Optical Coherence Tomography Angiography in Nonarteritic Anterior Ischemic Optic Neuropathy

Optical coherence tomography angiography (OCTA) has demonstrated good utility in qualitative analysis of retinal and choroidal vasculature and therefore may be relevant in the diagnostic and treatment efforts surrounding nonarteritic anterior ischemic optic neuropathy (NAION).; Retrospective, cross-sectional study of 10 eyes of 9 patients with a previous or new diagnosis of NAION that received imaging with OCTA between November 2015 and February 2016. Two independent readers qualitatively analyzed the retinal peripapillary capillaries (RPC) and peripapillary choriocapillaris (PCC) for flow impairment. Findings were compared with automated visual field and structural optical coherence tomography (OCT) studies.; ; Flow impairment seen on OCTA in the RPC corresponded to structural OCT deficits of the retinal nerve fiber layer (RNFL) and ganglion cell layer complex (GCC) in 80% and 100% of eyes, respectively, and to automated visual field deficits in 90% of eyes. Flow impairment seen on OCTA in the PCC corresponded to structural OCT deficits of the RNFL and GCC in 70% and 80% of eyes, respectively, and to visual field deficits in 60%-80% of eyes.; ; OCTA can noninvasively visualize microvascular flow impairment in patients with NAION.

Original Contribution Optical Coherence Tomography Angiography in Nonarteritic Anterior Ischemic Optic Neuropathy Emily Wright Mayes, MD, Emily D. Cole, BS, Sabin Dang, MD, Eduardo A. Novais, MD, Laurel Vuong, MD, Carlos Mendoza-Santiesteban, MD, Jay S. Duker, MD, Thomas R. Hedges III, MD Background: Optical coherence tomography angiography (OCTA) has demonstrated good utility in qualitative analysis of retinal and choroidal vasculature and therefore may be relevant in the diagnostic and treatment efforts surrounding nonarteritic anterior ischemic optic neuropathy (NAION). Methods: Retrospective, cross-sectional study of 10 eyes of 9 patients with a previous or new diagnosis of NAION that received imaging with OCTA between November 2015 and February 2016. Two independent readers qualitatively analyzed the retinal peripapillary capillaries (RPC) and peripapillary choriocapillaris (PCC) for flow impairment. Findings were compared with automated visual field and structural optical coherence tomography (OCT) studies. Results: Flow impairment seen on OCTA in the RPC corresponded to structural OCT deficits of the retinal nerve fiber layer (RNFL) and ganglion cell layer complex (GCC) in 80% and 100% of eyes, respectively, and to automated visual field deficits in 90% of eyes. Flow impairment seen on OCTA in the PCC corresponded to structural OCT deficits of the RNFL and GCC in 70% and 80% of eyes, respectively, and to visual field deficits in 60%-80% of eyes. New England Eye Center (EWM, EDC, SD, EAN, LV, CM-S, JSD, TRH), Tufts Medical Center, Boston, Massachusetts; and Universidade Federal de São Paulo (EAN), Escola Paulista de Medicina, São Paulo, Brazil. E. A. Novais is a researcher supported by CAPES Foundation, Miń istry of Education of Brazil, Brasilia, DF, Brazil. C. MendozaSantiesteban receives research support from The Dysautonomia Foundation Inc. T. R. Hedges and C. Mendoza-Santiesteban receive research support from The Massachusetts Lions Clubs/Research to Prevent Blindness Challenge Grant. J. S. Duker is a consultant for and receives research support from Carl Zeiss Meditec, OptoVue. C. Mendoza-Santiesteban has served as a consultant/advisory board member for EISAI/H3, Roland Consult and Carl Zeiss Meditec. The remaining authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the full text and PDF versions of this article on the journal's Web site (www. jneuro-ophthalmology.com). Address correspondence to Thomas R. Hedges III, MD, New England Eye Center, Tufts Medical Center, 800 Washington Street, Boston, MA 02111; E-mail: [e-mail] 358 Conclusions: OCTA can noninvasively visualize microvascular flow impairment in patients with NAION. Journal of Neuro-Ophthalmology 2017;37:358-364 doi: 10.1097/WNO.0000000000000493 © 2017 by North American Neuro-Ophthalmology Society N onarteritic anterior ischemic optic neuropathy (NAION) is the consequence of an acute ischemic event of the optic nerve head and may result in devastating visual sequelae (1). The pathophysiology of NAION remains unclear, but there is evidence that it may be the result of hypoperfusion of the optic disc microcirculation, namely the short posterior ciliary arteries (1-7). NAION is known to be associated with structural crowding of the optic disc, hypertension, diabetes, and hyperlipidemia and may have a possible association with hypercoagulable disorders, sleep apnea, and nocturnal hypotension (1). Furthermore, it is the most common acute optic neuropathy among patients older than 50 years (8). This statistic, in conjunction with the absence of an effective treatment or means of prevention, has sparked a great deal of interest in describing the microcirculatory level and extent of hypoperfusion involved in these ischemic events (2-7). Histopathology, color Doppler, fluorescein angiography (FA), and indocyanine green angiography (ICGA) have been used to investigate the microvascular pathophysiology in NAION (2,4-6,9). The earliest histopathological studies that examined patients with anterior ischemic optic neuropathy suggested that the posterior laminar and retrolaminar optic nerve were the most probable areas of infarction (6). Color Doppler velocimetry has not consistently produced reliable measurements of the posterior ciliary artery circulation of NAION eyes (9). One investigation of FA in NAION showed a statistically significant delay in both the onset and the time to completion of prelaminar optic Wright Mayes et al: J Neuro-Ophthalmol 2017; 37: 358-364 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution disc filling. However, there was no significant delay in the onset or completion of peripapillary choroidal filling in NAION eyes compared with age-matched controls (2). Similarly, Oto et al (4) found no statistically significant increase in the frequency of peripapillary choroidal watershed zone filling delay in NAION eyes compared with controls used both FA and ICGA. These investigators also concluded that ICGA was nonsuperior, and perhaps inferior to FA, in showing the vascular pathology in NAION. FA, however, is limited by its inability to clearly demonstrate laminar and retrolaminar blood flow. In vivo imaging of the peripapillary choriocapillaris (PCC), in particular, has been challenging with traditional FA given its location beneath the retinal pigment epithelium and dye leakage due to its fenestrated nature (10). Optical coherence tomography angiography (OCTA) is a technology that allows better visualization of vascular pathology in ocular diseases. This imaging technique compares the decorrelation signal between sequential optical coherence tomography (OCT) B scans acquired at the same depth to create en face angiograms that provide detailed images of retinal and choroidal blood flow. The decorrelation signal indicates a discrepancy in erythrocyte movement between sequential B scans. Hence, the reconstructed en face angiograms provide information regarding both microvascular structure and blood flow at a given depth. Advantageous qualities of OCTA include that it is non-invasive, depth resolved, and can be carried out rapidly (11,12). The purpose of our study was to use OCTA to qualitatively analyze the peripapillary vasculature in NAION eyes. We hypothesized that OCTA would provide details of the peripapillary microvasculature of NAION eyes that cannot be visualized with traditional FA, ICGA, color Doppler, and histopathological techniques. METHODS Patients with previous or newly diagnosed NAION were recruited for our retrospective, cross-sectional study. Study participants were diagnosed with NAION by a neuro-ophthalmologist (TRH) at the New England Eye Center at Tufts Medical Center. Participants were excluded if they had been diagnosed with a previous or concomitant, potentially confounding optic neuropathy or retinopathy. OCTA images were excluded if there was excessive motion artifact, low signal quality, or signal blockage obscuring accurate interpretation of areas of hypoperfusion in the retinal peripapillary capillaries (RPC). For each study participant, OCTA images of the peripapillary vasculature were acquired using the RTVue XR Avanti with prototype AngioVue software (Optovue, Inc, Fremont, CA), structural OCT images of the retinal nerve fiber layer (RNFL) and ganglion cell layer complex (GCC) were obtained using Cirrus HD-OCT (Carl Zeiss Meditec, Inc, Dublin, CA), and automated visual fields FIG. 1. Optical coherence tomography angiography (OCTA) with misplacement of automated segmentation of the peripapillary choriocapillaris (PCC) by the RTVue XR Avanti with prototype AngioVue software. A. Automated segmentation of the PCC occurs above the retinal pigment epithelium (RPE) at the level of the outer retina as seen in the B scan (yellow arrowheads). B. Manual correction of the segmentation of the horizontal blue line beneath the RPE (green arrowheads). C. OCTA of the missegmentation of the PCC shows no evidence of flow impairment. D. OCTA of the corrected segmentation of the PCC shows flow impairment on the angiogram (yellow arrows). Wright Mayes et al: J Neuro-Ophthalmol 2017; 37: 358-364 359 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution (Humphrey visual field analyzer) (Carl Zeiss Meditec, Inc) were obtained in both eyes. The OCTA device operates at w840 nm wavelength and scans at a rate of 70,000 A scans per second to acquire OCTA volumes consisting of 2 repeated B scans from 304 sequentially uniformly spaced locations. Each B scan consists of 304 A scans for a total of 2 · 304 · 304 A scans per acquisition, with a total acquisition time of approximately 3 seconds, and an axial optical resolution of w5 mm. Splitspectrum amplitude-decorrelation angiography software is used to improve the signal-to-noise ratio (13,14). Motion correction is performed using registration of 2 orthogonally acquired volumes (15,16). OCTA images were analyzed at the level of the RPC and PCC. The images first were segmented using OptoVue automated segmentation algorithms, then the segmentation lines were manually adjusted up or down to best visualize the RPC and PCC. This manual adjustment was necessary because the automated segmentation on the software erroneously detects the PCC to be above the retinal pigment epithelium (Fig. 1). OCTA images of eyes with NAION were qualitatively graded for areas of ischemia or flow impairment in the RPC and PCC by 2 independent Boston Image Reading Center graders who are experienced in the interpretation of OCTA images. The readers were masked to visual field defects and independently graded the angiograms. Any discrepancies were resolved by open adjudication. The en face OCTA were viewed alongside the structural en face OCT and corresponding regions of low OCT signal or signal blockage on the structural en face OCT were taken into account when analyzed by the readers and accordingly were not considered to be areas of flow impairment. Angiograms were analyzed by quadrants (superonasal, superotemporal, inferonasal, and inferotemporal) centered around the optic nerve head. The reader reported whether FIG. 2. Multimodal analysis of the right eye (OD) of a 63-year-old patient with acute nonarteritic anterior ischemic optic neuropathy (Patient 1). A. Optical coherence tomography angiogram (OCTA) segmented at the level of the retinal peripapillary capillaries. Yellow dotted lines outline region of sparse capillaries indicating flow impairment. B. Structural en face optical coherence tomography (OCT) corresponding to OCTA from A. Yellow arrowheads pointing to retinal folds indicative of the optic nerve head and peripapillary retinal nerve fiber layer (RNFL) edema and the acute phase of disease. C. OCTA segmented at the level of the peripapillary choriocapillaris, diffuse flow impairment can be appreciated as uniform patchy "moth-eaten" areas. D. Structural en face OCT corresponding to OCTA from C. E. OCT B scan corresponding to A and B. F. OCT B scan corresponding to C and D. G. OCT measurements of the RNFL and ganglion cell layer complex (GCC). H. Automated visual field (Humphrey) pattern standard deviation demonstrating an inferior hemi-field deficit. 360 Wright Mayes et al: J Neuro-Ophthalmol 2017; 37: 358-364 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution each quadrant had OCTA changes consistent with low flow. If $75% of the OCTA quadrants matched functional HVF or structural OCT RNFL and GCC findings for each eye, they were said to correspond (denoted as "YES" in Supplemental Digital Content 1 and 2, Tables E1 and E2, http://links.lww.com/WNO/A218 and http://links. lww.com/WNO/A219). If ,50% of OCT quadrants matched functional HVF or structural OCT RNFL and GCC findings for each NAION eye, they were considered to not have been in correspondence (denoted as "NO" in Supplemental Digital Content 2 and 3, Tables E2 and E3, http://links.lww.com/WNO/A219 and http://links. lww.com/WNO/A220). If 50%-74% of the OCTA quadrants matched functional HVF or structural OCT RNFL and GCC findings for each NAION eye, they were said to "partially" correspond. The quadrants identified were then compared with HVF findings and structural OCT RNFL and GCC measurements to assess for correlation. Both the NAION eye and fellow eye of each study participant were analyzed for masked interpretation, rendering the fellow eye the control eye. RESULTS Ten eyes of 9 patients (age range 45-78 years; average 61.5 years) were studied at variable lengths of time from symptom onset (range 1 week-10 years; average 23 months) between November 2015 and February 2016. Six of the patients were men (corresponding to 7 eyes); 3 were women (3 eyes). The degree of atrophy on the RNFL and GCC seen on OCT B scans corresponded well with HVF deficits (see Supplemental Digital Content 3, Table E3, http://links.lww.com/WNO/ A220). Qualitative assessment of peripapillary hypoperfusion by quadrants is reported for both the RPC and PCC in Supplemental Digital Content 2 and 3, Tables E2 and E3, http:// links.lww.com/WNO/A219 and http://links.lww.com/ WNO/A220, respectively. Hypoperfusion at the level of the FIG. 3. Multimodal analysis of the left eye (OS) of a 45-year-old patient with resolved nonarteritic anterior ischemic optic neuropathy (Patient 3). A. Optical coherence tomography angiogram (OCTA) segmented at the level of the retinal peripapillary capillaries. Yellow dotted lines and arrows indicate regions of sparse capillaries indicating flow impairment. B. Structural en face optical coherence tomography (OCT) corresponding to OCTA from A. C. OCTA segmented at the level of the peripapillary choriocapillaris, yellow arrows to regions of flow impairment seen again as patchy "moth-eaten" areas. D. Structural en face OCT corresponding to OCTA from C. E. OCT B scan corresponding to A and B. F. OCT B scan corresponding to C and D. G. OCT measurements of the retinal nerve fiber layer (RNFL) and ganglion cell layer complex (GCC). H. Automated visual field (Humphrey) pattern standard deviation demonstrating inferior arcuate and paracentral defects. Wright Mayes et al: J Neuro-Ophthalmol 2017; 37: 358-364 361 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution RPC was characterized as relatively dark regions with sparse or no visible capillaries. At the level of the PCC, flow impairment can be appreciated as patchy or "moth-eaten" areas as opposed to the dense granular pattern seen in the normally perfused choriocapillaris. Figures 2-5 demonstrate OCTA at the levels of the RPC and PCC as well as corresponding HVF and structural OCT findings for Patients 1, 3, and 7, respectively (Figs. 4 and 5 correspond to right and left eyes of Patient 7). All 10 eyes were graded to have OCTA RPC hypoperfusion in at least 2 quadrants, whereas 5 of the eyes (50%) were graded to have RPC hypoperfusion in all 4 quadrants. RPC hypoperfusion on OCTA corresponded to visual field deficits in 9 of 10 eyes (90%), and partially corresponded in the remaining eye. OCTA RPC hypoperfusion corresponded to RNFL atrophy on structural OCT in 8 of 10 eyes (80%) and partially in the remaining 2 eyes. Lastly, OCTA RPC hypoperfusion corresponded to GCC atrophy on OCT in 10 of 10 eyes (100%) (see Supplemental Digital Content 1, Table E1, http://links.lww.com/WNO/A218). All 10 eyes were graded to have OCTA PCC hypoperfusion in at least 2 quadrants, whereas 9 of the eyes (90%) were graded to have hypoperfusion of the PCC in all 4 quadrants. OCTA PCC hypoperfusion corresponded to visual field deficits in 6 of 10 eyes (60%), and partially corresponded in the remaining 4 eyes (40%). OCTA PCC hypoperfusion corresponded to RNFL atrophy on structural OCT in 7 of 10 eyes (70%) and partially in 3 eyes (30%). Qualitative OCTA PCC hypoperfusion corresponded to GCC atrophy on structural OCT in 8 of 10 eyes (80%), and partially corresponded in the remaining 2 eyes (20%) (see Supplemental Digital Content 2, Table E2, http://links.lww.com/WNO/A219). DISCUSSION Our study showed flow to both the RPC and PCC was affected in patients with NAION, and these areas of flow impairment corresponded to both functional and structural deficits. One previous report documented OCTA findings in FIG. 4. Multimodal analysis of the right eye (OD) of a 64-year-old patient with resolved nonarteritic anterior ischemic optic neuropathy (Patient 7). A. Optical coherence tomography angiogram (OCTA) segmented at the level of the retinal peripapillary capillaries. Yellow dotted line outlines region of sparse capillaries indicating flow impairment. B. Structural en face optical coherence tomography (OCT) corresponding to OCTA from A. Arrowheads to hyporeflective region that corresponds to flow impairment seen on OCTA in A, as well as retinal nerve fiber layer (RNFL) atrophy seen in G. C. OCTA segmented at the level of the peripapillary choriocapillaris. Global patchy atrophy is seen in all 4 quadrants; yellow arrows indicate regions of relatively greater flow impairment. D. Structural en face OCT corresponding to OCTA from C. E. OCT B scan corresponding to A and B. F. OCT B scan corresponding to C and D. G. OCT measurements of the RNFL and ganglion cell layer complex (GCC). H. Automated visual field (Humphrey) pattern standard deviation demonstrating inferior hemi-field defects. 362 Wright Mayes et al: J Neuro-Ophthalmol 2017; 37: 358-364 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 5. Multimodal analysis of the left eye (OS) of a 64-year-old patient with resolved nonarteritic anterior ischemic optic neuropathy (Patient 7). A. Optical coherence tomography angiogram (OCTA) segmented at the level of the retinal peripapillary capillaries. Yellow dotted line outlines region of sparse capillaries indicating flow impairment. B. Structural en face optical coherence tomography (OCT) corresponding to OCTA from A. Arrowheads to hyporeflective regions that correspond to flow impairment seen on OCTA in A, as well as retinal nerve fiber layer (RNFL) atrophy seen in G. C. OCTA segmented at the level of the peripapillary choriocapillaris. Global patchy atrophy is seen in all 4 quadrants. D. Structural en face OCT corresponding to OCTA from C. E. OCT B scan corresponding to A and B. F. OCT B scan corresponding to C and D. G. OCT measurements of the RNFL and ganglion cell layer complex (GCC). H. Automated visual field (Humphrey) pattern standard deviation demonstrating an inferior hemi-field deficit. a patient with NAION, demonstrating perfusion deficits in the RPC and superficial retinal capillaries in the macula that corresponded to both GCC atrophy and HVF deficits (17). However, this study did not examine the choriocapillaris. It has been postulated that the primary site of pathology in NAION involves the posterior ciliary arteries (5). However, changes at the level of the choriocapillaris have been difficult to demonstrate with traditional fundus angiography and color Doppler imaging. With the depth-encoded angiogram provided by OCTA, we were able to visualize perfusion deficits in the choriocapillaris. Hypoperfusion at the level of the RPC had the strongest correlation (100%) with GCC atrophy. A strong correlation (90%) between structural RPC hypoperfusion and functional HVF deficits also was detected. The intuitive assumption regarding RPC hypoperfusion in NAION is that this is a downstream consequence of the inciting ischemic event rather than the site of primary pathology. Although less likely, the converse must also be considered in that the initial site of ischemia could occur within the superficial peripapillary retina. Wright Mayes et al: J Neuro-Ophthalmol 2017; 37: 358-364 Flow impairment at the level of the PCC had the strongest correlation (80%) with GCC atrophy, much like at the level of the RPC. PCC hypoperfusion often occurred globally throughout the PCC rather than within discrete, localized regions (Figs. 2C, 4C, and 5C). Patient 3 is an exception (Fig. 3). In several of the study eyes with clear hemi-field defects and PCC hypoperfusion in all 4 quadrants, there often was a qualitatively greater degree of PCC hypoperfusion in the quadrants that corresponded to the field loss (see Supplemental Digital Content 2 and 3, Tables E2 and E3, http://links.lww.com/WNO/A219 and http://links.lww.com/WNO/A220; Patients 6, 7, and 9). Accordingly, in 2 of the 4 eyes in which PCC hypoperfusion was read as only partially corresponding with their HVF deficits (Patient 6, and the right eye of Patient 7; see Supplemental Digital Content 2, Table E2, http:// links.lww.com/WNO/A219), there was a relatively greater degree of hypoperfusion in the quadrants corresponding with the visual field deficits. Thus, at least 60%, and perhaps up to 80% of our study eyes had PCC flow 363 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution impairment patterns that corresponded with functional HVF deficits. These findings may support an investigation that used methyl-methacrylate microvascular corrosion casting of postmortem human orbits to characterize the morphology of the circle of Haller and Zinn (7). This showed an elliptical microvascular partial anastomosis between branches of the medial and lateral paraoptic short posterior ciliary arteries that was divided into superior and inferior parts. The authors proposed that this structural anatomy helps to explain the functional altitudinal visual field deficits often seen in patients with NAION. On OCTA, areas of signal blockage are characterized by dark, hyporeflective regions that appear as discrete areas of the same shape on both OCTA and structural en face OCT. These dark areas of signal blockage may be misinterpreted as flow impairment in the choriocapillaris or deeper segmentations. One must analyze OCTA alongside their corresponding en face OCT. Interestingly, in this study, dark, hyporeflective areas were visible on the corresponding en face OCT which appeared to correspond to areas of RNFL atrophy (Figs. 3B, 4B, and 5B). Because there were visible capillaries, albeit less dense, in these corresponding regions on the angiograms, we believe that these areas are not associated with signal blockage. One limitation of our study is the error and bias that may ensue with qualitative analysis performed by an independent reader. Quantitative flow impairment analysis in future studies could provide greater precision in localizing the pathology, particularly at the level of the choriocapillaris. Furthermore, each of the patients was studied at variable lengths of time from initial symptom onset rendering comparison of OCTA findings between our study eyes challenging. Additional limitations in our study include a small sample size and lack of longitudinal follow-up. We studied 2 sets of eyes of patients with optic disc edema in the acute phase of NAION (Patients 1 and 2). Routine use of OCTA prospective studies of NAION may provide informed regarding the time frame of microvascular damage. The use of OCTA in patients with unilateral NAION also would permit evaluation of the fellow eye in an effort to identify microvascular changes that may predispose patients to NAION. OCTA is an imaging technology that may help to develop a greater understanding of the microvasculopathy of NAION with the goal of one-day treating, and perhaps more importantly, preventing this vision-threatening optic neuropathy. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: E. Wright Mayes, T. R. Hedges, and E. D. Cole; b. Acquisition of data: E. Wright Mayes; c. Analysis and interpretation of data: E. Wright Mayes, E. D. Cole, S. 364 Dang, and T. R. Hedges. Category 2: a. Drafting the manuscript: E. Wright Mayes and E. D. Cole; b. Revising it for intellectual content: T. R. Hedges, L. Vuong, C. Mendoza-Santiesteban, and J. S. Duker. Category 3: a. Final approval of the completed manuscript: T. R. Hedges. REFERENCES 1. Arnold AC. 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Optical coherence tomography angiography in a patient with optic atrophy after non-arteritic anterior ischaemic optic neuropathy. Neuroophthalmology. 2016;40:146-149. Wright Mayes et al: J Neuro-Ophthalmol 2017; 37: 358-364 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.