Comparison of Retinal Vessel Diameter Between Open-Angle Glaucoma Patients with Initial Parafoveal Scotoma and Peripheral Nasal Step

Comparison of Retinal Vessel Diameter Between Open-Angle Glaucoma Patients With Initial Parafoveal Scotoma and Peripheral Nasal Step

EUNJOO YOO, CHUNGKWON YOO, TAE-EUN LEE, AND YONG YEON KIM

PURPOSE: To compare retinal vessel diameters (RVDs) LTHOUGH INTRAOCULAR PRESSURE (IOP) IS THE between open-angle glaucoma (OAG) patients with most important and only known modifiable risk initial parafoveal scotoma (PFS) and those with initial pe- A factor for glaucoma,1–4 not all patients with ripheral nasal step (PNS). glaucoma show elevated IOP. The Collaborative Normal- DESIGN: Retrospective, cross-sectional study. Tension Glaucoma study reported that 20% of the patients METHODS: We enrolled 151 eyes of 151 patients with with normal-tension glaucoma (NTG) show visual field OAG (83 with normal-tension glaucoma [NTG] and 68 (VF) deterioration, even after a 30% IOP reduction from with primary open-angle glaucoma [POAG]). The pa- baseline.2 Accumulating evidence indicates that, in addi- tients were categorized into the PFS and PNS groups ac- tion to mechanical factors, vascular pathology plays a role cording to the location of the initial visual field (VF) in open-angle glaucoma (OAG). The relationships between defect. Clinical characteristics and RVD indices—central glaucoma and vascular factors, such as migraine,5,6 optic retinal arteriolar equivalent (CRAE) and central retinal disc hemorrhage,7,8 and vasospasm,9 are well established. venular equivalent (CRVE)—were compared between Furthermore, many reports have suggested that glaucoma it- the groups. Subgroup analyses were conducted in the self is associated with the retinal vasculature. A previous NTG and POAG groups. study showed that retinal vessel diameter (RVD) decreases RESULTS: Forty-six patients had PFS and 105 had significantly with increasing glaucoma stage, independently PNS. The CRAE of the PFS group was significantly of the patients’ age.10 Large, population-based, cross- lower than that of the PNS group in all glaucoma pa- sectional studies have corroborated this result.11–13 tients (P [ .001). However, neither the mean devia- Several reports have documented that the location of tion in VF nor that in the average retinal nerve fiber the VF defect can vary according to glaucoma type. For layer thickness showed significant intergroup differ- instance, parafoveal scotomas (PFSs) occur more ences. In the NTG subgroup analysis, the CRAE of frequently in patients with NTG than in those with pri- the PFS group was significantly lower than that of mary open-angle glaucoma (POAG).14–16 This higher the PNS group (P [ .013). Conversely, in the frequency of central VF defect in patients with NTG POAG subgroup analysis, the CRAE in the PFS group suggests that the pathologic mechanism of PFS, unlike did not differ significantly from that in the PNS group that of peripheral VF loss, involves vascular factors. This (P [ .123). postulation has been supported by subsequent studies that CONCLUSIONS: Retinal arteriolar diameter was found a significant relationship between central VF narrower in OAG patients with initial PFS than in defect and vascular risk factors. Park and associates those with initial PNS, especially in the NTG reported that the maximum untreated IOP was lower, group. This suggests that the initial location of the and the frequency of disc hemorrhage detection higher, VF defect may be associated with the vascular mecha- in patients with an initial PFS than in patients with an nism in patients with glaucoma. (Am J Ophthalmol initial peripheral nasal step (PNS).17 Furthermore, the 2017;175:30–36. Ó 2016 Elsevier Inc. All rights prevalence of systemic vascular risk factors, including reserved.) hypotension, migraine, and Raynaud phenomenon, was significantly higher in the PFS group than in the PNS group.17 However, to our knowledge, RVDs have not yet been used to characterize VF defects. Based on the possibility that vascular pathology has an Supplemental Material available at AJO.com. influence on PFS, we hypothesized that RVDs differ ac- Accepted for publication Nov 20, 2016. cording to the location of the initial VF defect in patients From the Department of Ophthalmology, Korea University College of Medicine, Seoul, South Korea (E.Y., C.Y., Y.Y.K.); and Department of with glaucoma. The purpose of this study was to compare Ophthalmology, Chonbuk National University Medical School and the RVD indices between patients with OAG and an Hospital, Jeonju, South Korea (T.-E.L.). initial PFS and those with OAG and an initial PNS. In Inquiries to Yong Yeon Kim, Department of Ophthalmology, Korea University Guro Hospital, 148 Gurodong-ro, Guro-gu, Seoul 08308, addition, we assessed factors related to RVD in patients South Korea; e-mail: [email protected] with glaucoma.

30 © 2016 ELSEVIER INC.ALL RIGHTS RESERVED. 0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2016.11.012 Downloaded for Anonymous User (n/a) at Mercy Hospital St. Louis from ClinicalKey.com by Elsevier on April 02, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. METHODS as confirmed by at least 2 reliable VF test results and with a false-positive error <15%, a false-negative error THIS INVESTIGATION WAS A RETROSPECTIVE ANALYSIS OF <15%, and a fixation loss <20%. On the basis of the 151 patients with OAG who were enrolled from a clinical data from the Namil study,18 the patients with OAG database maintained at the glaucoma clinic of the Korea were categorized into 2 subgroups—NTG and POAG— University Guro Hospital, Seoul, South Korea. To identify depending on the level of untreated IOP. POAG was eligible participants for the study, we reviewed the records defined as OAG with a baseline IOP of >_20 mm Hg, of all patients with established glaucoma who had whereas NTG was defined as an IOP of <20 mm Hg presented to the glaucoma clinic between January 2, throughout the follow-up period. 2012 and March 31, 2014. Ethical approval for this retrospective study was obtained from the hospital’s Institu- VISUAL FIELD CRITERIA FOR PERIPHERAL NASAL STEP tional Review Board, and the study adhered to the tenets AND PARAFOVEAL SCOTOMA: In the glaucoma group, of the Declaration of Helsinki. only patients with an initial PFS or PNS in 1 hemifield, At the initial evaluation, each participant underwent as defined below, were enrolled. Based on a previous 17 a comprehensive ophthalmologic examination, including study, PFS was defined as a glaucomatous VF defect >_ a detailed review of medical and ocular histories, with (1) 3 adjacent points with P < 5% within the central >_ measurement of best-corrected visual acuity, slit-lamp 10 degrees of fixation, (2) 1 point with P < 1% at the biomicroscopy, autorefraction, Goldmann applanation innermost paracentral point, and (3) no VF abnormality tonometry, axial length measurement, central corneal outside the central 10 degrees. In contrast, PNS was defined >_ thickness measurement using a specular microscope, as a glaucomatous VF defect with (1) 3 adjacent points gonioscopic examination, and automated perimetry using with P < 5% in the nasal periphery outside the central the 30-2 Swedish Interactive Threshold Algorithm stan- 10 degrees of fixation, (2) a nasal-most point with P < dard program (Zeiss-Humphrey, San Leandro, California, 1%, and (3) no VF abnormality within the central 10 de- USA). The peripapillary retinal nerve fiber layer (RNFL) grees. In patients in whom both eyes were eligible for the thickness was measured using spectral-domain optical study, 1 eye was randomly chosen for inclusion. coherence tomography (3D OCT-1000 Mark II, software version 3.20; Topcon Corp, Tokyo, Japan). Dilated MEASUREMENT OF RETINAL VESSEL DIAMETER: Using a 30-degree stereoscopic photography and 50-degree red- fundus camera (model FF450 Plus; Carl Zeiss Meditec AG), free photography (model FF450 Plus; Carl Zeiss Meditec we obtained dilated 30-degree stereoscopic optic disc AG, Jena, Germany) were also conducted. photographs centered on the disc. The methodology The inclusion criteria were as follows: age >18 years, used for the measurement of RVD has been described 19–22 best-corrected visual acuity >20/30, spherical equivalent elsewhere. We used IVAN software version 1.3 between 6.0 and þ4.0 diopters, cylinder correction (Department of Ophthalmology and Visual Science, within 63.0 diopters, and at least 2 reliable VF results. University of Wisconsin, Madison, Wisconsin, USA) to The exclusion criteria were as follows: (1) history of ocular obtain the RVD indices. This is a semiautomated trauma or surgery including trabeculectomy or Ahmed software system that can measure the RVD on a digitized valve implantation, but with the exception of uncompli- retinal image. The IVAN program automatically cated cataract surgery; (2) any medial opacity that identified the optic disc and measured the diameter of prevented good-quality optic disc photography or other im- the individual vessels; it then automatically calculated aging tests; (3) history of any retinal disease, such as dia- 2 variables—the central retinal arteriolar equivalent betic retinopathy, retinal vessel occlusion, or epiretinal (CRAE) and the central retinal venular equivalent membrane; (4) optic nerve disease other than glaucoma; (CRVE)—by using the revised Parr-Hubbard formula. and (5) history of a cerebrovascular event that could The vessel equivalents were designed to represent the have affected the VF. average vessel diameter of the eye. Briefly, the 6 largest OAG was diagnosed on the basis of the presence of glau- arterioles and venules, passing completely through a comatous VF loss together with corresponding glaucoma- circumferential zone 0.5 to 1 disc diameter from the optic tous optic disc changes (neuroretinal rim thinning, disc margin, were identified. Then, the vessel equivalents notching, and excavation). Gonioscopy was used to were approximated by using the following formulas: À Á exclude angle closure, rubeosis, and secondary glaucoma. 1=2 Arterioles : W ¼ 0:88 w2 þ w2 A glaucomatous VF change was defined as (1) the consis- 1 2 tent presence of a cluster of 3 points with P < 5% on the À Á 1=2 pattern-deviation map in at least 1 hemifield, including Venules : W ¼ 0:95 w2 þ w2 at least 1 point with P < 1%; (2) glaucoma hemifield test 1 2 results outside of the normal limits; or (3) a pattern stan- where w1,w2, and W are, respectively, the widths of the dard deviation (PSD) beyond 95% of the normal limits, narrower branch, the wider branch, and the parent trunk.

VOL. 175 VESSEL DIAMETERS IN PARAFOVEAL SCOTOMA AND PERIPHERAL NASAL STEP 31

PFS (N ¼ 46) PNS (N ¼ 105) P Value NTG (N ¼ 83) POAG (N ¼ 68) P Value

Age, y 55.02 6 11.80 54.07 6 14.51 .695a 55.55 6 12.65 52.90 6 14.87 .237a Women, no. (%) 19 (41.3%) 50 (47.6%) .473b 41 (49.4%) 28 (41.2%) .313b Family history of glaucoma 4 (8.7%) 10 (9.5%) 1.000c 6 (7.2%) 8 (11.8%) .339b Hypertension 23 (50.0%) 38 (36.2%) .111b 37 (44.6%) 24 (35.3%) .247b Diabetes mellitus 4 (8.7%) 12 (11.4%) .777c 9 (10.8%) 7 (10.3%) .913b Body mass index, kg/m2 23.33 6 2.75 23.51 6 2.74 .726a 23.41 6 2.78 23.50 6 2.71 .848a Axial length, mm 24.43 6 1.29 24.37 6 1.29 .824a 24.31 6 1.40 24.48 6 1.13 .499a Central corneal thickness, mm 528.00 6 40.19 530.68 6 32.16 .682a 526.16 6 36.16 534.34 6 32.33 .171a Intraocular pressure, mm Hg 18.63 6 4.56 18.86 6 4.68 .576d 15.57 6 2.09 22.72 6 3.75 <.001d Disc hemorrhage, no. (%) 2 (4.3%) 2 (1.9%) .390 3 (3.6%) 1 (1.5%) .414 Spherical equivalent, diopters 1.14 6 2.45 1.58 6 3.01 .558d 1.37 6 3.02 1.57 6 2.66 .346d Mean deviation, dB 3.28 6 2.43 2.79 6 1.85 .314d 3.02 6 1.95 2.84 6 2.17 .570d Pattern standard deviation, dB 4.96 6 3.54 3.63 6 2.26 .026d 4.01 6 2.56 4.07 6 3.03 .681d Visual ﬁeld index, % 91.45 6 8.06 96.33 6 3.78 <.001d 94.41 6 5.99 95.60 6 5.43 .104d Average RNFL thickness, mm 91.38 6 14.46 95.58 6 13.55 .091a 93.26 6 13.24 95.57 6 14.68 .237d

NTG ¼ normal-tension glaucoma; PFS ¼ parafoveal scotoma; PNS ¼ peripheral nasal step; POAG ¼ primary open-angle glaucoma; RNFL ¼ retinal nerve ﬁber layer. aComparison of the 2 groups by Student t test. bComparison of the 2 groups by x2 test. cComparison of the 2 groups by Fisher exact test. dComparison of the 2 groups by Mann-Whitney U test.

Using an iterative procedure of pairing the largest vessel RESULTS with the smallest until we reached a single number, we 23 could calculate a central vessel equivalent. BASELINE CHARACTERISTICS OF SUBJECTS: During the study period, 46 glaucomatous eyes with initial PFS (30 SUBGROUP ANALYSES: To investigate whether the with NTG and 16 with POAG) and 105 eyes with initial retinal vessel profiles or clinical characteristics of patients PNS (53 with NTG and 52 with POAG) were enrolled with NTG differed from those of patients with POAG, in this cross-sectional study. The demographic and clinical we performed the following subgroup analyses: patients variables of the PFS and PNS groups, and those of the NTG with (1) initial PFS vs those with PNS, (2) NTG vs those and POAG groups, are summarized in Table 1. The PFS with POAG, (3) NTG and PFS vs those with NTG and and PNS groups showed no statistically significant differ- PNS, and (4) POAG and PFS vs those with POAG and ences in age, sex, family history of glaucoma, hypertension, PNS. diabetes mellitus, body mass index, axial length, central corneal thickness, IOP, presence of disc hemorrhage, STATISTICAL ANALYSIS: To determine the significance spherical equivalent, or average RNFL thickness. Mean de- of differences between the groups, Student t test or the viations (MDs) were similar between the PFS and PNS Mann-Whitney U test was used for continuous variables, groups (P ¼ .314), whereas the PSD was significantly and the x2 test or Fisher exact test was used for categor- greater and the VF index significantly lower in the PFS ical variables, depending on the normality of distribu- group than in the PNS group (P ¼ .026 and P < .001, tion. We used the PASW Statistics for Windows, respectively). The NTG and POAG groups did not differ Version 18.0 (SPSS Inc, Chicago, Illinois, USA) for sta- significantly in terms of any parameters except IOP (P < tistical analyses. To identify the factors related to the .001). The proportion of eyes with initial PFS was higher CRAE in patients with glaucoma, simple linear regres- in the NTG group (30/83, 36.14%) than in the POAG sion analyses were performed. In addition, to control group (16/68, 23.53%), but the difference was not signifi- for the confounding effects of multiple covariates, a mul- cant (P ¼ .094, x2 test). tiple linear regression analysis was performed using the variablesthathadaP value of <.10 in the simple linear COMPARISONS OF RETINAL VESSEL DIAMETER INDICES: regression analyses. All reported P values are 2-sided, The CRAE was significantly lower in the PFS group than in and differences at a level of P < .05 were considered sta- the PNS group across all patients with glaucoma (P ¼ tistically significant. .001). However, the CRVE values did not differ between

32 AMERICAN JOURNAL OF OPHTHALMOLOGY MARCH 2017

a a a subgroups (Table 2). Value

P When the ‘‘NTG with PFS’’ subgroup was compared with primary

¼ the ‘‘NTG with PNS’’ subgroup, the CRAE of the PFS group was signiﬁcantly lower than that of the PNS group (P ¼ .013). No signiﬁcant difference in the CRAE was 52) 19.4119.92 .123 .201 14.95 .382 ¼ observed between the ‘‘POAG with PFS’’ and ‘‘POAG 6 6 6 cotoma Groups 68)

¼ with PNS’’ subgroups (P ¼ .123) (Table 2).

RELATIONSHIP BETWEEN DEMOGRAPHIC AND CLIN- ICAL VARIABLES AND CENTRAL RETINAL ARTERIOLAR EQUIVALENT: The relationship between the demographic peripheral nasal step; POAG 16) PNS (N 13.8920.26 173.94 278.64 13.85 96.44 ¼ and clinical variables and the CRAE was evaluated using ¼ 6 6 6 simple and multiple linear regression analyses (Table 3). In the simple linear regression analysis, axial length and 92.74 165.77 271.25 hypertension were found to have signiﬁcant negative relationships with the CRAE (P ¼ .042 and P ¼ .024, respec-

b a a tively), whereas average RNFL thickness, diagnosis of

Value PFS (N POAG, and initial PNS were positively associated with P < ¼ ¼

parafoveal scotoma; PNS the CRAE (P .001, P .001, and P .001, respectively).

¼ Age, sex, central corneal thickness, and diabetes mellitus were not associated with the CRAE (P > .05 in all cases). 53) 12.07 .314 16.2508.99 .013 .986

¼ In the multiple linear regression analysis of the signiﬁ- 6 6 6 83) POAG (N cant variables from the simple linear regression analysis, ¼ the CRAE was signiﬁcantly associated with average RNFL thickness, diagnosis of POAG, and initial PNS (P < .001, P ¼ .037, and P ¼ .012, respectively). 30) PNS (N 14.97 94.72 13.0818.18 165.86 268.09 ¼ normal-tension glaucoma; PFS 6 6 6 ¼ DISCUSSION 90.63 157.08 268.01 IN THE PRESENT STUDY, WE CLASSIFIED THE PATIENTS WITH glaucoma according to the initial location of the VF defect; a a a

Value PFS (N we then compared the RVD indices between the PFS and P PNS groups. The PFS group had a signiﬁcantly lower CRAE than did the PNS group, particularly among patients with NTG. 13.5518.26 .091 .001 20.07 .232

105) Our observations are consistent with the ﬁndings of pre- 151) NTG (N ¼ 6 6 6

¼ vious studies, which have implied that vascular mecha-

central retinal venular equivalent; NTG nisms inﬂuence the initial location of the VF defect. test. ¼

U For instance, one prospective study on patients with NTG showed a signiﬁcant relationship between central test. All Glaucoma (N t VF defect and autonomic dysfunction that assessed with heart rate variability or peripheral microcirculation by us- 46) PNS (N 14.4613.86 95.59 169.86 18.77 273.332 24 ¼ 6 6 6 ing nailfold capillaroscopy. Another study showed differ-

retinal nerve ﬁber layer. ences in the prevalence of several systemic risk factors PFS (N ¼ between the PFS and PNS groups; the authors of that study postulated that IOP-independent factors such as decreased or unstable ocular perfusion may preferentially damage the

m 91.38 neuroretinal rim or RNFL closer to the papillomacular m 17 Comparison of Central Retinal Arteriolar Equivalent and Central Retinal Venular Equivalent Between the Initial Parafoveal Scotoma and Paranasal S bundle. m 160 m 269.14 central retinal arteriolar equivalent; CRVE It remains unclear whether retinal arteriolar narrowing m m ¼ precedes or follows the development of glaucomatous dam- TABLE 2. Comparison of the 2 groups by Mann-Whitney Comparison of the 2 groups by Student age. Previously, our group reported that retinal arteriolar CRAE, CRVE, CRAE a b RNFL thickness, Retinal vessel indices open-angle glaucoma; RNFL narrowing can occur very early in OAG development, even before any RNFL defect or VF deterioration becomes

VOL. 175 VESSEL DIAMETERS IN PARAFOVEAL SCOTOMA AND PERIPHERAL NASAL STEP 33

Downloaded for Anonymous User (n/a) at Mercy Hospital St. Louis from ClinicalKey.com by Elsevier on April 02, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. TABLE 3. Simple and Multiple Linear Regression Analyses of Central Retinal Arteriolar Equivalent in Patients With Open-Angle Glaucoma

Simple Analysis Multiple Analysis

Variable Regression Coefﬁcient 95% CI P Value Regression Coefﬁcient 95% CI P Value

Age, y 0.151 -0.357 to 0.055 .150 Women (vs men) 0.763 6.456 to 4.930 .792 Axial length, mm 2.632 5.173 to 0.091 .042 0.154 0.976 to 1.285 .787 Central corneal thickness, mm 0.049 0.0.039 to 0.137 .270 Average RNFL thickness, mm 0.523 0.336 to 0.710 <.001 0.554 0.333 to 0.776 <.001 Presence of hypertension 6.543 12.226 to 0.860 .024 3.514 9.738 to 2.711 .265 (vs absence) Presence of diabetes 4.341 4.848 to 13.530 .352 mellitus (vs absence) Diagnosis of POAG (vs NTG) 9.337 3.839 to 14.834 .001 6.185 0.381 to 11.989 .037 Initial peripheral nasal 9.759 3.802 to 15.716 .001 8.131 1.809 to 14.454 .012 step (vs parafoveal scotoma)

NTG ¼ normal-tension glaucoma; POAG ¼ primary open-angle glaucoma; RNFL ¼ retinal nerve fiber layer. apparent.22 The Blue Mountains Eye Study showed that a The greater vulnerability of central fibers according to smaller retinal arteriolar diameter was associated with an the changes in vessel diameter may be attributed to the increased long-term risk of OAG after adjusting for known arrangement of retinal vessels. A previous study on human risk factors for glaucoma, suggesting that early vascular donor eyes showed that the radial peripapillary capillaries changes are involved in the pathogenesis of OAG.25 How- had significantly smaller diameter in the temporal region ever, Kim and associates reported that the vascular narrow- compared with superior, inferior, and nasal regions.29 ing is likely owing to the decreased demand for retinal Furthermore, in a recent study using OCT angiography, blood flow in damaged areas of the retina.26 In our study, the peripapillary and inside disc vessel densities tended to the RVD narrowing in the PFS group compared with the be lower in the temporal sector than in the superior or nasal PNS group was only significant in patients with NTG but sectors even in the normal controls.30 Because the central not in those with POAG (Table 2), although there was fibers from the macula occupy the temporal part of the no difference in MD and average RNFL thickness between optic nerve head,31 they may be primarily damaged by the 2 groups (Table 1). If retinal vessel narrowing were sim- vascular insufficiency. Jia and associates suggested that ply a secondary phenomenon following the decreased the temporal sector of the optic nerve head was a critical demand for retinal blood flow in a damaged area, this region for monitoring glaucoma because the reduction of discrepancy would not occur, because the patients with vessel density was greater in the temporal region, which NTG and those with POAG had a similar level of glaucom- is devoid of a major retinal vessel, than in the whole disc atous damage. Therefore, there may be additional mecha- even at the preperimetric stage.32 The above evidence sup- nisms regarding PFS development and RVD narrowing ports the view that a central VF deterioration may develop in NTG. when vascular insufficiency is involved in the pathogenesis The central fibers from the macula may be more vulner- of glaucoma, and may explain why the narrowing of RVD is able to vascular insufficiency than the fibers from the more prominent and why the prevalence of PFS is higher in periphery. The ganglion cells and intraretinal layer of un- NTG than in POAG. myelinated ganglion cell axons have a high level of cyto- Our study had some limitations. First, it was not chromecoxidase,indicatingahighenergydemand.27 population-based, but a hospital-based study. Therefore, Because neurons depend almost entirely on oxidative our data may have been subject to a selection bias. Second, metabolism for their energy supply, a sufficient blood many systemic diseases and medications can influence flow is essential for proper delivery of oxygen and RVD.33,34 For instance, previous large, population-based glucose.27 Considering that the resistance varies inversely studies have revealed negative correlations between blood with the fourth power of vessel radius, small changes pressure and retinal arteriolar diameter.35,36 in vessel diameter can significantly alter the blood Hypertension, as well as diabetes mellitus37,38 and flow.28 Becausetheremaybenarrowingofretinalarteriole atherosclerosis,39 is associated with RVD. In our study pop- vessels in NTG, a decreased amount of blood flow to these ulation, simple regression analysis revealed that the CRAE central neurons may cause nerve damage owing to lack of was associated with hypertension, but not with diabetes sufficient energy. mellitus. However, this relationship disappeared in the

34 AMERICAN JOURNAL OF OPHTHALMOLOGY MARCH 2017

Downloaded for Anonymous User (n/a) at Mercy Hospital St. Louis from ClinicalKey.com by Elsevier on April 02, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. multiple regression analysis. The relationship between migraine,42 and sleep apnea.43 Finally, one could argue that atherosclerosis and CRAE could not be assessed because our result is confounded because a greater proportion of pa- we had limited information regarding the patients’ systemic tients had NTG in the PFS group (30/46, 65.22%) than in diseases. In addition, we were unable to check whether the the PNS group (53/105, 50.48%). However, multiple patients had taken any systemic medications, ascertain the regression analysis showed that the CRAE was associated exact types of medications they had been prescribed, and not only with the initial location of the VF defect, but determine their blood pressure after taking the medication. also with the type of glaucoma (eg, the ‘‘NTG vs POAG’’ Third, we could not obtain blood pressure data while taking group). the disc photographs. In addition, RVD may be inﬂuenced In conclusion, OAG patients with initial PFS showed by the cardiac cycle. However, a previous study showed narrower retinal arteriolar diameter than did those with minimal variations in the CRAE and CRVE in this re- initial PNS, particularly in the NTG group. This ﬁnding gard.40 Fourth, because of the retrospective nature of this suggests that the initial location of the VF deterioration study, it was not possible to check the prevalence of sys- may be associated with a vascular mechanism in patients temic vascular risk factors such as Raynaud phenomenon,41 with glaucoma.

FUNDING/SUPPORT: NO FUNDING OR GRANT SUPPORT. FINANCIAL DISCLOSURES: THE FOLLOWING AUTHORS HAVE NO ﬁnancial disclosures: Eunjoo Yoo, Chungkwon Yoo, Tae-Eun Lee, and Yong Yeon Kim. All authors attest that they meet the current ICMJE criteria for authorship. The authors thank Dr Nicola Ferrier (University of Wisconsin, Madison School of Engineering and Fundus Photograph Reading Center, Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison) for granting permission to use the IVAN software.

REFERENCES 10. Jonas JB, Nguyen XN, Naumann GO. Parapapillary retinalvesseldiameterinnormalandglaucomaeyes.I. 1. Collaborative Normal-Tension Glaucoma Study Group. Morphometric data. Invest Ophthalmol Vis Sci 1989; Comparison of glaucomatous progression between untreated 30(7):1599–1603. patients with normal-tension glaucoma and patients with 11. Wang S, Xu L, Wang Y, Wang Y, Jonas JB. Retinal vessel therapeutically reduced intraocular pressures. Am J Ophthal- diameter in normal and glaucomatous eyes: the Beijing Eye mol 1998;126(4):487–497. Study. Clin Experiment Ophthalmol 2007;35(9):800–807. 2. Collaborative Normal-Tension Glaucoma Study Group. The 12. Mitchell P, Leung H, Wang JJ, et al. Retinal vessel diameter effectiveness of intraocular pressure reduction in the treat- and open-angle glaucoma: the Blue Mountains Eye Study. ment of normal-tension glaucoma. Am J Ophthalmol 1998; Ophthalmology 2005;112(2):245–250. 126(4):498–505. 13. Amerasinghe N, Aung T, Cheung N, et al. Evidence of 3. The AGIS Investigators. The Advanced Glaucoma Interven- retinal vascular narrowing in glaucomatous eyes in an Asian tion Study (AGIS): 7. The relationship between control population. Invest Ophthalmol Vis Sci 2008;49(12): of intraocular pressure and visual field deterioration. Am J 5397–5402. Ophthalmol 2000;130(4):429–440. 14. Hitchings RA, Anderton SA. A comparative study of visual 4. Leske MC, Heijl A, Hyman L, Bengtsson B, Dong L, field defects seen in patients with low-tension glaucoma and Yang Z. Predictors of long-term progression in the Early chronic simple glaucoma. Br J Ophthalmol 1983;67(12): Manifest Glaucoma Trial. Ophthalmology 2007;114(11): 818–821. 1965–1972. 15. Caprioli J, Spaeth GL. Comparison of visual field defects in 5. Klein BE, Klein R, Meuer SM, Goetz LA. Migraine headache the low-tension glaucomas with those in the high-tension and its association with open-angle glaucoma: the Beaver glaucomas. Am J Ophthalmol 1984;97(6):730–737. Dam Eye Study. Invest Ophthalmol Vis Sci 1993;34(10): 16. Thonginnetra O, Greenstein VC, Chu D, Liebmann JM, 3024–3027. Ritch R, Hood DC. Normal versus high tension glaucoma: 6. Wang JJ, Mitchell P, Smith W. Is there an association be- a comparison of functional and structural defects. J Glaucoma tween migraine headache and open-angle glaucoma? Findings 2010;19(3):151–157. from the Blue Mountains Eye Study. Ophthalmology 1997; 17. Park SC, De Moraes CG, Teng CC, Tello C, Liebmann JM, 104(10):1714–1719. Ritch R. Initial parafoveal versus peripheral scotomas in glau- 7. Drance SM. Disc hemorrhages in the glaucomas. Surv coma: risk factors and visual field characteristics. Ophthal- Ophthalmol 1989;33(5):331–337. mology 2011;118(9):1782–1789. 8. Healey PR, Mitchell P, Smith W, Wang JJ. Optic disc hem- 18. Kim CS, Seong GJ, Lee NH, Song KC. Prevalence of primary orrhages in a population with and without signs of glaucoma. open-angle glaucoma in central South Korea the Namil Ophthalmology 1998;105(2):216–223. study. Ophthalmology 2011;118(6):1024–1030. 9. Drance SM, Douglas GR, Wijsman K, Schulzer M, Britton RJ. 19. Hubbard LD, Brothers RJ, King WN, et al. Methods for eval- Response of blood flow to warm and cold in normal and low- uation of retinal microvascular abnormalities associated with tension glaucoma patients. Am J Ophthalmol 1988;105(1): hypertension/sclerosis in the Atherosclerosis Risk in Com- 35–39. munities Study. Ophthalmology 1999;106(12):2269–2280.

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Downloaded for Anonymous User (n/a) at Mercy Hospital St. Louis from ClinicalKey.com by Elsevier on April 02, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. 20. Chang M, Yoo C, Kim SW, Kim YY. Retinal vessel diameter, 32. Jia Y, Morrison JC, Tokayer J, et al. Quantitative OCT angi- retinal nerve fiber layer thickness, and intraocular pressure ography of optic nerve head blood flow. Biomed Opt Express in Korean patients with normal-tension glaucoma. Am J 2012;3(12):3127–3137. Ophthalmol 2011;151(1):100–105.e101. 33. Liew G, Mitchell P, Leeder SR, Smith W, Wong TY, 21. Yoo E, Yoo C, Lee BR, Lee TE, Kim YY. Diagnostic ability of Wang JJ. Regular aspirin use and retinal microvascular signs: retinal vessel diameter measurements in open-angle glau- the Blue Mountains Eye Study. J Hypertens 2006;24(7): coma. Invest Ophthalmol Vis Sci 2015;56(13):7915–7922. 1329–1335. 22. Yoo E, Yoo C, Lee TE, Kim YY. Retinal vessel diameter in 34. Howard KP, Klein BE, Dreyer JO, Danforth LG, Klein R. bilateral glaucoma suspects: comparison between the eye Cross-sectional associations of medication and supplement converted to glaucoma and the contralateral non-converted use with retinal vascular diameter in the Beaver Dam Eye eye. Graefes Arch Clin Exp Ophthalmol 2016;254(8): Study. JAMA Ophthalmol 2014;132(1):23–31. 1599–1608. 35. Sharrett AR, Hubbard LD, Cooper LS, et al. Retinal arteri- 23. Knudtson MD, Lee KE, Hubbard LD, Wong TY, Klein R, olar diameters and elevated blood pressure: the Atheroscle- Klein BE. Revised formulas for summarizing retinal vessel di- rosis Risk in Communities Study. Am J Epidemiol 1999; ameters. Curr Eye Res 2003;27(3):143–149. 150(3):263–270. 24. Park HY, Jung KI, Na KS, Park SH, Park CK. Visual field 36. Klein R, Myers CE, Knudtson MD, et al. Relationship of characteristics in normal-tension glaucoma patients with blood pressure and other factors to serial retinal arteriolar autonomic dysfunction and abnormal peripheral microcircu- diameter measurements over time: the Beaver Dam Eye lation. Am J Ophthalmol 2012;154(3):466–475.e461. Study. Arch Ophthalmol 2012;130(8):1019–1027. 25. Kawasaki R, Wang JJ, Rochtchina E, Lee AJ, Wong TY, 37. Jeganathan VS, Sabanayagam C, Tai ES, et al. Retinal Mitchell P. Retinal vessel caliber is associated with the vascular caliber and diabetes in a multiethnic Asian popula- 10-year incidence of glaucoma: the Blue Mountains Eye tion. Microcirculation 2009;16(6):534–543. Study. Ophthalmology 2013;120(1):84–90. 38. Kifley A, Wang JJ, Cugati S, Wong TY, Mitchell P. Retinal 26. Kim JM, Sae Kim M, Ju Jang H, Ho Park K, Caprioli J. The vascular caliber and the long-term risk of diabetes and association between retinal vessel diameter and retinal impaired fasting glucose: the Blue Mountains Eye Study. nerve fiber layer thickness in asymmetric normal tension Microcirculation 2008;15(5):373–377. glaucoma patients. Invest Ophthalmol Vis Sci 2012;53(9): 39. Liao D, Wong TY, Klein R, Jones D, Hubbard L, Sharrett AR. 5609–5614. Relationship between carotid artery stiffness and retinal arte- 27. Wong-Riley MT. Energy metabolism of the visual system. Eye riolar narrowing in healthy middle-aged persons. Stroke 2004; Brain 2010;2:99–116. 35(4):837–842. 28. Wheeler EC, Brenner ZR. Peripheral vascular anatomy, phys- 40. Hao H, Sasongko MB, Wong TY, et al. Does retinal vascular iology, and pathophysiology. AACN Clin Issues 1995;6(4): geometry vary with cardiac cycle? Invest Ophthalmol Vis Sci 505–514. 2012;53(9):5799–5805. 29. Yu PK, Cringle SJ, Yu DY. Correlation between the radial 41. Salmenson BD, Reisman J, Sinclair SH, Burge D. Macular peripapillary capillaries and the retinal nerve fibre layer in capillary hemodynamic changes associated with Raynaud’s the normal human retina. Exp Eye Res 2014;129:83–92. phenomenon. Ophthalmology 1992;99(6):914–919. 30. Rao HL, Pradhan ZS, Weinreb RN, et al. Regional compari- 42. Liew G, Mitchell P, Wong TY, Wang JJ. Retinal vascular sons of optical coherence tomography angiography vessel caliber and migraine: the Blue Mountains Eye Study. Head- density in primary open angle glaucoma. Am J Ophthalmol ache 2006;46(6):997–1004. 2016;171:75–83. 43. Lin GM, Redline S, Klein R, et al. Sex-specific association of 31. Hoyt WF, Luis O. Visual fiber anatomy in the infragenicu- obstructive sleep apnea with retinal microvascular signs: The late pathway of the primate. Arch Ophthalmol 1962;68: Multi-Ethnic Study of Atherosclerosis. J Am Heart Assoc 94–106. 2016;5(7). e003598.

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