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Macular Vascularity in Ischemic Optic Neuropathy Compared to Glaucoma by Projection-Resolved Optical Coherence Tomography Angiography
Journal Pre-proof Macular Vascularity in Ischemic Optic Neuropathy Compared to Glaucoma by Projection-Resolved Optical Coherence Tomography Angiography Masoud Aghsaei Fard, Ghasem Fakhraee, Hossein Ghahvechian, Alireza Sahraian, Sasan Moghimi, Robert Ritch PII:
S0002-9394(19)30473-8
DOI:
https://doi.org/10.1016/j.ajo.2019.09.015
Reference:
AJOPHT 11084
To appear in:
American Journal of Ophthalmology
Received Date: 5 June 2019 Revised Date:
12 August 2019
Accepted Date: 17 September 2019
Please cite this article as: Fard MA, Fakhraee G, Ghahvechian H, Sahraian A, Moghimi S, Ritch R, Macular Vascularity in Ischemic Optic Neuropathy Compared to Glaucoma by Projection-Resolved Optical Coherence Tomography Angiography, American Journal of Ophthalmology (2019), doi: https:// doi.org/10.1016/j.ajo.2019.09.015. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Inc. All rights reserved.
Abstract: PURPOSE: To compare macular vasculature in patients with primary open-angle glaucoma (POAG) POAG and atrophic non-arteritic anterior ischemic optic neuropathy (NAION). DESIGN: Prospective, cross-sectional study METHODS: Thirty seven eyes with moderate and advanced POAG, 19 eyes with atrophic NAION, and 40 eyes of normal subjects were imaged using optical coherence tomography angiography (OCT-A). Macular ganglion cell complex (GCC) and peripapillary retinal nerve fiber layer (RNFL) thicknesses were measured in addition to macular superficial and deep vasculature after projection removal using custom software. RESULTS: Linear models showed that while averaged peripapillary RNFL and macular GCC were not different between NAION and POAG eyes, both were significantly thinner than control eyes. Whole image macular superficial vessel density was significantly lower in NAION and glaucoma eyes (P=0.003 and <0.001, respectively) than in normal eyes, with lower vessel density in glaucoma than in NAION eyes (P=0.01). Whole image and parafoveal deep macular vessels in glaucoma eyes (21.0±8.7%, 24.4±9.6%) were significantly lower than in control eyes (27.4%±8.6%, 31.9%±10.6%) (P = 0.01 and P = 0.01, respectively). No significant differences in deep vessels were observed between NAION and control eyes. Glaucoma eyes had lower temporal and inferior parafoveal deep vasculature values than NAION eyes (P=0.007 and 0.03, respectively). CONCLUSIONS: In NAION and POAG with similar RNFL and macular damage, macular OCT-A shows less involvement of superficial and deep vascular plexus in NAION in contrast to POAG, which might show a primary vascular insult in addition to secondary vascular damage due to ganglion cell damage.
Macular Vascularity in Ischemic Optic Neuropathy Compared to Glaucoma by Projection-Resolved Optical Coherence Tomography Angiography
Short title: Macular Vessels in Ischemic Optic Neuropathy and Glaucoma Authors: Masoud Aghsaei Fard1, Ghasem Fakhraee1, Hossein Ghahvechian1, Alireza Sahraian1, Sasan Moghimi1,2, Robert Ritch3 Affiliations: 1
Farabi Eye Hospital, Tehran University of Medical science, Iran
2
Department of Ophthalmology, Shiley Eye Institute, University of California, San Diego
3
Einhorn Clinical Research Center, New York Eye and Ear Infirmary of Mount Sinai, New York, NY
Corresponding author: Masoud Aghsaei Fard, Qazvin Sq, Farabi Eye Hospital, Tehran University of Medical Science. Tehran, Iran, [email protected]
1
Introduction While primary open angle glaucoma (POAG) consists of progressive loss of retinal ganglion cells and their axons, nonarteritic anterior ischemic optic neuropathy (NAION) is characterized by acute optic nerve damage. Although NAION is associated with hypoperfusion of the short posterior ciliary arteries and infarction in the retrolaminar region of the optic nerve head, the role of the retinal and macular vascular system in the pathogenesis of POAG and NAION is not well understood.1-3 Optical coherence tomography angiography (OCT-A) can assess the circulation in the retina and optic nerve. Peripapillary and macular vasculature compromise in both NAION and glaucoma eyes has been reported using OCT-A. Several studies have found decreased peripapillary vessel density (VD) at the corresponding location of visual field defects in POAG and NAION.4-7 We previously reported that the degrees of peripapillary capillary density in these two forms of optic nerve damage were not different.8 It seems that dropout of peripapillary vessels is not specific to POAG or NAION. Similarly, prior studies have evaluated the role of the macular vasculature in both POAG and NAION. Reduced macular VD was shown in chronic NAION,9 in contrast to earlier work showing no macular vascular changes.10 However, in those studies, projection artifacts and duplication of superficial vascular patterns in the deeper retinal layers may have obfuscated the interpretation of data, as the authors had mentioned as limitations.10, 11 In addition, macular vascular dropout in various types of glaucomatous eyes suggests that the vascular system has an important role in the early diagnosis of glaucoma and in understanding its pathogenesis.12-16 Some studies showed that vascular abnormality and macular ganglion cell complex (GCC) thickness change might be interdependent,17-19 which raises the question as to whether the vessel dropout is a primary event or is the result of ganglion cell damage. While several studies noted that total macular GCC thickness does not differ between NAION and moderate and severe POAG,10, 20, 21 the amount of damage to the macular superficial and deep plexus has not been clearly defined, particularly after resolving projection artifacts. These two different optic neuropathies with similar ganglion cell loss make a model to test whether microvasculature impairment could vary in different diseases and thus provide further evidence that loss of vascular and neural tissue are independent.17-19 The purpose of the current study was to characterize and compare macular and parafoveal superficial and deep VDs and GCC thickness in NAION and POAG eyes after resolving projection.
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Material and Methods Subjects Patients with moderate and severe POAG and post-acute NAION who were examined at New York Eye and Ear Infirmary of Mount Sinai and Farabi Eye Hospital between March 2016 and September 2017 were enrolled in this prospective, cross-sectional, comparative study. The study was approved by the research ethics committee of Farabi Eye Hospital and NYEEI Institutional Review Board. Informed consent was obtained from all patients, and all investigations adhered to the tenets of the Declaration of Helsinki. Participants with age ≥18 years, a spherical refraction within ±5.0 diopters (D), and cylinder correction within ±3.0 D were included. Diagnosis of NAION and POAG was established by two authors (MAF, RR) based on evaluation of the patient's history, examination, and review of diagnostic testing such as OCT and visual fields, if available. Patients with POAG manifested enlargement of the vertical cup-to-disc ratio, diffuse or focal thinning of the neuroretinal rim, and an open iridocorneal angle on gonioscopy. Presence of a PSD outside 95% normal limits, which were confirmed on at least 2 consecutive, reliable tests and glaucoma hemifield test outside normal limits were used for the glaucoma diagnosis.22 Moderate and severe POAG eyes with 24-2 mean deviation (MD) of less than -6 dB were recruited so that the glaucoma and NAION groups would be similar in terms of severity.21,22 Chronic NAION was defined as patients having had a history of sudden visual loss >6 months prior to enrollment, previous documented optic disc edema, developing a pale optic disc with complete resolution of disc edema at the time of the study, absence of proptosis, and an ophthalmologically normal fellow eye. Patients with other ocular or neurologic disease or evidence of giant cell arteritis with high erythrocyte sedimentation rate and C-reactive protein, or inflammatory optic neuritis were excluded. The control group comprised subjects with a best-corrected visual acuity of ≥20/30, normal optic disc appearance on fundus examination, normal RNFL thickness by OCT, and IOP <21 mmHg. All participants underwent a comprehensive ophthalmic examination, which included assessment of visual acuity, IOP measurement by Goldmann applanation tonometry, slit lamp examination, gonioscopy, fundus examination, VF testing by standard automated perimetry (SAP, Humphrey Field Analyzer; 24-2 Swedish interactive threshold algorithm; Carl Zeiss Meditec, Jena, Germany), and OCT-A imaging. Optical Coherence Tomography Angiography and Spectral-Domain Optical Coherence Tomography All subjects underwent OCT-A and SD-OCT imaging using the AngioVue imaging system (Optovue, Inc., Fremont, CA, USA, RTVue XR version 2018.0.0.18) that has been described previously. Macular 6 mm x 6 mm scans centered on the fovea were acquired with the OCT-A AngioVue system. Patients with poor image clarity, and scans with signal strength index of <40 were excluded. Retinal layers were 3
automatically segmented in order to visualize the superficial vascular plexus in a slab from the internal limiting membrane to 9 µm above the junction between the inner plexiform layer (IPL) and the inner nuclear layer (INL), deep retinal vasculatures from 9 µm above the IPL-INL junction to 9 µm below the outer plexiform layer and outer nuclear layer (OPL-ONL).23, 24 Blood flow information as a VD map (%) in superficial slabs was obtained in whole macular image and parafoveal regions. Parafoveal VD was measured in an annulus centered on the fovea with an inner diameter of 1 mm and outer diameter of 3 mm. The parafoveal region was divided into four sectors (superior, inferior, temporal, and nasal) in addition to superior and inferior hemispheric areas. We then employed customized MATLAB software (The MathWorks, Inc., Natick, MA, USA) for calculating deep VD after removing the large vessels of superficial layer that had been projected into the deep layer which is similar to the method we have described previously for removing large peripapillary vessels.25 The latest commercial software (PAR algorithm) resolves the flow projection issue in the parafovea, but projection removal is not perfect and duplication of superficial vessels were still visible in whole macular deep images. To calculate deep VD values, thresholding grayscale deep retinal images of OCT-A were performed to create binary images with threshold values, which were changed manually in each image to remove the large projecting vessels. Then, deep VD was calculated in whole-image, whole parafovea, and each quadrant of parafovea. A standard 360°, 3.4 mm diameter circular scan was used to measure RNFL thickness, and the mean and each sector RNFL values were recorded. The macula cube scanning protocol measured the GCC thickness over a 7 mm diameter and parafoveal GCC was measured over 3 mm diameter centered on the fovea. Total, superior and inferior hemispheres GCC were recorded for both macular and parafoveal areas. Statistical Analysis The distribution of continuous variables was assessed by inspecting histograms and using Shapiro-Wilk W tests of normality. Linear mixed modeling was used for the comparison between groups, after accounting for inter-eye correlation and adjusting for age and multiple comparisons with Bonferroni correction. In this method, the correlation in outcomes between paired eyes of a subject was accounted for by adding a random effect. In addition, Pearson correlation analysis was used to find associations between thickness of ganglion cell complex, visual field MD, visual acuity and macular vascular densities. Finally, to evaluate the inter-observer reproducibility of our deep vessel measurements, 18 NAION eyes, 12 POAG eyes, and 20 normal controls were randomly selected. Analysis was based on 2 independent series of re-evaluations made by two different investigators. The absolute agreement of the measurements conducted by the 2 observers were calculated with the intraclass correlation coefficient (ICC) from a 2-way mixed effect
model. All statistical analyses were performed with the SPSS software (IBM Corp. Released 2013. IBM SPSS Statistics for Windows, Version 22.0. Armonk, NY: IBM Corp.). P-values <0.05 were considered significant.
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Results: Ninety six eyes were included after excluding 15 eyes due to segmentation errors: 40 control eyes, 19 chronic NAION, and 37 POAG eyes. One NAION patient and four POAG patients had both eyes included in the study. Median time elapsed after visual loss in chronic NAION eyes was 28.6 weeks (range 24-34 weeks), respectively. Demographic information and structural RNFL values are summarized in Table 1. Mean age in the NAION, POAG, and control eyes was not significantly different. Retinal nerve fiber layer thicknesses in chronic NAION and POAG were not significantly different from each other (64.5±13.6 vs 59.1±17.4, respectively, P=0.46), while both were thinner than control eyes. Total macular GCC thickness was lower in chronic NAION eyes (70.01±12.4 µm) and POAG eyes ( 72.71±13.8 µm) than control eyes, without significant difference between chronic NAION and POAG eyes (P=0.46). Parafoveal GCC thickness was also not different between POAG and NAION eyes and both were lower than in the control group (Table 1). Superficial retinal vasculature density: OCT-A results showed that the whole macular and parafoveal superficial VDs in POAG eyes with values of 39.6±6.9% and 43.7±5.2% were significantly lower compared to controls. (51.1±3.3 % and 54.2±4.1%, both P<0.001). Chronic NAION eyes also had significantly lower whole macular and parafoveal VDs with values of 44.1±4.3% and 48.0±5.4% than control eyes, respectively (Both P<0.001). Comparison between NAION and POAG eyes showed that whole macular and parafoveal VDs were significantly lower in POAG eyes than NAION eyes. Specifically, superficial vasculature of the superior and inferior hemi-parafoveal values and its quadrants in POAG eyes was also lower than in NAION eyes (Table 2). Deep retinal vasculature density after projection removal: All deep vessel values using customized Matlab software showed an excellent interobserver reproducibility that ranged from an ICC of 0.973 to 0.996 for the various parameters (Table 3). Significantly lower whole image and parafoveal vessel values were found in POAG eyes with values of 21.03±8.7% and 24.43±9.6% compared to control eyes with values of 27.40±8.63% and 31.92±10.58%, respectively (P=0.01 and 0.01). Whole image and parafoveal deep vascular values of NAION eyes were not different from control eyes (P=0.34, P=0.89, respectively). Glaucoma eyes had lower temporal and inferior parafoveal vasculature values than NAION eyes (P=0.007 and 0.03, respectively). Whole macula and parafoveal values were not significantly different between POAG and NAION eyes (Table 4). Results from the Pearson correlation analysis showed that total GCC and superior and inferior hemi-GCC were significantly correlated to corresponding whole image and superior and inferior hemiretinal superficial VD (r=0.64, P<0.001; r=0.64, P<0.001; r=0.60, P<0.001). Similarly parafoveal GCC and parafoveal superficial VD were correlated (r=0.41, P=0.001). While there was weak correlation between total GCC with whole macular deep vasculature (r=0.35, P=0.004), correlation was not found between parafoveal GCC and parafoveal deep VD (r=0.1, P=0.45). Our 5
analysis also showed correlations between whole macular and parafoveal superficial VDs and visual field MD (r=0.37, P=0.001 and r=0.36, P=0.002, respectively). Whole image deep vessel density but not parafoveal deep vascular value was weakly correlated to visual field MD (r=0.26, P=0.03 and r=0.20, P=0.10, respectively). Visual acuity was not correlated with any vascular densities.
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Discussion: We compared whole macula and parafoveal VD in control, NAION and POAG eyes with moderate and severe glaucomatous damage. While we found lower superficial and deep vasculatures in POAG eyes than in control eyes, only superficial vasculature was lower in NAION eyes than in control eyes. There were no significant differences between POAG and NAION groups in the peripapillary RNFL and macular GCC, allowing for analysis of groups with comparable optic nerve and macular damage. When comparing macular vasculature between NAION and POAG, significantly lower superficial vasculature of the whole macula and parafovea was found in POAG eyes than NAION eyes. From parafoveal sectors, inferior and temporal areas had lower deep vessels in POAG eyes than NAION eyes. In addition, we found significant associations between superficial vasculature density and corresponding GCC and visual field MD. Such correlation was not found for parafoveal GCC and deep VD. Many published studies have focused on the reduced VD in the superficial layer in glaucomatous eyes13, 14, 17-19, 26-28 because the ganglion cell layer receives its blood supply from the superficial retinal vascular plexus.29 However, only a few papers have provided information on the deep plexus in glaucomatous eyes, with differing results.11, 15,16, 18 While Lommatzsch et al.15 showed decreased deep vessels in mild glaucoma cases compared to control eyes, of note, their measured higher density of deep vessels than superficial macula ones might be due to duplication of superficial vessels on deep vessels. Hou et al.18 did not observe loss of deep macular vessels in glaucoma suspect and mild glaucoma cases without removing projection flow. Two studies11,16 used customized software. Choi et al.16 found a decrease in both superficial and deep macular vasculature in different stages of glaucoma and reported 25% as the mean deep VD in healthy eyes. In our study, we addressed the issue of duplication of superficial vessels on deep vasculature and found lower deep and superficial macular vessel in glaucoma than normal eyes. In our study the value of deep VD in control group was 27%, similar to Choi et al.16 In contrast, Takusagawa et al.11 did not find a lower density of deep vascular plexus in mild to moderate glaucoma cases after projection removal. It seems the difference in deep vessel involvement between their study and our study might be related to the glaucoma severity. Additionally, we also measured those vessels in NAION eyes. We found lower density of superficial vessels but not deep vessels compared to normal controls. Augstburger et al.9 reported lower VD of macular capillaries in the superficial and deep plexus. But again they reported a higher value of deep vessels (58%) due to duplication of superficial vessels and “apparently” decreased deep vessels were due to decreased superficial projections. In another study on 13 NAION patients, Liu et al.10 observed lower whole image VD but not parafoveal involvement, without a distinction of superficial and deep plexus. Comparing VD of two different optic neuropathies with similar involvements of RNFL and GCC gives insight to evaluate the relationship between neural loss and vascular damage. We found more macular superficial vasculature and temporal and inferior parafovea deep vessel loss in POAG than NAION eyes. First, this might indicate that 7
while the amount of macular superficial vessel dropout in NAION could be caused by GCC damage as secondary microvascular changes, POAG eyes showed more vessel loss with the given amount of GCC damage and therefore, reduced ocular blood flow could contribute primarily to this thickness/microvascular mismatch.17, 18 Similarly, Shoji et al.17 found a faster rate of macula VD loss without a change in GCC thickness in glaucoma eyes. In fact in most participants with moderate glaucoma, macula VD dropout exceeded the macular GCC loss. Additionally, reduced macular microcirculation in the normal hemisphere of glaucomatous eyes and unaffected fellow eyes supports the concept that perfusion defects may be independent of macular neuronal changes.26, 30 Second, involvement of inferior and temporal parafoveal deep vascularity in POAG than NAION also shows the vulnerability zones which are more prone to glaucomatous damage.31 This vulnerability zone does not have a role in NAION eyes. Finally, less involvement of the superficial plexus in NAION could explain the absence of deep plexus damage because deep vessels represent anastomotic capillary networks supplied by vertically oriented interconnecting arteries and veins from the superficial plexus and retinal autoregulation of the blood flow.32 With more severe involvement of the superficial plexus in POAG, compensatory mechanisms could not able to restore the blood supply to the deep vascular plexus. Our results from the correlation analysis showed that whole macula and parafoveal superficial VD correlated significantly with corresponding GCC thickness and visual field MD, but deep VD did not show meaningful correlation in the parafovea with GCC. Other studies have reported significant positive correlations between macular superficial VD and macular ganglion cells in different sectors.33Similar to our study, Soo et al.34 showed associations of superficial macular VD with structural and functional measurements, but deep macular VD did not show significant correlations with ganglion cell thickness. On the other hand, deep macular VD was associated to the central visual function. There are several limitations to the present study. First, it was a cross sectional study focused on moderate and severe POAG and NAION eyes. Earlier involvement of vessels or ganglion cells and patterns of vessel affection in other types of glaucoma could not be interpreted from our study. Second, it included a small sample of patients. Finally, while we measured only the superficial and deep plexus densities, measurement of three vascular plexuses (superficial, intermediate, and deep)32 could show different results. In conclusion, eyes with POAG had significantly more loss of OCT-A macula superficial VD and deep VD in the inferior and temporal parafoveal sectors than NAION with the same GCC and RNFL thicknesses. While this observation may indicate that at least some part of macular vessel involvement in POAG happens primarily in addition to secondary ganglion cell involvement, prospective longitudinal studies are needed to elucidate the relation between ganglion cells and their vascular supply.
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Acknowledgement: a. Funding/Support: Supported in part by the Michael and Francesca Freedman Glaucoma Research Fund of the New York Eye and Ear Infirmary of Mount Sinai, New York, NY (RR) b. Financial Disclosures: None References: 1. Arnold AC. Ischemic optic neuropathy. In: Miller NR, Newman NJ, Biousse V, eds. Clinical Neuro-Ophthalmology. 6th ed. Vol. 1. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:349–384. 2. Grieshaber MC, Mozaffarieh M, Flammer J. What is the link between vascular dysregulation and glaucoma? Surv Ophthalmol 2007; 52 Suppl 2: S144-54. 3. Flammer J, Orgul S, Costa VP, et al. The impact of ocular blood flow in glaucoma. Prog Retin Eye Res 2002; 21(4): 359-93. 4. Alnawaiseh M, Lahme L, Muller V, Rosentreter A, Eter N. Correlation of flow density, as measured using optical coherence tomography angiography, with structural and functional parameters in glaucoma patients. Graefes Arch Clin Exp Ophthalmol 2018;256(3): 589-97. 5. Yarmohammadi A, Zangwill LM, Diniz-Filho A, Suh MH, Yousefi S, Saunders LJ, et al. Relationship between optical coherence tomography angiography vessel density and severity of visual field loss in glaucoma. Ophthalmology 2016; 123:2498-2508. 6. Wright Mayes E, Cole ED, Dang S, Novais EA, Vuong L, Mendoza-Santiesteban C, Duker JS, Hedges TR 3rd. Optical coherence tomography angiography in nonarteritic anterior ischemic optic neuropathy. J Neuroophthalmol. 2017 Dec;37(4):358-364. 7. Hata M, Oishi A, Muraoka Y, Miyamoto K, Kawai K, Yokota S, et al. Structural and functional analyses in nonarteritic anterior ischemic optic neuropathy: Optical coherence tomography angiography. J Neuroophthalmol. 2017; 37:140-148. 8. Fard MA, Suwan Y, Moghimi S, Geyman LS, Chui TY, Rosen RB, Ritch R. Pattern of peripapillary capillary density loss in ischemic optic neuropathy compared to that in primary open-angle glaucoma. PLoS One. 2018 Jan 10;13(1):e0189237. 9. Augstburger E, Zéboulon P, Keilani C, Baudouin C, Labbé A. Retinal and choroidal microvasculature in nonarteritic anterior ischemic optic neuropathy: an optical coherence tomography angiography study. Invest Ophthalmol Vis Sci. 2018;59:870–877. 10. Liu CH, Wu WC, Sun MH, Kao LY, Lee YS, Chen HS. Comparison of the retinal microvascular density between open angle glaucoma and nonarteritic anterior ischemic optic neuropathy. Invest Ophthalmol Vis Sci. 2017;58:3350–3356. 11. Takusagawa HL, Liu L, Ma KN, et al. Projection-resolved optical coherence tomography angiography of macular retinal circulation in glaucoma. Ophthalmology 2017; 124(11): 1589-99. 12. Philip S, Najafi A, Tantraworasin A, Chui TYP, Rosen RB, Ritch R. Macula vessel density and foveal avascular zone parameters in exfoliation glaucoma compared to primary open-angle glaucoma. Invest Ophthalmol Vis Sci. 2019;60(4):1244-1253.
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13. Triolo G, Rabiolo A, Shemonski ND, et al. Optical coherence tomography angiography macular and peripapillary vessel perfusion density in healthy subjects, glaucoma suspects, and glaucoma patients. Invest Ophthalmol Vis Sci 2017;58(13):5713-22. 14. Chen HS, Liu CH, Wu WC, Tseng HJ, Lee YS. Optical Coherence Tomography Angiography of the superficial microvasculature in the macular and peripapillary areasin glaucomatous and healthy eyes. Invest Ophthalmol Vis Sci 2017; 58(9): 3637-45. 15. Lommatzsch C, Rothaus K, Koch JM, Heinz C, Grisanti S. OCTA vessel density changes in the macular zone in glaucomatous eyes. Graefes Arch Clin Exp Ophthalmol. 2018 Aug;256(8):1499-1508. 16. Choi J, Kwon J, Shin JW, Lee J, Lee S, Kook MS. Quantitative optical coherence tomography angiography of macular vascular structure and foveal avascular zone in glaucoma. PLoS One 2017; 12(9): e0184948. 17. Shoji T, Zangwill LM, Akagi T, et al. Progressive macula vessel density loss in primary open-angle glaucoma: a longitudinal study. Am J Ophthalmol. 2017;182:107–117. 18. Hou H, Moghimi S, Zangwill LM, Shoji T, Ghahari E, Penteado RC, et al. Macula vessel density and thickness in early primary open-angle glaucoma. Am J Ophthalmol. 2019 Mar;199:120-132. 19. Akagi T, Iida Y, Nakanishi H, Terada N, Morooka S, Yamada H, et al. Microvascular density in glaucomatous eyes with hemifield visual field defects: An optical coherence tomography angiography study. Am J Ophthalmol 2016: 168:237-49. 20. Lee YH, Kim KN, Heo DW, Kang TS, Lee SB, Kim CS. Difference in patterns of retinal ganglion cell damage between primary open-angle glaucoma and nonarteritic anterior ischaemic optic neuropathy. PLoS One. 2017;12(10):e0187093. 21. Fard MA, Afzali M, Abdi P, Yasseri M, Ebrahimi KB, Moghimi S. Comparison of the pattern of macular ganglion cell-inner plexiform layer defect between ischemic optic neuropathy and open–angle glaucoma. Invest Ophthalmol Vis Sci 2016; 57:1011–1016. 22. Hodapp E, Parrish RK II, Anderson DR. Clinical Decisions in Glaucoma. St Louis, MO: The CV Mosby Co.; 1993:52–61. 23. Lavia C, Bonnin S, Maule M, Erginay A, Tadayoni R, Gaudric A. Vessel density of superficial, intermediate, and deep capillary plexuses using optical coherence tomography angiography. Retina. 2019;39(2):247-258. 24. Fard MA, Ghahvechian H, Sahrayan A, Subramanian PS. Early macular vessel density loss in acute ischemic optic neuropathy compared to papilledema: implications for pathogenesis. Trans Vis Sci Tech. 2018; 7: 10. 25. Fard MA, Jalili J, Sahraiyan A, Khojasteh H, Hejazi M, Ritch R, Subramanian PS. Optical coherence tomography angiography in optic disc swelling. Am J Ophthalmol. 2018;191:116-123. 26. Yarmohammadi A, Zangwill LM, Manalastas PIC, et al. Peripapillary and macular vessel density in patients with primary open-angle glaucoma and unilateral visual field loss. Ophthalmology 2017;125(4):578-87. 27. Kim JS, Kim YK, Baek SU, Ha A, Kim YW, Jeoung JW, Park KH. Topographic correlation between macular superficial microvessel density and ganglion cell-inner 10
plexiform layer thickness in glaucoma-suspect and early normal-tension glaucoma. Br J Ophthalmol. 2019 Apr 2. pii: bjophthalmol-2018-313732. doi: 10.1136/bjophthalmol-2018-313732. 28. Ghahari E, Bowd C, Zangwill LM, Proudfoot J, Hasenstab KA, Hou H, et al. Association of macular and circumpapillary microvasculature with visual field sensitivity in advanced glaucoma. Am J Ophthalmol. 2019 Mar 13. pii: S00029394(19)30102-3. doi: 10.1016/j.ajo.2019.03.004. 29. Kur J, Newman EA, Chan-Ling T (2012) Cellular and physiological mechanisms underlying blood flow regulation in the retina choroid in health disease. Prog Retin Eye Res 31:377–406.] 30. Yarmohammadi A, Zangwill LM, Diniz-Filho A, et al. Peripapillary and macular vessel density in patients with glaucoma and single-hemifield visual defect. Ophthalmology. 2017;124:709–719. 31. Hood DC, Raza AS, de Moraes CGV, Liebmann JM, Ritch R. Glaucomatous damage of the macula. Prog Retin Eye Res.2013;32:1–21. 32. Campbell JP, Zhang M, Hwang TS, Bailey ST, Wilson DJ, Jia Y, Huang D. Detailed vascular anatomy of the human retina by projection-resolved optical coherence tomography angiography. Sci Rep. 2017; 7: 42201. 33. Kim JS, Kim YK, Baek SU, Ha A, Kim YW, Jeoung JW, Park KH. Topographic correlation between macular superficial microvessel density and ganglion cell-inner plexiform layer thickness in glaucoma-suspect and early normal-tension glaucoma. Br J Ophthalmol. 2019 Apr 2. pii: bjophthalmol-2018-313732. doi: 10.1136/bjophthalmol-2018-313732. 34. Jeon sj, Park HYL, Park CK. Effect of macular vascular density on central visual function and macular structure in glaucoma patients. Sci Rep. 2018; 8: 16009.
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Figure legend: Optical coherence tomography angiography (OCT-A) of macular vasculature in control, nonarteritic anterior ischemic optic neuropathy (NAION), and primary open angle glaucoma. Left column: ganglion cell complex (GCC) maps. NAION and POAG subjects had similar GCC thickness values; Second column: OCT-A images of superficial vessel density (SVD); Third column: Deep macular vessel density with projection. Forth column: deep vessel density (DVD) after projection removal Vessel density values of POAG eye were lower than NAION eye.
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Table 1. Demographic and ocular characteristics of healthy, chronic anterior ischemic optic neuropathy (cAION) and glaucomatous patients.
Age, years Visual Acuity, logMARa Visual field, MDb dB Average RNFLc, µm Superior RNFL, µm Temporal RNFL, µm Inferior RNFL, µm Nasal RNFL, µm Total GCCd, µm Superior GCC, µm Inferior GCC, µm ParaFovea GCC, µm Superior parafoveal GCC, µm Inferior parafoveal GCC, µm
cAION
Glaucoma
Control
56.7 ± 14.7 0.03 ± 0.005 -0.65±1.5 104.18 ± 6.92 127.42 ± 11.77 78.93 ± 8.54 128.15 ± 14.33 83.05 ± 12.15 99.80 ± 5.60 99.02 ± 5.83 100.50 ± 5.80 121.40 ± 9.54 120.73 ± 10.89
P value cAION vs Control >0.99 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001
P value Glaucoma vs Control 0.051 0.297 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001
P value cAION vs Glaucoma 0.18 <0.001 <0.99 0.46 0.18 >0.99 0.04 <0.99 0.463 0.763 0.22 0.777 0.629
57.4 ± 12.2 0.73 ± 0.74 -14.0±5.3 64.5 ± 13.6 77.6 ± 18.9 53.1 ± 14.1 79.1 ± 21.8 55.3 ± 13.9 70.01 ± 12.4 68.94 ± 13.48 71.11 ± 12.36 95.47 ± 16.60 97.58 ± 16.45
63.6 ± 10.4 0.17 ± 0.18 -12.7 ± 5.5 59.10 ± 17.45 68.94 ± 18.04 54.45 ± 17.53 65.64 ± 21.05 52.82 ± 14.63 72.71 ± 13.82 72.91 ± 13.81 72.69 ± 14.65 99.24 ± 12.67 96.17 ± 14.21
93.21 ± 18.28
96.17 ± 14.21
122.00 ± 8.54
<0.001
<0.001
0.884
a; logarithm of the minimum angle of resolution, b; mean deviation, c; retinal nerve fiber layer, d; ganglion cell complex. Comparisons are based on linear mixed model analysis. P < 0.05 was considered significant.
Table 2. Optical coherence tomography angiography of superficial macular vessel densities in healthy, chronic anterior ischemic optic neuropathy (cAION) and glaucomatous patients.
Vessel density
cAION
Glaucoma
Control
Whole Enface, % Superior EnFace, %
44.15 ± 4.35 43.96 ± 4.34
39.64 ± 6.92 39.79 ± 4.38
51.12 ± 3.37 50.96 ± 3.61
44.34 ± 4.63 40.02 ± 4.19 50.79 ± 3.51 Inferior EnFace, % 48.04 ± 5.48 43.72 ± 5.29 54.19 ± 4.10 Para fovea, % 48.32 ± 5.34 44.03 ± 6.16 54.87 ± 4.46 Para fovea hemi superior, % 47.76 ± 6.33 43.42 ± 4.96 53.51 ± 4.14 Para fovea hemi inferior, % 47.94 ± 7.29 44.16 ± 4.65 55.44 ± 3.67 Para fovea Temporal % 48.32 ± 5.06 43.63 ± 6.90 55.00 ± 4.69 Para fovea Superior, % 48.66 ± 5.26 44.05 ± 6.99 53.35 ± 6.05 Para fovea Nasal , % 47.25 ± 7.23 43.05 ± 5.50 53.04 ± 4.93 Para fovea Inferior, % Comparisons are based on linear mixed model analysis. P < 0.05 was considered significant.
P value cAION vs Control <0.001 <0.001
P value Glaucoma vs Control <0.001 <0.001
P value cAION vs Glaucoma 0.008 0.009
<0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.022 0.002
<0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001
0.005 0.007 0.019 0.004 0.020 0.015 0.026 0.029
Table 3. Interclass coefficient correlation (ICC) with 95% confidence interval (CI) for deep macular vessel densities. Vessel area Interobserver ICC (95% CI) Whole Enface, % 0.992 (0.981-0.996) Para fovea,% 0.979 (0.963-0.988) Para fovea Temporal, % 0.973 (0.932-0.987) Para fovea Superior, % 0.990 (0.983-0.994) Para fovea Nasal , % 0.978 (0.954-0.989) Para fovea Inferior, % 0.974 (0.950-0.986)
Vessel density
cAION
Glaucoma
Control
27.40 ± 8.63
P value cAION vs Control 0.348
P value Glaucoma vs Control 0.010
P value cAION vs Glaucoma 0.620
Whole Enface, %
23.72 ± 7.53
21.03 ± 8.70
Para fovea,%
29.81 ± 9.77
24.42 ± 9.67
31.92 ± 10.58
0.849
0.011
0.191
Para fovea Temporal, %
31.05 ± 9.66
22.33 ± 8.57
33.51 ± 10.78
0.773
<0.001
0.007
Para fovea Superior, %
28.24 ± 9.46
23.09 ± 10.53
31.84 ± 10.76
0.497
0.003
0.244
Para fovea Nasal , %
29.79 ± 10.60
27.67 ± 12.56
32.83 ± 10.42
0.734
0.203
0.891
Para fovea Inferior, %
30.84 ± 10.48
23.01 ± 11.10
31.78 ± 11.10
0.986
0.004
0.036
Table 4. Optical coherence tomography angiography of deep vessel densities using customized software in healthy, chronic anterior ischemic optic neuropathy (cAION) and glaucomatous patients
Comparisons are based on linear mixed model analysis. P < 0.05 was considered significant.
• • •
Macular superficial vessel density was significantly lower in NAION and glaucoma eyes than in normal eyes, with lower vessel density in glaucoma than in NAION eyes. Deep macular vessels in glaucoma eyes were significantly lower than in control eyes. Glaucoma eyes had lower temporal and inferior parafoveal vasculature values than NAION eyes.
S0002-9394(19)30473-8
DOI:
https://doi.org/10.1016/j.ajo.2019.09.015
Reference:
AJOPHT 11084
To appear in:
American Journal of Ophthalmology
Received Date: 5 June 2019 Revised Date:
12 August 2019
Accepted Date: 17 September 2019
Please cite this article as: Fard MA, Fakhraee G, Ghahvechian H, Sahraian A, Moghimi S, Ritch R, Macular Vascularity in Ischemic Optic Neuropathy Compared to Glaucoma by Projection-Resolved Optical Coherence Tomography Angiography, American Journal of Ophthalmology (2019), doi: https:// doi.org/10.1016/j.ajo.2019.09.015. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Inc. All rights reserved.
Abstract: PURPOSE: To compare macular vasculature in patients with primary open-angle glaucoma (POAG) POAG and atrophic non-arteritic anterior ischemic optic neuropathy (NAION). DESIGN: Prospective, cross-sectional study METHODS: Thirty seven eyes with moderate and advanced POAG, 19 eyes with atrophic NAION, and 40 eyes of normal subjects were imaged using optical coherence tomography angiography (OCT-A). Macular ganglion cell complex (GCC) and peripapillary retinal nerve fiber layer (RNFL) thicknesses were measured in addition to macular superficial and deep vasculature after projection removal using custom software. RESULTS: Linear models showed that while averaged peripapillary RNFL and macular GCC were not different between NAION and POAG eyes, both were significantly thinner than control eyes. Whole image macular superficial vessel density was significantly lower in NAION and glaucoma eyes (P=0.003 and <0.001, respectively) than in normal eyes, with lower vessel density in glaucoma than in NAION eyes (P=0.01). Whole image and parafoveal deep macular vessels in glaucoma eyes (21.0±8.7%, 24.4±9.6%) were significantly lower than in control eyes (27.4%±8.6%, 31.9%±10.6%) (P = 0.01 and P = 0.01, respectively). No significant differences in deep vessels were observed between NAION and control eyes. Glaucoma eyes had lower temporal and inferior parafoveal deep vasculature values than NAION eyes (P=0.007 and 0.03, respectively). CONCLUSIONS: In NAION and POAG with similar RNFL and macular damage, macular OCT-A shows less involvement of superficial and deep vascular plexus in NAION in contrast to POAG, which might show a primary vascular insult in addition to secondary vascular damage due to ganglion cell damage.
Macular Vascularity in Ischemic Optic Neuropathy Compared to Glaucoma by Projection-Resolved Optical Coherence Tomography Angiography
Short title: Macular Vessels in Ischemic Optic Neuropathy and Glaucoma Authors: Masoud Aghsaei Fard1, Ghasem Fakhraee1, Hossein Ghahvechian1, Alireza Sahraian1, Sasan Moghimi1,2, Robert Ritch3 Affiliations: 1
Farabi Eye Hospital, Tehran University of Medical science, Iran
2
Department of Ophthalmology, Shiley Eye Institute, University of California, San Diego
3
Einhorn Clinical Research Center, New York Eye and Ear Infirmary of Mount Sinai, New York, NY
Corresponding author: Masoud Aghsaei Fard, Qazvin Sq, Farabi Eye Hospital, Tehran University of Medical Science. Tehran, Iran, [email protected]
1
Introduction While primary open angle glaucoma (POAG) consists of progressive loss of retinal ganglion cells and their axons, nonarteritic anterior ischemic optic neuropathy (NAION) is characterized by acute optic nerve damage. Although NAION is associated with hypoperfusion of the short posterior ciliary arteries and infarction in the retrolaminar region of the optic nerve head, the role of the retinal and macular vascular system in the pathogenesis of POAG and NAION is not well understood.1-3 Optical coherence tomography angiography (OCT-A) can assess the circulation in the retina and optic nerve. Peripapillary and macular vasculature compromise in both NAION and glaucoma eyes has been reported using OCT-A. Several studies have found decreased peripapillary vessel density (VD) at the corresponding location of visual field defects in POAG and NAION.4-7 We previously reported that the degrees of peripapillary capillary density in these two forms of optic nerve damage were not different.8 It seems that dropout of peripapillary vessels is not specific to POAG or NAION. Similarly, prior studies have evaluated the role of the macular vasculature in both POAG and NAION. Reduced macular VD was shown in chronic NAION,9 in contrast to earlier work showing no macular vascular changes.10 However, in those studies, projection artifacts and duplication of superficial vascular patterns in the deeper retinal layers may have obfuscated the interpretation of data, as the authors had mentioned as limitations.10, 11 In addition, macular vascular dropout in various types of glaucomatous eyes suggests that the vascular system has an important role in the early diagnosis of glaucoma and in understanding its pathogenesis.12-16 Some studies showed that vascular abnormality and macular ganglion cell complex (GCC) thickness change might be interdependent,17-19 which raises the question as to whether the vessel dropout is a primary event or is the result of ganglion cell damage. While several studies noted that total macular GCC thickness does not differ between NAION and moderate and severe POAG,10, 20, 21 the amount of damage to the macular superficial and deep plexus has not been clearly defined, particularly after resolving projection artifacts. These two different optic neuropathies with similar ganglion cell loss make a model to test whether microvasculature impairment could vary in different diseases and thus provide further evidence that loss of vascular and neural tissue are independent.17-19 The purpose of the current study was to characterize and compare macular and parafoveal superficial and deep VDs and GCC thickness in NAION and POAG eyes after resolving projection.
2
Material and Methods Subjects Patients with moderate and severe POAG and post-acute NAION who were examined at New York Eye and Ear Infirmary of Mount Sinai and Farabi Eye Hospital between March 2016 and September 2017 were enrolled in this prospective, cross-sectional, comparative study. The study was approved by the research ethics committee of Farabi Eye Hospital and NYEEI Institutional Review Board. Informed consent was obtained from all patients, and all investigations adhered to the tenets of the Declaration of Helsinki. Participants with age ≥18 years, a spherical refraction within ±5.0 diopters (D), and cylinder correction within ±3.0 D were included. Diagnosis of NAION and POAG was established by two authors (MAF, RR) based on evaluation of the patient's history, examination, and review of diagnostic testing such as OCT and visual fields, if available. Patients with POAG manifested enlargement of the vertical cup-to-disc ratio, diffuse or focal thinning of the neuroretinal rim, and an open iridocorneal angle on gonioscopy. Presence of a PSD outside 95% normal limits, which were confirmed on at least 2 consecutive, reliable tests and glaucoma hemifield test outside normal limits were used for the glaucoma diagnosis.22 Moderate and severe POAG eyes with 24-2 mean deviation (MD) of less than -6 dB were recruited so that the glaucoma and NAION groups would be similar in terms of severity.21,22 Chronic NAION was defined as patients having had a history of sudden visual loss >6 months prior to enrollment, previous documented optic disc edema, developing a pale optic disc with complete resolution of disc edema at the time of the study, absence of proptosis, and an ophthalmologically normal fellow eye. Patients with other ocular or neurologic disease or evidence of giant cell arteritis with high erythrocyte sedimentation rate and C-reactive protein, or inflammatory optic neuritis were excluded. The control group comprised subjects with a best-corrected visual acuity of ≥20/30, normal optic disc appearance on fundus examination, normal RNFL thickness by OCT, and IOP <21 mmHg. All participants underwent a comprehensive ophthalmic examination, which included assessment of visual acuity, IOP measurement by Goldmann applanation tonometry, slit lamp examination, gonioscopy, fundus examination, VF testing by standard automated perimetry (SAP, Humphrey Field Analyzer; 24-2 Swedish interactive threshold algorithm; Carl Zeiss Meditec, Jena, Germany), and OCT-A imaging. Optical Coherence Tomography Angiography and Spectral-Domain Optical Coherence Tomography All subjects underwent OCT-A and SD-OCT imaging using the AngioVue imaging system (Optovue, Inc., Fremont, CA, USA, RTVue XR version 2018.0.0.18) that has been described previously. Macular 6 mm x 6 mm scans centered on the fovea were acquired with the OCT-A AngioVue system. Patients with poor image clarity, and scans with signal strength index of <40 were excluded. Retinal layers were 3
automatically segmented in order to visualize the superficial vascular plexus in a slab from the internal limiting membrane to 9 µm above the junction between the inner plexiform layer (IPL) and the inner nuclear layer (INL), deep retinal vasculatures from 9 µm above the IPL-INL junction to 9 µm below the outer plexiform layer and outer nuclear layer (OPL-ONL).23, 24 Blood flow information as a VD map (%) in superficial slabs was obtained in whole macular image and parafoveal regions. Parafoveal VD was measured in an annulus centered on the fovea with an inner diameter of 1 mm and outer diameter of 3 mm. The parafoveal region was divided into four sectors (superior, inferior, temporal, and nasal) in addition to superior and inferior hemispheric areas. We then employed customized MATLAB software (The MathWorks, Inc., Natick, MA, USA) for calculating deep VD after removing the large vessels of superficial layer that had been projected into the deep layer which is similar to the method we have described previously for removing large peripapillary vessels.25 The latest commercial software (PAR algorithm) resolves the flow projection issue in the parafovea, but projection removal is not perfect and duplication of superficial vessels were still visible in whole macular deep images. To calculate deep VD values, thresholding grayscale deep retinal images of OCT-A were performed to create binary images with threshold values, which were changed manually in each image to remove the large projecting vessels. Then, deep VD was calculated in whole-image, whole parafovea, and each quadrant of parafovea. A standard 360°, 3.4 mm diameter circular scan was used to measure RNFL thickness, and the mean and each sector RNFL values were recorded. The macula cube scanning protocol measured the GCC thickness over a 7 mm diameter and parafoveal GCC was measured over 3 mm diameter centered on the fovea. Total, superior and inferior hemispheres GCC were recorded for both macular and parafoveal areas. Statistical Analysis The distribution of continuous variables was assessed by inspecting histograms and using Shapiro-Wilk W tests of normality. Linear mixed modeling was used for the comparison between groups, after accounting for inter-eye correlation and adjusting for age and multiple comparisons with Bonferroni correction. In this method, the correlation in outcomes between paired eyes of a subject was accounted for by adding a random effect. In addition, Pearson correlation analysis was used to find associations between thickness of ganglion cell complex, visual field MD, visual acuity and macular vascular densities. Finally, to evaluate the inter-observer reproducibility of our deep vessel measurements, 18 NAION eyes, 12 POAG eyes, and 20 normal controls were randomly selected. Analysis was based on 2 independent series of re-evaluations made by two different investigators. The absolute agreement of the measurements conducted by the 2 observers were calculated with the intraclass correlation coefficient (ICC) from a 2-way mixed effect
model. All statistical analyses were performed with the SPSS software (IBM Corp. Released 2013. IBM SPSS Statistics for Windows, Version 22.0. Armonk, NY: IBM Corp.). P-values <0.05 were considered significant.
4
Results: Ninety six eyes were included after excluding 15 eyes due to segmentation errors: 40 control eyes, 19 chronic NAION, and 37 POAG eyes. One NAION patient and four POAG patients had both eyes included in the study. Median time elapsed after visual loss in chronic NAION eyes was 28.6 weeks (range 24-34 weeks), respectively. Demographic information and structural RNFL values are summarized in Table 1. Mean age in the NAION, POAG, and control eyes was not significantly different. Retinal nerve fiber layer thicknesses in chronic NAION and POAG were not significantly different from each other (64.5±13.6 vs 59.1±17.4, respectively, P=0.46), while both were thinner than control eyes. Total macular GCC thickness was lower in chronic NAION eyes (70.01±12.4 µm) and POAG eyes ( 72.71±13.8 µm) than control eyes, without significant difference between chronic NAION and POAG eyes (P=0.46). Parafoveal GCC thickness was also not different between POAG and NAION eyes and both were lower than in the control group (Table 1). Superficial retinal vasculature density: OCT-A results showed that the whole macular and parafoveal superficial VDs in POAG eyes with values of 39.6±6.9% and 43.7±5.2% were significantly lower compared to controls. (51.1±3.3 % and 54.2±4.1%, both P<0.001). Chronic NAION eyes also had significantly lower whole macular and parafoveal VDs with values of 44.1±4.3% and 48.0±5.4% than control eyes, respectively (Both P<0.001). Comparison between NAION and POAG eyes showed that whole macular and parafoveal VDs were significantly lower in POAG eyes than NAION eyes. Specifically, superficial vasculature of the superior and inferior hemi-parafoveal values and its quadrants in POAG eyes was also lower than in NAION eyes (Table 2). Deep retinal vasculature density after projection removal: All deep vessel values using customized Matlab software showed an excellent interobserver reproducibility that ranged from an ICC of 0.973 to 0.996 for the various parameters (Table 3). Significantly lower whole image and parafoveal vessel values were found in POAG eyes with values of 21.03±8.7% and 24.43±9.6% compared to control eyes with values of 27.40±8.63% and 31.92±10.58%, respectively (P=0.01 and 0.01). Whole image and parafoveal deep vascular values of NAION eyes were not different from control eyes (P=0.34, P=0.89, respectively). Glaucoma eyes had lower temporal and inferior parafoveal vasculature values than NAION eyes (P=0.007 and 0.03, respectively). Whole macula and parafoveal values were not significantly different between POAG and NAION eyes (Table 4). Results from the Pearson correlation analysis showed that total GCC and superior and inferior hemi-GCC were significantly correlated to corresponding whole image and superior and inferior hemiretinal superficial VD (r=0.64, P<0.001; r=0.64, P<0.001; r=0.60, P<0.001). Similarly parafoveal GCC and parafoveal superficial VD were correlated (r=0.41, P=0.001). While there was weak correlation between total GCC with whole macular deep vasculature (r=0.35, P=0.004), correlation was not found between parafoveal GCC and parafoveal deep VD (r=0.1, P=0.45). Our 5
analysis also showed correlations between whole macular and parafoveal superficial VDs and visual field MD (r=0.37, P=0.001 and r=0.36, P=0.002, respectively). Whole image deep vessel density but not parafoveal deep vascular value was weakly correlated to visual field MD (r=0.26, P=0.03 and r=0.20, P=0.10, respectively). Visual acuity was not correlated with any vascular densities.
6
Discussion: We compared whole macula and parafoveal VD in control, NAION and POAG eyes with moderate and severe glaucomatous damage. While we found lower superficial and deep vasculatures in POAG eyes than in control eyes, only superficial vasculature was lower in NAION eyes than in control eyes. There were no significant differences between POAG and NAION groups in the peripapillary RNFL and macular GCC, allowing for analysis of groups with comparable optic nerve and macular damage. When comparing macular vasculature between NAION and POAG, significantly lower superficial vasculature of the whole macula and parafovea was found in POAG eyes than NAION eyes. From parafoveal sectors, inferior and temporal areas had lower deep vessels in POAG eyes than NAION eyes. In addition, we found significant associations between superficial vasculature density and corresponding GCC and visual field MD. Such correlation was not found for parafoveal GCC and deep VD. Many published studies have focused on the reduced VD in the superficial layer in glaucomatous eyes13, 14, 17-19, 26-28 because the ganglion cell layer receives its blood supply from the superficial retinal vascular plexus.29 However, only a few papers have provided information on the deep plexus in glaucomatous eyes, with differing results.11, 15,16, 18 While Lommatzsch et al.15 showed decreased deep vessels in mild glaucoma cases compared to control eyes, of note, their measured higher density of deep vessels than superficial macula ones might be due to duplication of superficial vessels on deep vessels. Hou et al.18 did not observe loss of deep macular vessels in glaucoma suspect and mild glaucoma cases without removing projection flow. Two studies11,16 used customized software. Choi et al.16 found a decrease in both superficial and deep macular vasculature in different stages of glaucoma and reported 25% as the mean deep VD in healthy eyes. In our study, we addressed the issue of duplication of superficial vessels on deep vasculature and found lower deep and superficial macular vessel in glaucoma than normal eyes. In our study the value of deep VD in control group was 27%, similar to Choi et al.16 In contrast, Takusagawa et al.11 did not find a lower density of deep vascular plexus in mild to moderate glaucoma cases after projection removal. It seems the difference in deep vessel involvement between their study and our study might be related to the glaucoma severity. Additionally, we also measured those vessels in NAION eyes. We found lower density of superficial vessels but not deep vessels compared to normal controls. Augstburger et al.9 reported lower VD of macular capillaries in the superficial and deep plexus. But again they reported a higher value of deep vessels (58%) due to duplication of superficial vessels and “apparently” decreased deep vessels were due to decreased superficial projections. In another study on 13 NAION patients, Liu et al.10 observed lower whole image VD but not parafoveal involvement, without a distinction of superficial and deep plexus. Comparing VD of two different optic neuropathies with similar involvements of RNFL and GCC gives insight to evaluate the relationship between neural loss and vascular damage. We found more macular superficial vasculature and temporal and inferior parafovea deep vessel loss in POAG than NAION eyes. First, this might indicate that 7
while the amount of macular superficial vessel dropout in NAION could be caused by GCC damage as secondary microvascular changes, POAG eyes showed more vessel loss with the given amount of GCC damage and therefore, reduced ocular blood flow could contribute primarily to this thickness/microvascular mismatch.17, 18 Similarly, Shoji et al.17 found a faster rate of macula VD loss without a change in GCC thickness in glaucoma eyes. In fact in most participants with moderate glaucoma, macula VD dropout exceeded the macular GCC loss. Additionally, reduced macular microcirculation in the normal hemisphere of glaucomatous eyes and unaffected fellow eyes supports the concept that perfusion defects may be independent of macular neuronal changes.26, 30 Second, involvement of inferior and temporal parafoveal deep vascularity in POAG than NAION also shows the vulnerability zones which are more prone to glaucomatous damage.31 This vulnerability zone does not have a role in NAION eyes. Finally, less involvement of the superficial plexus in NAION could explain the absence of deep plexus damage because deep vessels represent anastomotic capillary networks supplied by vertically oriented interconnecting arteries and veins from the superficial plexus and retinal autoregulation of the blood flow.32 With more severe involvement of the superficial plexus in POAG, compensatory mechanisms could not able to restore the blood supply to the deep vascular plexus. Our results from the correlation analysis showed that whole macula and parafoveal superficial VD correlated significantly with corresponding GCC thickness and visual field MD, but deep VD did not show meaningful correlation in the parafovea with GCC. Other studies have reported significant positive correlations between macular superficial VD and macular ganglion cells in different sectors.33Similar to our study, Soo et al.34 showed associations of superficial macular VD with structural and functional measurements, but deep macular VD did not show significant correlations with ganglion cell thickness. On the other hand, deep macular VD was associated to the central visual function. There are several limitations to the present study. First, it was a cross sectional study focused on moderate and severe POAG and NAION eyes. Earlier involvement of vessels or ganglion cells and patterns of vessel affection in other types of glaucoma could not be interpreted from our study. Second, it included a small sample of patients. Finally, while we measured only the superficial and deep plexus densities, measurement of three vascular plexuses (superficial, intermediate, and deep)32 could show different results. In conclusion, eyes with POAG had significantly more loss of OCT-A macula superficial VD and deep VD in the inferior and temporal parafoveal sectors than NAION with the same GCC and RNFL thicknesses. While this observation may indicate that at least some part of macular vessel involvement in POAG happens primarily in addition to secondary ganglion cell involvement, prospective longitudinal studies are needed to elucidate the relation between ganglion cells and their vascular supply.
8
Acknowledgement: a. Funding/Support: Supported in part by the Michael and Francesca Freedman Glaucoma Research Fund of the New York Eye and Ear Infirmary of Mount Sinai, New York, NY (RR) b. Financial Disclosures: None References: 1. Arnold AC. Ischemic optic neuropathy. In: Miller NR, Newman NJ, Biousse V, eds. Clinical Neuro-Ophthalmology. 6th ed. Vol. 1. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:349–384. 2. Grieshaber MC, Mozaffarieh M, Flammer J. What is the link between vascular dysregulation and glaucoma? Surv Ophthalmol 2007; 52 Suppl 2: S144-54. 3. Flammer J, Orgul S, Costa VP, et al. The impact of ocular blood flow in glaucoma. Prog Retin Eye Res 2002; 21(4): 359-93. 4. Alnawaiseh M, Lahme L, Muller V, Rosentreter A, Eter N. Correlation of flow density, as measured using optical coherence tomography angiography, with structural and functional parameters in glaucoma patients. Graefes Arch Clin Exp Ophthalmol 2018;256(3): 589-97. 5. Yarmohammadi A, Zangwill LM, Diniz-Filho A, Suh MH, Yousefi S, Saunders LJ, et al. Relationship between optical coherence tomography angiography vessel density and severity of visual field loss in glaucoma. Ophthalmology 2016; 123:2498-2508. 6. Wright Mayes E, Cole ED, Dang S, Novais EA, Vuong L, Mendoza-Santiesteban C, Duker JS, Hedges TR 3rd. Optical coherence tomography angiography in nonarteritic anterior ischemic optic neuropathy. J Neuroophthalmol. 2017 Dec;37(4):358-364. 7. Hata M, Oishi A, Muraoka Y, Miyamoto K, Kawai K, Yokota S, et al. Structural and functional analyses in nonarteritic anterior ischemic optic neuropathy: Optical coherence tomography angiography. J Neuroophthalmol. 2017; 37:140-148. 8. Fard MA, Suwan Y, Moghimi S, Geyman LS, Chui TY, Rosen RB, Ritch R. Pattern of peripapillary capillary density loss in ischemic optic neuropathy compared to that in primary open-angle glaucoma. PLoS One. 2018 Jan 10;13(1):e0189237. 9. Augstburger E, Zéboulon P, Keilani C, Baudouin C, Labbé A. Retinal and choroidal microvasculature in nonarteritic anterior ischemic optic neuropathy: an optical coherence tomography angiography study. Invest Ophthalmol Vis Sci. 2018;59:870–877. 10. Liu CH, Wu WC, Sun MH, Kao LY, Lee YS, Chen HS. Comparison of the retinal microvascular density between open angle glaucoma and nonarteritic anterior ischemic optic neuropathy. Invest Ophthalmol Vis Sci. 2017;58:3350–3356. 11. Takusagawa HL, Liu L, Ma KN, et al. Projection-resolved optical coherence tomography angiography of macular retinal circulation in glaucoma. Ophthalmology 2017; 124(11): 1589-99. 12. Philip S, Najafi A, Tantraworasin A, Chui TYP, Rosen RB, Ritch R. Macula vessel density and foveal avascular zone parameters in exfoliation glaucoma compared to primary open-angle glaucoma. Invest Ophthalmol Vis Sci. 2019;60(4):1244-1253.
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Figure legend: Optical coherence tomography angiography (OCT-A) of macular vasculature in control, nonarteritic anterior ischemic optic neuropathy (NAION), and primary open angle glaucoma. Left column: ganglion cell complex (GCC) maps. NAION and POAG subjects had similar GCC thickness values; Second column: OCT-A images of superficial vessel density (SVD); Third column: Deep macular vessel density with projection. Forth column: deep vessel density (DVD) after projection removal Vessel density values of POAG eye were lower than NAION eye.
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Table 1. Demographic and ocular characteristics of healthy, chronic anterior ischemic optic neuropathy (cAION) and glaucomatous patients.
Age, years Visual Acuity, logMARa Visual field, MDb dB Average RNFLc, µm Superior RNFL, µm Temporal RNFL, µm Inferior RNFL, µm Nasal RNFL, µm Total GCCd, µm Superior GCC, µm Inferior GCC, µm ParaFovea GCC, µm Superior parafoveal GCC, µm Inferior parafoveal GCC, µm
cAION
Glaucoma
Control
56.7 ± 14.7 0.03 ± 0.005 -0.65±1.5 104.18 ± 6.92 127.42 ± 11.77 78.93 ± 8.54 128.15 ± 14.33 83.05 ± 12.15 99.80 ± 5.60 99.02 ± 5.83 100.50 ± 5.80 121.40 ± 9.54 120.73 ± 10.89
P value cAION vs Control >0.99 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001
P value Glaucoma vs Control 0.051 0.297 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001
P value cAION vs Glaucoma 0.18 <0.001 <0.99 0.46 0.18 >0.99 0.04 <0.99 0.463 0.763 0.22 0.777 0.629
57.4 ± 12.2 0.73 ± 0.74 -14.0±5.3 64.5 ± 13.6 77.6 ± 18.9 53.1 ± 14.1 79.1 ± 21.8 55.3 ± 13.9 70.01 ± 12.4 68.94 ± 13.48 71.11 ± 12.36 95.47 ± 16.60 97.58 ± 16.45
63.6 ± 10.4 0.17 ± 0.18 -12.7 ± 5.5 59.10 ± 17.45 68.94 ± 18.04 54.45 ± 17.53 65.64 ± 21.05 52.82 ± 14.63 72.71 ± 13.82 72.91 ± 13.81 72.69 ± 14.65 99.24 ± 12.67 96.17 ± 14.21
93.21 ± 18.28
96.17 ± 14.21
122.00 ± 8.54
<0.001
<0.001
0.884
a; logarithm of the minimum angle of resolution, b; mean deviation, c; retinal nerve fiber layer, d; ganglion cell complex. Comparisons are based on linear mixed model analysis. P < 0.05 was considered significant.
Table 2. Optical coherence tomography angiography of superficial macular vessel densities in healthy, chronic anterior ischemic optic neuropathy (cAION) and glaucomatous patients.
Vessel density
cAION
Glaucoma
Control
Whole Enface, % Superior EnFace, %
44.15 ± 4.35 43.96 ± 4.34
39.64 ± 6.92 39.79 ± 4.38
51.12 ± 3.37 50.96 ± 3.61
44.34 ± 4.63 40.02 ± 4.19 50.79 ± 3.51 Inferior EnFace, % 48.04 ± 5.48 43.72 ± 5.29 54.19 ± 4.10 Para fovea, % 48.32 ± 5.34 44.03 ± 6.16 54.87 ± 4.46 Para fovea hemi superior, % 47.76 ± 6.33 43.42 ± 4.96 53.51 ± 4.14 Para fovea hemi inferior, % 47.94 ± 7.29 44.16 ± 4.65 55.44 ± 3.67 Para fovea Temporal % 48.32 ± 5.06 43.63 ± 6.90 55.00 ± 4.69 Para fovea Superior, % 48.66 ± 5.26 44.05 ± 6.99 53.35 ± 6.05 Para fovea Nasal , % 47.25 ± 7.23 43.05 ± 5.50 53.04 ± 4.93 Para fovea Inferior, % Comparisons are based on linear mixed model analysis. P < 0.05 was considered significant.
P value cAION vs Control <0.001 <0.001
P value Glaucoma vs Control <0.001 <0.001
P value cAION vs Glaucoma 0.008 0.009
<0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.022 0.002
<0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001
0.005 0.007 0.019 0.004 0.020 0.015 0.026 0.029
Table 3. Interclass coefficient correlation (ICC) with 95% confidence interval (CI) for deep macular vessel densities. Vessel area Interobserver ICC (95% CI) Whole Enface, % 0.992 (0.981-0.996) Para fovea,% 0.979 (0.963-0.988) Para fovea Temporal, % 0.973 (0.932-0.987) Para fovea Superior, % 0.990 (0.983-0.994) Para fovea Nasal , % 0.978 (0.954-0.989) Para fovea Inferior, % 0.974 (0.950-0.986)
Vessel density
cAION
Glaucoma
Control
27.40 ± 8.63
P value cAION vs Control 0.348
P value Glaucoma vs Control 0.010
P value cAION vs Glaucoma 0.620
Whole Enface, %
23.72 ± 7.53
21.03 ± 8.70
Para fovea,%
29.81 ± 9.77
24.42 ± 9.67
31.92 ± 10.58
0.849
0.011
0.191
Para fovea Temporal, %
31.05 ± 9.66
22.33 ± 8.57
33.51 ± 10.78
0.773
<0.001
0.007
Para fovea Superior, %
28.24 ± 9.46
23.09 ± 10.53
31.84 ± 10.76
0.497
0.003
0.244
Para fovea Nasal , %
29.79 ± 10.60
27.67 ± 12.56
32.83 ± 10.42
0.734
0.203
0.891
Para fovea Inferior, %
30.84 ± 10.48
23.01 ± 11.10
31.78 ± 11.10
0.986
0.004
0.036
Table 4. Optical coherence tomography angiography of deep vessel densities using customized software in healthy, chronic anterior ischemic optic neuropathy (cAION) and glaucomatous patients
Comparisons are based on linear mixed model analysis. P < 0.05 was considered significant.
• • •
Macular superficial vessel density was significantly lower in NAION and glaucoma eyes than in normal eyes, with lower vessel density in glaucoma than in NAION eyes. Deep macular vessels in glaucoma eyes were significantly lower than in control eyes. Glaucoma eyes had lower temporal and inferior parafoveal vasculature values than NAION eyes.