Optical Coherence Tomography Angiography of a Pale Optic Disc in Demyelinating Optic Neuritis and Ischemic Optic Neuropathy

Background: In the setting of a pale optic disc, distinguishing a previous episode of optic neuritis (ON) from that of nonarteritic anterior ischemic optic neuropathy (NAION) may be difficult on clinical examination. Differences in peripapillary vascular network structures, if present, might be of diagnostic utility. Methods: Thirty-five eyes with demyelinating ON, 33 eyes with NAION, and 81 eyes of normal subjects were imaged with optical coherence tomography angiography (OCT-A) to assess peripapillary vascular density (VD). In addition, OCT was used to measure peripapillary retinal nerve fiber layer (RNFL) thickness. Areas under the receiver operating characteristic curves were used to differentiate ON vs NAION. Results: NAION eyes had significantly thinner RNFL thickness than ON eyes. Age-adjusted analysis showed that the peripapillary VD values were significantly reduced in NAION (48.3 ± 7.4%) and ON eyes (54.7 ± 6.1%) compared with healthy controls (62.1 ± 4.6%); pairwise comparisons showed statistically significant differences among all 3 groups. After adjustment for severity of optic nerve injury according to mean RNFL thickness, all VD parameters were not significantly different between ON and NAION eyes. The area under the receiver operating characteristic curves for differentiating NAION from ON eyes was similar for VD (0.75) and RNFL thickness (0.74). Conclusions: Peripapillary VD measurement performs as well as RNFL thickness for distinguishing previous episodes ON and NAION. VD decline might be secondary to RNFL damage and, therefore, VD data have a limited role differentiating these 2 disorders.

Original Contribution Optical Coherence Tomography Angiography of a Pale Optic Disc in Demyelinating Optic Neuritis and Ischemic Optic Neuropathy Masoud Aghsaei Fard, MD, FICO, Samira Yadegari, MD, Hosein Ghahvechian, MD, Sasan Moghimi, MD, Reza Soltani-Moghaddam, MD, Prem S. Subramanian, MD, PhD Background: In the setting of a pale optic disc, distinguishing a previous episode of optic neuritis (ON) from that of nonarteritic anterior ischemic optic neuropathy (NAION) may be difficult on clinical examination. Differences in peripapillary vascular network structures, if present, might be of diagnostic utility. Methods: Thirty-five eyes with demyelinating ON, 33 eyes with NAION, and 81 eyes of normal subjects were imaged with optical coherence tomography angiography (OCT-A) to assess peripapillary vascular density (VD). In addition, OCT was used to measure peripapillary retinal nerve fiber layer (RNFL) thickness. Areas under the receiver operating characteristic curves were used to differentiate ON vs NAION. Results: NAION eyes had significantly thinner RNFL thickness than ON eyes. Age-adjusted analysis showed that the peripapillary VD values were significantly reduced in NAION (48.3 ± 7.4%) and ON eyes (54.7 ± 6.1%) compared with healthy controls (62.1 ± 4.6%); pairwise comparisons showed statistically significant differences among all 3 groups. After adjustment for severity of optic nerve injury according to mean RNFL thickness, all VD parameters were not significantly different between ON and NAION eyes. The area under the receiver operating characteristic curves for differentiating NAION from ON eyes was similar for VD (0.75) and RNFL thickness (0.74). Conclusions: Peripapillary VD measurement performs as well as RNFL thickness for distinguishing previous episodes ON and NAION. VD decline might be secondary to RNFL damage and, therefore, VD data have a limited role differentiating these 2 disorders. Journal of Neuro-Ophthalmology 2019;39:339-344 doi: 10.1097/WNO.0000000000000775 © 2019 by North American Neuro-Ophthalmology Society Farabi Eye Hospital (MAF, SY, HG, SM), Eye Research Center, Department of Ophthalmology, Tehran University of Medical Science, Tehran, Iran; Department of Ophthalmology (RSM), Rasht University of Medical Science, Rasht, Iran; and Department of Ophthalmology, Neurology, and Neurosurgery (PSS), University of Colorado School of Medicine, Aurora, Colorado. The authors report no conflicts of interest. Address correspondence to Masoud Aghsaei Fard, MD, FICO, Farabi Eye Hospital, Department of Ophthalmology, Tehran University of Medical Science, Qazvin Sq, Tehran, Iran 15531; E-mail: [e-mail] Fard et al: J Neuro-Ophthalmol 2019; 39: 339-344 A lthough the acute clinical presentations and funduscopic findings of nonarteritic anterior ischemic optic neuropathy (NAION) and optic neuritis (ON) typically are quite different, they both result in optic atrophy. While there may be some clues pointing to either ON or NAION in the atrophic stage, it may be difficult to identify the origin of the optic atrophy based on observation alone (1). Patients may present after their acute vision loss has resolved and also may not recall the events surrounding its onset. Because there are different systemic risk factors and future implications in the 2 disorders, making the correct diagnosis in retrospect is important for the patients' visual and systemic health. Optic disc pallor is associated with local vascular changes. Histologically, Quigley et al (2) observed that disc capillaries are still present in atrophic optic discs, and it has been shown that primary neurogenic optic atrophy induces a decrease in blood flow to the anterior optic nerve in cats (3). A number of methods have been used for measuring optic nerve head perfusion in acute and late NAION and ON. Fluorescein angiography after dye injection provides vascular patterns of the optic nerve head in ON and NAION by means of fractal analysis (4). Both laser Doppler flowmetry (5,6) and laser speckle flowgraphy (7,8) can show differences between NAION and ON. However, the clinical application of these research tools for differentiating NAION and ON is limited. Optical coherence tomography angiography (OCT-A) has identified a decrease in the peripapillary vasculature in eyes with NAION and ON compared with controls (9-11). Without comparing vascular density (VD) impairment in both optic neuropathies, it is unknown if NAION and ON result in different patterns of vascular loss in the atrophic stage. We previously demonstrated no difference in the peripapillary vasculature in postacute NAION and openangle glaucoma (12). Comparison of peripapillary capillary density in different optic neuropathies with disc swelling also has been reported (13). We hypothesized that blood 339 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution supply of the peripapillary retina will demonstrate different patterns in NAION and ON eyes despite a pale optic nerve appearance in both conditions. Therefore, the objective of this study was to quantitatively evaluate the OCT-A VD of the optic nerve and spectral domain optical coherence tomography (SD-OCT) retinal nerve fiber layer (RNFL) thickness to find potential differences between patients with NAION and ON. MATERIAL AND METHODS Patients Patients with resolved ON and NAION who were examined at Farabi Eye Hospital between February 2016 and May 2017 were recruited in this prospective, crosssectional, comparative study. The study was approved by the research ethics committee of Farabi Eye Hospital. Written informed consent was obtained from all patients, and the study was conducted in accordance with the Declaration of Helsinki. All the patients underwent a thorough ophthalmic evaluation, including best-corrected visual acuity, slit-lamp biomicroscopy, and a dilated fundus examination. Visual acuities were converted to logarithm of minimum angle of resolution (logMAR) scale scores for statistical analysis. RNFL imaging using SD-OCT and OCT-A imaging (AngioVue; Optovue, Inc, Fremont, CA) was also performed in all subjects as described previously (12,13). Inclusion criteria for NAION were (a) a history of sudden visual loss .3 months before enrollment, with documented optic disc edema with or without disc hemorrhage, (b) complete resolution of ophthalmoscopic disc edema at the time of study, (c) optic disc-related visual field defects, and (d) an ophthalmologically normal fellow eye. Patients with other ocular or neurologic disease such as glaucoma, bilateral NAION, acute NAION, evidence of giant cell arteritis with an erythrocyte sedimentation rate .50 mm/hour and a positive C-reactive protein, or inflammatory ON were excluded from NAION group. Inclusion criteria ON were (a) an attack of painful, subacute vision loss between 3 and 12 months before enrollment (14), (b) age 18-45 years, (3) gadoliniumenhanced MRI demonstrating optic nerve enhancement (15) with or without periventricular plaques typical of multiple sclerosis, and (d) a diagnosis of multiple sclerosis or clinically isolated syndrome. Patients with other ocular pathology, recent attack of ON, or history of other autoimmune disease were excluded. The control group comprised patients with a bestcorrected visual acuity of better than or equal to 20/30, normal optic disc appearance, and normal RNFL thickness on OCT. In all groups, patients with refractive errors $ +5.00 or # 25.00 D were also excluded. Only one eye in all patients was analyzed for the study. 340 Optical Coherence Tomography Angiography Measurements Images were obtained using SD-OCT. 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. For OCT-A, we used the AngioVue to obtain blood flow information at the radial peripapillary capillary layer as a VD map (%) in a 4.5 · 4.5-mm rectangle scan centered on the optic disc. VD data (software version 2016.1.0.90) in the radial peripapillary capillary layer was measured in the slab from the inner limiting membrane to the junction of the RNFL and inner plexiform and inside optic disc enface image, and whole-image VDs were measured in addition to peripapillary vascular density (ppVD) (12,13). Whole image was obtained over the entire 4.5 · 4.5mm scan field, and peripapillary region was measured in a 750mm-wide elliptical annulus extending outward from the optic disc margin, where the inner contour is fitted to the disc boundary. The peripapillary area was divided into 6 sectors, and superotemporal, superonasal, nasal, inferotemporal, inferonasal, and temporal sextants values were recorded (Fig. 1). Statistical Analysis Analysis of covariance (ANCOVA) adjusted for age was used for the comparison among the 3 groups, and the Tukey post hoc test was performed to adjust for multiple comparisons. ANCOVA adjusted for age and RNFL thickness was also performed. Pearson correlation analysis was performed to assess correlation of average RNFL thickness and VD values in all study eyes. Associations between VD and average RNFL thickness after adjusting for age and sex were evaluated with multivariate linear regression analysis. Diagnostic accuracy for differentiating between NAION and ON eyes was evaluated by calculating the area under the receiver operating characteristic curves (AUROC). Statistical analysis was performed using SPSS software version 22 (SPSS, Inc, Chicago, IL). Differences were significant if P was less than 0.05. RESULTS One hundred forty-nine eyes were included: 81 control eyes, 33 NAION eyes, and 35 ON eyes. Six normal, 3 NAION, and 4 ON eyes were excluded because of poor image quality and/or segmentation error. Of 35 patients with ON, multiple sclerosis was diagnosed in 10, and clinically isolated syndrome was diagnosed in 25. From all patients with NAION and ON, 38 were examined 6 months or more after the event. Median time elapsed after visual loss in NAION and ON groups was 22 weeks (range: 12-31 weeks) and 25 weeks (range 12-32 weeks), respectively. Demographic information and structural RNFL values are summarized in Table 1. Mean age in the NAION and control eyes was not significantly different. However, the patients in the ON group were significantly younger than both control and NAION patients (P = 0.015 and 0.003, respectively), and therefore, all comparisons between groups were age-adjusted. Fard et al: J Neuro-Ophthalmol 2019; 39: 339-344 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 1. Optical coherence tomography angiography (OCT-A) of peripapillary vasculature in control, nonarteritic anterior ischemic optic neuropathy (NAION), and optic neuritis eyes. Left column: retinal nerve fiber layer thickness of 3 subjects. Three subjects had different nerve fiber layer thickness values; right column: OCT-A images of peripapillary vascular density (VD) within 750-mm-wide elliptical annulus between inner and outer elliptical contours. Both retinal nerve fiber layer thickness and VD values of NAION eyes are lower than optic neuritis eyes. NAION, nonarteritic anterior ischemic optic neuropathy. RNFL thicknesses were significantly thinner in ON and NAION eyes than control subjects. NAION eyes had, on average, thinner RNFL compared with ON eyes (Table 1). Age-adjusted ANCOVA showed that the vascular density was significantly different among the 3 groups (P , 0.001 for both whole-image VD and ppVD). The whole-image VD values were significantly lower in NAION eyes (45.9 ± 5.8%), followed by ON eyes (50.5 ± 4.4%) and control eyes (56.5 ± 3.4%) (Bonferroni correction, P , 0.05 for all pairwise comparisons). Similarly, NAION eyes had significantly lower ppVD (48.3 ± 7.4%) when compared with control eyes and ON eyes (62.1 ± 4.6% and 54.7 ± 6.1%, respectively) (Both P , 0.001). All sector VD also was lower in NAION and ON than control eyes. NAION eyes had lower sectoral VD than ON eyes except for peripapillary superonasal and temporal sectors, which were not different from each other (Table 2). AUROC ± stardard error (SE) for discriminating between NAION and ON eyes was similar for whole-image VD (0.75 ± 0.06), pp VD (0.75 ± 0.06), and RNFL thickness (0.74 ± 0.07) (Fig. 2). Peripapillary VD of less than 51.2% had 75% sensitivity and 76% specificity for distinction of NAION from ON. Fard et al: J Neuro-Ophthalmol 2019; 39: 339-344 Results from the Pearson correlation analysis showed that whole-image VD and ppVD were significantly correlated with average RNFL thickness in all study eyes (r = 0.71, 0.69, respectively, both P , 0.001). Age- and sex-adjusted multivariate linear regression analysis showed that each 1-mm loss in RNFL thickness was associated with 0.24% and 0.19% decrease in ppVD and whole-image VD, respectively (both P , 0.001). In addition, a separate analysis was performed to compare vessel density values between NAION and ON groups after adjustment for average RNFL as a measure of damage. Analysis of variance (ANOVA) after adjusting for age and average RNFL showed no difference in whole-image VD and ppVD values between NAION and ON eyes. All VD sector values were not statistically different between ON eyes and NAION eyes (Table 2). DISCUSSION The clinical distinction between resolved NAION and ON in a given patient can be challenging but is important because of differing systemic and therapeutic implications. Thus, we evaluated the peripapillary retinal VD in NAION, ON, and healthy eyes as measured by OCT-A to identify differences 341 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. Demographic and ophthalmic characteristics of patients with nonarteritic ischemic optic neuropathy, optic neuritis, and healthy controls NAION (n = 33) Age (yrs) Visual acuity (LogMAR) Average RNFL, mm Superior RNFL, mm Temporal RNFL, mm Inferior RNFL, mm Nasal RNFL, mm Optic Neuritis (n = 35) P value; NAION Control (n = 81) vs Control 55.8 ± 10.6 41.5 ± 17 51.5 ± 19.5 0.8 ± 0.9 0.6 ± 0.3 0.0 ± 0.1 65.5 ± 21.1 84.5 ± 19.6 102.5 ± 6.7 67.9 ± 29.4 105.1 ± 26.2 125.4 ± 10.6 50.6 ± 27.5 61.2 ± 14.7 76.9 ± 7.3 58.5 ± 28.9 167.3 ± 272.4 126.9 ± 9.9 75.4 ± 25.6 68.9 ± 17.6 80.2 ± 9.4 P value; Optic Neuritis vs Control P value; Optic Neuritis vs NAION 0.015 ,0.001 0.004 0.051 0.085 0.707 0.788 0.003 0.406 0.006 ,0.001 0.264 0.027 0.947 0.693 ,0.001 ,0.001 ,0.001 ,0.001 0.130 0.920 LogMAR, logarithm of minimum angle of resolution; NAION, nonarteritic anterior ischemic optic neuropathy; RNFL, retinal nerve fiber layer. flux in the radial peripapillary capillaries was affected in patients with NAION, and this area of flow impairment corresponded to both functional and structural deficits and had the strongest correlation with ganglion cell complex atrophy (9). Hata et al (10) observed that the peripapillary VD was reduced at the corresponding location of the visual field defects following an episode of NAION. Decreased macular VD in multiple sclerosis with and without a history of ON also has been reported (11,16-18). Furthermore, eyes of patients with multiple sclerosis or clinically isolated syndrome with previous ON demonstrated lower macular vasculature by OCT-A as compared to eyes of healthy controls eyes without previous ON (16). Macular impairment in ON may be due to reduced metabolic activity within the retina following optic nerve damage (16). We are not aware of previous reports directly comparing VD between pale optic discs in NAION and ON eyes using OCT-A. Previous Doppler velocimetry studies in these 2 that might separate the 2 disorders. Both ON and NAION eyes had significantly lower whole-image and peripapillary VD when compared with control eyes, and when adjusted for age alone, both whole-image and peripapillary VD were lower in NAION than ON eyes, and both differed from controls eyes. Multivariate analysis results also demonstrated a significant positive correlation between VD values and RNFL thickness. Because NAION eyes had significantly more RNFL thinning than ON eyes, we also fitted our model with RNFL thickness. When ANOVA was adjusted for RNFL thickness and age, neither whole-image VD nor peripapillary VD were different between NAION and ON eyes, and the AUROC for discriminating between NAION and ON eyes was similar for whole-image VD, ppVD, and RNFL thickness. Previous studies have reported a decrease in the peripapillary vasculature density by OCT-A in eyes following NAION (9,10) or ON (11) compared with controls. One study showed vessel TABLE 2. Optical coherence tomography angiography vessel densities in healthy, anterior ischemic optic neuropathy (NAION), and optic neuritis subjects before and after adjustment for retinal nerve fiber layer thickness Vessel Density (%) NAION Whole image 45.9 ± 5.8 Inside disc 42 ± 8.8 Total peripapillary 48.3 ± 7.4 Nasal peripapillary 48 ± 7.8 Inferonasal peripapillary 49.5 ± 8.7 Inferotemporal 148.9 ± 9.6 peripapillary Superotemporal 47.2 ± 10.5 peripapillary Superonasal 49.3 ± 10 peripapillary Temporal peripapillary 47.9 ± 9.5 Optic Neuritis Control P value; NAION vs Control P value; Optic Neuritis vs P value; P value; NAION (After Optic Optic Neuritis vs Neuritis vs Adjustment for RNFL) NAION Control 3.4 3.4 4.6 5.2 5.3 5.2 ,0.001 0.001 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 0.002 ,0.001 ,0.001 ,0.001 0.001 0.002 0.99 ,0.001 0.004 ,0.001 ,0.001 55.6 ± 9.2 64.3 ± 5.7 ,0.001 ,0.001 0.001 0.12 52.9 ± 8.3 60.1 ± 6.1 ,0.001 ,0.001 0.147 0.875 53.7 ± 7.5 61.9 ± 6.6 ,0.001 ,0.001 0.058 0.637 50.5 50.5 54.7 54.1 57.2 57 ± ± ± ± ± ± 4.4 4.4 6.1 6.2 8.8 7.3 56.5 56.5 62.1 60.4 63.8 65.2 ± ± ± ± ± ± 0.918 0.095 0.327 0.683 0.085 0.788 NAION, nonarteritic anterior ischemic optic neuropathy; RNFL, retinal nerve fiber layer. 342 Fard et al: J Neuro-Ophthalmol 2019; 39: 339-344 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 2. Area under the receiver operating characteristic curves shows the diagnostic accuracy of average peripapillary vascular density and peripapillary nerve fiber layer thickness for distinguishing ischemic nonarteritic anterior optic neuropathy from optic neuritis. conditions evaluated the blood supply of the optic nerve head and found significantly lower values in eyes with NAION than ON (5). However, the differences in the circulatory abnormalities were not large enough to enable the clinician to distinguish between ON and NAION in an individual patient. We believe that VD loss likely mirrors retinal ganglion cell axonal damage, and that the decrease in VD may reflect a diminished need for blood flow in the RNFL regardless of the cause of the optic neuropathy (19). Blood flow autoregulation may mediate this vascular response (20,21). This is supported by our findings that the degree of peripapillary VD loss following NAION and open-angle glaucoma was not different, suggesting that dropout of vessels is not specific to NAION and might be secondary to retinal nerve fiber damage (12). An association between vessel dropout and RNFL thickness along with a nonspecific decline in peripapillary vasculature in various optic neuropathies including glaucoma has led to the proposition that vascular rarefaction is a degenerative response to loss of metabolically active retinal nerve fiber axons through a neurovascular coupling mechanism and not necessarily the primary cause of an optic neuropathy (22,23). Our study had several limitations. First, the sample size was small. Second, the distinction between NAON and ON was clinical, and it is possible that a diagnosis was given in error. Third, we evaluated patients at a single time point, and therefore, our findings cannot be used to determine cause-effect relationships between VD and RNFL. Longitudinal evaluation of patients will help clarify relationships between vascular changes and RNFL damage. STATEMENT OF AUTHORSHIP Category 1: a. conception and design: M. A. Fard, P. Subramanian, and H. Ghahvechian; b. acquisition of data: H. Ghahvechian and S. Yadegari; c. analysis and interpretation of data: H. Ghahvechian, S. Yadegari, and M. A. Fard. Category 2: drafting the manuscript: R. S. Moghaddam, S. Moghimi, and M. A. Fard; a. revising it for intellectual content: R. S. Moghaddam, S. Moghimi, S. Yadegari, and P. Fard et al: J Neuro-Ophthalmol 2019; 39: 339-344 Subramanian. Category 3: a. final approval of the completed manuscript: M. A. Fard and P. Subramanian. REFERENCES 1. Smith CH. Optic neuritis. In: Miller NR, Newman NJ, Biousse V, eds. Clinical Neuro-Ophthalmology. 6th ed. Vol 1. 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