correspond known to be associated with the glaucomatous severity.9–12 with previous histologic studies showing that age-related Future studies with larger numbers of glaucomatous eyes with atrophy of the RPE-BM complex, known to be a main typical cPPA completely devoid of BM are warranted. Second, mechanism of the bPPAþBM, was associated with the complete as three devices were used for determining the presence of loss of adjacent choriocapillaris.3,40 Differences across the cPPA in this study, variability of registration across images may studies may be related to differences in study design. The have reduced the strength of the associations. Spectralis SD- present study utilized an in vivo imaging device, whereas OCT and SS-OCT, instruments that enabled good visualization previous studies used histopathologic analysis. Technical limits of the deeper layers, were utilized to visualize the RPE and of the current OCT-A device and qualitative analysis of the BMO tips, choroidal tissue, and presence of focal LC defects, deep-layer microvasculature dropout may also hinder detection whereas Avanti OCT-A was utilized to assess deep-layer of the subtle loss of parapapillary deep-layer microvasculature microvasculature.12 However, the three devices were aligned in this study.12 Further improvement of the OCT-A technique by using large retinal vessels for determining the location of and quantitative analysis of the deep-layer microvasculature is dropout within the cPPA, thereby reducing the likelihood of needed. large misalignment between images.16 Third, it is still unclear Despite controversy over the relationship between the whether optic disc margin based on the infrared fundus image choroidal thickness and deep-layer microvasculature drop- may reflect an anatomically correct structure, since disc out,12,17 the current result concurs with a recently published margin does not uniformly correspond to the BMO-based disc study that choroidal thickness is not related to the presence of margin of SD-OCT images.6,9,19,20,41 This may limit an accurate the deep-layer microvasculature dropout.17 Considering their determination of the RPE and BM and thus may lead to a topographical relationship, it will be important to investigate variation in the measurement of the bPPA, cPPA, and bPPAþBM the association between the parapapillary deep-layer micro- width. However, interobserver agreement for measurement of TABLE 6. Multivariate Logistic Regression Testing the Association Between the Parapapillary Deep-Layer Microvasculature Dropout and bPPA Width (n ¼ 74) Multivariate Model 1 Multivariate Model 2 With VF MD, AXL, With Focal LC Defect, Multivariate Model 3 With and CT included AXL, and CT Included cpVD, AXL, and CT Included Odds Ratio, Odds Ratio, Odds Ratio, Variables 95% CI P Value 95% CI P Value 95% CI P Value bPPA width, per 1 mm larger 1.00, 1.00–1.01 0.176 1.00, 1.00–1.01 0.112 1.00, 1.00–1.01 0.166 AXL, per 1 mm longer 1.25, 0.76–2.03 0.380 1.27, 0.79–2.06 0.323 1.28, 0.78–2.10 0.323 CT, per 1 lm thinner 1.01, 1.00–1.02 0.212 1.01, 1.00–1.02 0.313 1.01, 1.00–1.02 0.233 VF MD, per 1 dB worse 1.24, 1.08–1.43 0.002 Focal LC defect, presence 3.15, 1.09–9.05 0.033 cpVD, per 1% lower 1.16, 1.04–1.29 0.006 Statistically significant values are shown in bold. Deep-Layer Microvasculature Dropout and PPA IOVS j April 2018 j Vol. 59 j No. 5 j 2004 the bPPA and cPPA width was good (Fig. 2), and adjunct usage 11. Akagi T, Iida Y, Nakanishi H, et al. Microvascular density in of the infrared fundus images synchronous to the SD-OCT also glaucomatous eyes with hemifield visual field defects: an helped to accurately determine the RPE and BMO tips. optical coherence tomography angiography study. Am J In conclusion, parapapillary deep-layer microvasculature Ophthalmol. 2016;168:237–249. dropout was significantly associated with the presence and 12. Suh MH, Zangwill LM, Manalastas PI, et al. Deep retinal layer larger width of the bPPA without BM (cPPA) in glaucomatous microvasculature dropout detected by the optical coherence eyes, but not with the width of bPPA with intact BM. These tomography angiography in glaucoma. 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OCT Supported in part by National Institutes of Health/National Eye angiography vessel density in healthy, glaucoma suspects, and Institute Grants P30EY022589, EY11008, EY019869, EY021818, glaucoma. Invest Ophthalmol Vis Sci. 2016;57:OCT451– and an unrestricted grant from Research to Prevent Blindness OCT459. (New York, NY, USA) and the donors of the National Glaucoma 16. Suh MH, Zangwill LM, Manalastas PI, et al. Optical coherence Research, a BrightFocus Foundation. The funding organizations tomography angiography vessel density in glaucomatous eyes had no role in the design or conduct of this research. with focal lamina cribrosa defects. Ophthalmology. 2016;123: Disclosure: M.H. Suh, None; L.M. Zangwill, Carl Zeiss Meditec 2309–2317. (F), Heidelberg Engineering (F), Merck (C), National Eye Institute 17. Lee EJ, Kim TW, Lee SH, Kim JA. Underlying microstructure of (F), Optovue (F), Topcon (F); P.I.C. 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