Position of Central Retinal Vascular Trunk and Preferential Location of Glaucomatous Damage in Myopic Normal-Tension Glaucoma  Kyoung Min Lee, MD, Martha Kim, MD, Sohee Oh, PhD, Seok Hwan Kim, MD  Ophthalmology Glaucoma  Volume 1, Issue 1, Pages 32-43 (July 2018) DOI: 10.1016/j.ogla.2018.05.003 Copyright © 2018 American Academy of Ophthalmology Terms and Conditions

Figure 1 Measurement of central retinal vascular trunk deviation. A, Red-free fundus photograph. A singular retinal nerve fiber layer (RNFL) defect is observed in the inferior hemisphere (between the dotted lines). An infrared image obtained by spectral-domain optical coherence tomography (SD OCT) is transposed to show the margin of the Bruch membrane opening (BMO) and the foveal–BMO axis. Using 24 radial scan images, SD OCT delineates the BMO margin (red dots) and calculates the foveal–BMO axis. B, Magnified view of peripapillary area. The red dots indicate the BMO margin, and the green line indicates the reference line. The angular deviation of the vascular trunk (α) is measured clockwise, with the nasal horizontal midline as 0°. A positive value indicates the superior location and a negative value indicates the inferior location relative to the reference line. The angular location of the RNFL defect (β) is measured clockwise, with the temporal horizontal midline as 0°. A positive value indicates the superior location and a negative value indicates the inferior location relative to the reference line. From the BMO center, the distances are measured to the vascular trunk (a) and to the BMO margin in a same direction (b). The ratio of these distances is defined as the “shift index” (a/b), which is used to measure the extent of shift. C, Disc photograph. The dotted line indicates the location of the SD OCT scan, targeted to the central retinal vascular trunk (arrowhead). D, Cross-sectional image of SD OCT clearly showing emergence of central retinal vascular trunk (arrowhead). Ophthalmology Glaucoma 2018 1, 32-43DOI: (10.1016/j.ogla.2018.05.003) Copyright © 2018 American Academy of Ophthalmology Terms and Conditions

Figure 2 Angular deviation of the vascular trunk deviation from the Bruch membrane opening (BMO) center determining angular location of the retinal nerve fiber layer (RNFL) defect. A–C, Polar plots demonstrate the deviation of vascular trunks (red lines) and the locations of RNFL defects (blue lines). The data on the left eyes are flipped to the right-eye orientation. The shift index of each subject is incorporated into the same length of both red and blue lines. A, Inferior RNFL defect dominant group. B, Superior RNFL defect dominant group. C, Bi-equivalent RNFL defects in both hemispheres group. The mean of the foveal–BMO axis in each group is drawn as a dashed black line. The hemispheric dominancy of glaucomatous damage occurred in the exact opposite hemisphere of LC shift (A, B). All eyes with superonasal LC shift and still inferior to the foveal–BMO axis were associated with inferior RNFL defects (A). In eyes of bi-equivalent RNFL defects, the angular locations of the larger-width RNFL defects are drawn. Eyes with severe shift (shift index = 1.0) were excluded, because we could not define the location of the vascular trunk. Ophthalmology Glaucoma 2018 1, 32-43DOI: (10.1016/j.ogla.2018.05.003) Copyright © 2018 American Academy of Ophthalmology Terms and Conditions

Figure 3 Sample case of mild-shift group. A, Red-free fundus photographs show retinal nerve fiber layer (RNFL) defects (between dotted lines). Infrared funduscopic images of spectral-domain optical coherence tomography (SD OCT) are transposed to show the Bruch membrane opening margin (red dots). B, Magnified view of peripapillary area, showing the superior vascular trunk deviation (red arrow) and the inferior RNFL defect (yellow arrow). C, Disc photograph. The arrowhead indicates the location of the central vascular trunk. The dotted lines indicate the location of SD OCT scans. D, Emergence of central vascular trunk is evident (arrowhead). E, On opposite side of vascular trunk shift, focal lamina cribrosa (LC) defects are observed. A B-scan SD OCT image (left) and the same image with the lines demarcated along the anterior surface of the LC (right; green lines) are presented. Ophthalmology Glaucoma 2018 1, 32-43DOI: (10.1016/j.ogla.2018.05.003) Copyright © 2018 American Academy of Ophthalmology Terms and Conditions

Figure 4 Sample case of mild inferior vascular trunk shift. A, Red-free fundus photograph shows singular superior retinal nerve fiber layer (RNFL) defect (between dotted lines). The infrared funduscopic spectral-domain optical coherence tomography (SD OCT) image is transposed to show the Bruch membrane opening margin (red dots). B, Magnified view of peripapillary area. The vascular trunk is deviated inferiorly (red arrow) and the RNFL defect is in the superior hemisphere (yellow arrow). C, Disc photograph. The arrowhead indicates the vascular trunk. The dotted line indicates the location of the SD OCT scan. D, Emergence of central vascular trunk is evident (arrowhead). Ophthalmology Glaucoma 2018 1, 32-43DOI: (10.1016/j.ogla.2018.05.003) Copyright © 2018 American Academy of Ophthalmology Terms and Conditions

Figure 5 Sample case from moderate-shift group. A, Red-free fundus photograph shows bi-hemispheric, inferior dominant retinal nerve fiber layer (RNFL) defects (between dotted lines). The Humphrey visual field result shows superior arcuate scotoma corresponding to the inferior RNFL defect. The infrared funduscopic spectral-domain optical coherence tomography (SD OCT) image is transposed to show the Bruch membrane opening margin (red dots). B, Magnified view of peripapillary area, showing the angular deviation of the central vascular trunk (red arrow) and the angular location of the RNFL defect (yellow arrow). C, Disc photograph. The arrowhead indicates the location of the central vascular trunk. The dotted line indicates the location of the SD OCT scan. D, B-scan SD OCT image shows exactly where the central vascular trunk emerges (arrowhead). Ophthalmology Glaucoma 2018 1, 32-43DOI: (10.1016/j.ogla.2018.05.003) Copyright © 2018 American Academy of Ophthalmology Terms and Conditions

Figure 6 Sample case from severe-shift group. A, Red-free fundus photograph shows bi-equivalent retinal nerve fiber layer defects in both hemispheres (between dotted lines). The infrared funduscopic spectral-domain optical coherence tomography (SD OCT) image is transposed to show the Bruch membrane opening (BMO) margin (red dots). B, Disc photography could not show emergence of the central vascular trunk. The dotted line indicates the location of SD OCT scan. C, Infrared funduscopic image with delineated BMO margin (red dots). D, Fluorescein angiography image proving vascular trunk position is outside BMO. E, B-scan SD-OCT image showing that tilt could not explain extent of disc change. The BMO plane (red dotted lines), anterior scleral plane (green dotted line), and anterior lamina cribrosa (LC) surface (yellow dotted lines) are delineated for comparison. The LC is not tilted but rather is shifted. Ophthalmology Glaucoma 2018 1, 32-43DOI: (10.1016/j.ogla.2018.05.003) Copyright © 2018 American Academy of Ophthalmology Terms and Conditions

Figure 7 Conditional inference tree analysis. By a recursive partitioning method, this analysis allows unbiased testing of both categorical and continuous variables without any statistical assumptions. The angular location of retinal nerve fiber layer (RNFL) defects (RNFLD) is determined according to the angular deviation of vascular trunk and the shift index. Superior vascular trunk deviation is associated with dominant RNFL defect in the inferior hemisphere, whereas severe vascular trunk deviation is associated with bi-equivalent bi-hemispheric RNFL defects. Black indicates subjects with inferior-dominant RNFL defects, red indicates subjects with superior-dominant RNFL defects, and green indicates subjects with bi-equivalent bi-hemispheric RNFL defects. A red dashed line is drawn along an angular deviation of vascular trunk of −0.37°, and a black dashed line is drawn along a shift index of 0.883 to visualize the distribution of each group according to these 2 variables. The eyes with severe shift (shift index = 1.0) are not drawn in the scatterplot because we could not locate the angular deviation of vascular trunk in those cases. Ophthalmology Glaucoma 2018 1, 32-43DOI: (10.1016/j.ogla.2018.05.003) Copyright © 2018 American Academy of Ophthalmology Terms and Conditions

Figure 8 Effect of lamina cribrosa (LC) shift on location of glaucomatous damage. A, B, Red dotted circles indicate Bruch membrane opening margin, black solid circles indicate LC, portions with apricot color represent visible part of LC via funduscopic examination (clinical disc margin), and red ellipsoids indicate superotemporal and inferotemporal pores that are more susceptible to glaucomatous damage. A, When the shift axis collides with the radial collagen fiber orientation, the LC shift could not propagate easily, which resulted in only a mild shift. The vulnerable pores in the direction opposite to the LC shift might be stretched or broken, which makes them more susceptible to glaucomatous damage (marked with blue line). B, When the shift axis is in the radial collagen fiber orientation, LC could be shifted more easily. Then, the vulnerable pores in both hemispheres will be equally affected by glaucomatous damage (marked with blue lines). Ophthalmology Glaucoma 2018 1, 32-43DOI: (10.1016/j.ogla.2018.05.003) Copyright © 2018 American Academy of Ophthalmology Terms and Conditions

Figure S1 Measurement of angular location of each parapapillary atrophy (PPA) and optic nerve head parameters. A: Disc photograph. B: Infrared fundus photograph with demarcated Bruch membrane opening (BMO) margin (red dots). The ovality index is defined as the ratio between the largest and smallest diameters of the clinical disc margin (v/h). The torsion degree is defined as the deviation of the long axis of the clinical disc margin (orange arrow) from the vertical meridian, defined as the perpendicular line to the foveal–BMO axis. A positive torsion value indicated an inferotemporal torsion, and a negative value indicated a superonasal torsion. C: Red-free fundus photography and infrared image obtained by spectral-domain optical coherence tomography are transposed to show margin of BMO (red dots) and foveal–BMO axis. For each βBM-zone and γ-zone PPA, the point of maximum width is marked from the BMO center (red dot): blue and red arrows, respectively. The angular location of PPA is measured clockwise from the reference line (green line), with the temporal side as 0°. Ophthalmology Glaucoma 2018 1, 32-43DOI: (10.1016/j.ogla.2018.05.003) Copyright © 2018 American Academy of Ophthalmology Terms and Conditions

Figure S2 Conditional inference tree analysis according to hemispheric location of visual field defect. Each visual field was classified into (1) superior visual field defect, (2) inferior visual field defect, and (3) bi-hemispheric visual field defect. For this analysis, we evaluated whether the scotoma cluster (3 abnormal points, with a P value less than 5% probability of being normal and 1 with a P value less than 1% by pattern deviation) exists in superior, inferior, or both hemispheres, separately. Black indicates subjects with superior visual field defect, red indicates subjects with inferior visual field defect, and green indicates subjects with bi-hemispheric visual field defect. A red dashed line is drawn along an angular deviation of vascular trunk of −0.37°, and a black dashed line is drawn along a shift index of 0.883, to visualize the distribution of each group according to these 2 variables. The eyes with severe shift (shift index = 1.0) are not drawn in the scatterplot, because in those cases we could not locate the angular deviation of vascular trunk. As expected, this analysis revealed nearly identical results to those plotted in Figure 7. Ophthalmology Glaucoma 2018 1, 32-43DOI: (10.1016/j.ogla.2018.05.003) Copyright © 2018 American Academy of Ophthalmology Terms and Conditions