Bilateral Simultaneous Nonarteritic Anterior Ischemic Optic Neuropathy: Demographics, Risk Factors, and Visual Outcomes

Although nonarteritic anterior ischemic optic neuropathy is a well-known cause of vision loss, it typically presents unilaterally. Simultaneous, bilateral nonarteritic anterior ischemic optic neuropathy (sNAION) is rare and poorly studied in comparison. This study seeks to characterize the clinical features and risk factors of patients with sNAION compared with unilateral NAION (uNAION).

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Bilateral Simultaneous Nonarteritic Anterior Ischemic Optic Neuropathy: Demographics, Risk Factors, and Visual Outcomes Jennifer E. Chung, BA, Janani Singaravelu, MD, Bradley S. Wilson, MA, Annah P. Baykal, BS, Michael S. Lee, MD, Collin M. McClelland, MD, John J. Chen, MD, PhD, M. Tariq Bhatti, MD, Andrew T. Melson, MD, Gregory P. Van Stavern, MD Background: Although nonarteritic anterior ischemic optic neuropathy is a well-known cause of vision loss, it typically presents unilaterally. Simultaneous, bilateral nonarteritic anterior ischemic optic neuropathy (sNAION) is rare and poorly studied in comparison. This study seeks to characterize the clinical features and risk factors of patients with sNAION compared with unilateral NAION (uNAION). Methods: In this retrospective case–control study, we reviewed 76 eyes (38 patients) with sNAION and 38 eyes (38 patients) with uNAION (controls) from 4 academic institutions examined between 2009 and 2020. Demographic information, medical history, medication use, symptom course, paraclinical evaluation, and visual outcomes were collected for all patients. Results: No significant differences were observed in demographics, comorbidities and their treatments, and medication usage between sNAION and uNAION patients. sNAION patients were more likely to undergo an investigative workup with erythrocyte sedimentation rate measurement (P = 0.0061), temporal artery biopsy (P = 0.013), lumbar puncture (P = 0.013), and MRI (P , 0.0001). There were no significant differences between the 2 groups for visual Department of Ophthalmology and Visual Sciences, Washington University School of Medicine (JEC, JS, BSW, GPVS), St. Louis, MO; Department of Ophthalmology, Dean McGee Eye Institute, Oklahoma University Health Science Center (APB, ATM), Oklahoma City, OK; Department of Ophthalmology and Visual Neurosciences, University of Minnesota (MSL, CMM), Minneapolis, MN; and Department of Ophthalmology and Neurology, Mayo Clinic (JJC, MTB), Rochester, MN. This work was supported in part by an unrestricted grant to the Washington University in St. Louis Department of Ophthalmology and Visual Sciences from Research to Prevent Blindness. This funding did not apply to University of Oklahoma, Mayo Clinic, and University of Minnesota. This project was presented as a poster at the North American NeuroOphthalmology Society 47th Annual Meeting, February 21, 2021. The authors report no conflicts of interest. Address correspondence to Gregory P. Van Stavern, MD, 660 S. Euclid Avenue, Department of Ophthalmology and Visual Sciences, Washington University in St. Louis, St. Louis MO 63110; E-mail: [e-mail] 86 acuity, mean visual field deviation, peripapillary retinal nerve fiber layer thickness, or ganglion cell-inner plexiform layer thickness at presentation, nor at final visit for those with $3 months of follow-up. The sNAION eyes with $3 months of follow-up had a smaller cup-to-disc ratio (CDR) at final visit (P = 0.033). Ten patients presented with incipient NAION, of which 9 suffered vision loss by final visit. Conclusion: Aside from CDR differences, the risk factor profile and visual outcomes of sNAION patients seem similar to those of uNAION patients, suggesting similar pathophysiology. Journal of Neuro-Ophthalmology 2023;43:86–90 doi: 10.1097/WNO.0000000000001642 © 2022 by North American Neuro-Ophthalmology Society N onarteritic anterior ischemic optic neuropathy (NAION) is the most common cause of acute optic neuropathy in patients greater than 50 years of age, with an estimated annual incidence of 2.3–10.3 per 100,000 (1,2). It typically presents as unilateral, sudden, painless vision loss accompanied by optic disc edema (3). However, it is not uncommon for patients to experience fellow eye involvement in subsequent years, with an estimated incidence of 14.7%– 24% (4,5). In comparison, bilateral simultaneous (s) NAION unrelated to surgical blood loss is comparatively rare and poorly described in the existing literature. This raises questions about whether there are differences between unilateral (u) NAION and sNAION in terms of potential risk factors, visual outcomes, and the most appropriate investigative workup. Previous reports have suggested associations between NAION and a wide variety of factors, including but not limited to vascular disease (6), obstructive sleep apnea (7), medications (8,9), and optic disc morphology (10,11). However, our review of the PubMed database indicates that there have been no large-scale published studies Chung et al: J Neuro-Ophthalmol 2023; 43: 86-90 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution characterizing patients experiencing sNAION unrelated to perioperative ischemic optic neuropathy. A comprehensive analysis of patient presentation, risk factors, and visual outcomes may contribute to a better understanding of sNAION pathophysiology, and develop a more streamlined and cost-effective evaluation. Therefore, this study aims to characterize the clinical features, risk factors, and visual outcomes of patients with sNAION in comparison to uNAION. METHODS This multicenter, retrospective case–control study was conducted using patient records from 2009 to 2020 from the neuro-ophthalmology services at Washington University (St. Louis,MO) Mayo Clinic (Rochester, MN), University of Minnesota (Minneapolis, MN), and University of Oklahoma (Oklahoma City, OK) with the goal of identifying patients with sNAION, defined as (1) bilateral optic disc swelling at presentation at the first neuro-ophthalmology encounter, or (2) development of optic disc edema in the contralateral eye within 7 days of presentation. Alternative etiologies, such as giant cell arteritis, were excluded. Patients with a history of amiodarone usage, surgery within 1 week of vision loss, and no follow-up encounters were excluded from the study. A matching number of uNAION patients were randomly selected as controls by their respective institutions. To identify controls, patients in each center’s database were assigned a number. A random number generator was then used to compile a list of numbers equal to the number of study subjects. Those patients whose assigned numbers were included on this list were then selected as controls. All control patients had been diagnosed with uNAION by clinical and paraclinical criteria and had been seen for at least one follow-up examination. Data collected included demographic information, laboratory results including lumbar puncture and temporal artery biopsy, neuroimaging, existing medical conditions, ongoing treatments, and medication use. Visual and ocular information from the initial and final neuro-ophthalmic visits were also recorded. Visual acuity was recorded in LogMAR, with counting fingers = 1.3, hand movements = 2.0, and light perception = 2.3 (12). Comparisons between the 2 groups were performed using a t test for continuous measures and chi-square for categorical measures. Analyses of vision measures were performed using a mixed-model analysis of variance that accounted for correlation between both eyes of a patient. Final outcomes were compared against patients with at least 3 months of follow-up. As this study is an exploratory, hypothesis-generating analysis to identify potential factors related to sNAION development, corrections for multiple comparisons were not made. All data analyses were performed using SAS version 9.4 (SAS Inc, Cary, NC). Chung et al: J Neuro-Ophthalmol 2023; 43: 86-90 Institutional review board approval was obtained at each participating site. This study adhered to the tenets of the Declaration of Helsinki and complied with the Health Insurance Portability and Accountability Act. RESULTS Seventy-six eyes (38 patients) of sNAION patients and 38 uNAION eyes serving as the control group were analyzed. For any metrics where data were partially unavailable, the number of patients is stated. The mean age was 61.4 years (SD = 8.3) for the sNAION group and 61.4 years (SD = 10.6) for the uNAION group (P = 0.99). Fifteen (39.5%) sNAION patients and 12 (31.6%) uNAION patients were women (P = 0.47). Thirty-five (92.1%) sNAION patients and all (100%) uNAION patients were White (P = 0.21). No significant differences between the 2 groups for existing medical conditions, their treatments (i.e., dialysis, CPAP), and phosphodiesterase (PDE)-5 inhibitor usage were observed (Table 1). For laboratory results and imaging findings obtained during clinical investigation, sNAION patients were more likely to have had an erythrocyte sedimentation rate measurement (94.7% vs. 71.1%; P = 0.0061), temporal artery biopsy (34.2% vs. 10.5%; P = 0.013), lumbar puncture (73.7% vs. 5.3%; P = 0.013), and MRI (94.7% vs. 55.3%; P , 0.0001) than uNAION patients (Table 2). C-reactive protein testing did not differ significantly between the 2 cohorts (P = 0.054). At initial presentation, sNAION patients did not seem to be associated with worse visual acuity, worse mean visual field deviation, or demonstrate significant differences in peripapillary retinal nerve fiber layer thickness (pRNFL) or ganglion cell-inner plexiform layer (GC-IPL) thickness (Table 3). Cup-to-disc ratio (CDR) at presentation could not be analyzed, as the bilateral optic disc swelling precluded accurate measurements. At final visit for patients with $3 months of follow-up, there were no significant differences between sNAION and control eyes for visual acuity (0.5 [0.6], 95% confidence interval [CI] [0.4–0.7], n = 56 vs. 0.5 [0.6], 95% CI [0.3–0.7], n = 27; P = 0.76), mean visual field deviation (215.0 [8.5], 95% CI [217.6 to 212.3], n = 43 vs. 213.7 [6.5], 95% CI [216.7 to 210.8], n = 21; P = 0.62), pRNFL thickness (76.1 [24], 95% CI [68.2–84], n = 38 vs. 66.5 [13.8], 95% CI [60.7–72.3], n = 24; P = 0.11), or GC-IPL thickness (60.6 [6.7], 95% CI [56.7–64.4], n = 14 vs. 60 [9.7], 95% CI [55.8–64.3], n = 22; P = 0.86). However, sNAION eyes had lower CDR compared with controls (0.1 [0.1], 95% CI [0.1–0.2], n = 44 vs. 0.2 [0.1], 95% CI [0.2–0.3], n = 27; P = 0.033). Interestingly, of the 38 sNAION patients, 10 presented as incipient or presymptomatic NAION (13), with optic disc edema but no visual dysfunction in the fellow eye at presentation. Nine of these patients had worse visual acuity 87 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. Simultaneous and unilateral nonarteritic anterior ischemic optic neuropathy: Demographics, comorbidities, and phosphodiesterase inhibitor use Demographics Mean age (SD) Female N (%) White N (%) Existing conditions and history Hypertension Diabetes mellitus Hyperlipidemia Active malignancy Remote history of malignancy Mean months from remission (SD) Active renal insufficiency Dialysis Anemia Obstructive sleep apnea Continuous positive airway pressure PDE-5 inhibitor ,1 Week prior to vision loss PDE-5 inhibitor .1 Week prior to vision loss sNAION (95% CI) uNAION (95% CI) 61.4 (8.3) 15 (39.5) 35 (92.1) 61.4 (10.6) 12 (31.6) 38 (100) 68.4% 31.6% 55.3% 2.6% 15.8% 12.7 7.9% 0.0% 21.1% 26.3% 30.0% 5.3% 7.9% (53.6–83.2) (16.8–46.4) (39.5–71.1) (0.0–7.7) (4.2–27.4) (11.0) (0.0–16.5) (0.0–0.0) (8.1–34.0) (12.3–40.3) (1.6–58.4) (0.0–12.4) (0.0–16.5) 57.9% 23.7% 52.6% 2.6% 13.2% 49.0 2.6% 0.0% 7.9% 26.3% 60.0% 0.0% 13.2% (42.4–73.6) (10.2–37.2) (36.8–68.5) (0.0–7.7) (2.4–23.9) (50.6) (0.0–7.7) (0.0–0.0) (0.0–16.5) (12.3–40.3) (29.6–90.4) (0.0–0.0) (2.4–23.9) P 0.99 0.47 0.21 0.34 0.44 0.82 1.0 0.74 0.29 0.30 N/A 0.10 1.0 0.18 0.15 0.45 CI, confidence interval; NAION, nonarteritic anterior ischemic optic neuropathy; PDE, phosphodiesterase; s, simultaneous; u, unilateral. or visual field mean deviation measurements for the incipient eye at final visit when compared with their initial presentation, indicating progression to clinically apparent NAION over time and vision loss. One patient remained asymptomatic with ultimate resolution of the disc edema. Vision loss manifested in the incipient eye at varying time points postpresentation, including a patient who developed loss at 3 days and another at 20 days after initial presentation. The timing of vision loss for all incipient patients was not available. CONCLUSIONS We did not observe any significant differences between sNAION and uNAION regarding demographics, comorbidities and their treatments, and PDE-5 inhibitor usage. Visual acuity, visual field mean deviation, pRNFL, and GCL-IPL thickness at presentation for all patients and at final visit for patients with $3 months of follow-up were also similar. Among those with $3 months of follow-up, sNAION eyes had lower CDR at final visit. The lower final CDR in sNAION patients may indicate that sNAION has a smaller CDR before disease manifestation. This is difficult to assess as optic disc edema at presentation prevents measurement of the true CDR, and CDR measurement is somewhat subjective. However, a smaller CDR may potentially be a predisposing factor to sNAION. Unsurprisingly, sNAION patients underwent greater paraclinical testing than uNAION patients. Considering how uncommonly providers encounter sNAION presentation, a thorough investigation to rule out all other possible etiologies is expected. Of note, most patients included in this study were observed before measurements of myelin oligodendrocyte glycoprotein (MOG) immunoglobulin G (IgG) were common practice. MOG IgG-associated optic neuritis can occasionally resemble NAION (14), with 86% and 14% of patients presenting with disc edema and lack of pain, respectively (15). Thus, clinicians could consider a MRI orbits and/or MOG antibody evaluation in the workup of patients suspected for sNAION. TABLE 2. Simultaneous and unilateral nonarteritic anterior ischemic optic neuropathy: Paraclinical evaluation sNAION (95% CI) Erythrocyte sedimentation rate C-reactive protein Temporal artery biopsy Lumbar puncture MRI 94.7% 86.8% 34.2% 73.7% 94.7% (87.6–100.0) (76.1–97.6) (19.1–49.3) (59.7–87.7) (87.6–100.0) uNAION (95% CI) 71.1% 68.4% 10.5% 5.3% 55.3% (56.6–85.5) (53.6–83.2) (0.8–20.3) (0.0–12.4) (39.5–71.1) P 0.0061 0.054 0.013 0.013 ,0.0001 CI, confidence interval; NAION, nonarteritic anterior ischemic optic neuropathy; s, simultaneous; u, unilateral. 88 Chung et al: J Neuro-Ophthalmol 2023; 43: 86-90 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 3. Simultaneous and unilateral nonarteritic anterior ischemic optic neuropathy: Visual and optical coherence tomography outcomes uNAION N Mean (SD) sNAION 95% CI At presentation* Visual acuity (logMAR) 38 0.4 (0.5) 0.2 to 0.5 Visual field mean deviation (decibels) 33 211.7 (5.0) 213.4 to 29.9 pRNFL (mm) 31 169.5 (75.2) 141.9 to 197 GCL-IPL (mm) 17 69.7 (10.1) 64.5 to 74.9 At final visit† Visual acuity (logMAR) 27 0.5 (0.6) 0.3 to 0.7 Visual field mean deviation (decibels) 21 213.7 (6.5) 216.7 to 210.8 pRNFL (mm) 24 66.5 (13.8) 60.7 to 72.3 GCL-IPL (mm) 22 60 (9.7) 55.8 to 64.3 CDR 27 0.2 (0.1) 0.2 to 0.3 N Mean (SD) 95% CI P 76 0.5 (0.6) 0.4 to 0.7 58 213.0 (8.5) 215.2 to 210.7 46 190.7 (72.1) 169.3 to 212.1 14 107.5 (96.2) 52 to 163 0.13 0.53 0.25 0.18 56 43 38 14 44 0.76 0.62 0.11 0.86 0.033 0.5 215 76.1 60.6 0.1 (0.6) (8.5) (24) (6.7) (0.1) 0.4 to 0.7 217.6 to 212.3 68.2 to 84 56.7 to 64.4 0.1 to 0.2 *Comparisons were made between total sNAION eyes and total uNAION eyes. † Comparisons were made between sNAION and uNAION eyes whose final visits were at least 3 months after initial presentation. CI, confidence interval; CDR, cup-to-disc ratio; GCL-IPL, ganglion cell layer-inner plexiform layer; N, number; NAION, nonarteritic anterior ischemic optic neuropathy; PD, phosphodiesterase; pRNFL, peripapillary retinal nerve fiber layer; SD, SD; s, simultaneous; u, unilateral. Interestingly, 10 sNAION patients experienced incipient NAION in one eye. This condition is characterized by optic disc swelling without associated optic nerve-related vision loss and is likely the earliest observable stage of NAION (13). The mechanism is uncertain but may represent reversible ischemia to the prelaminar optic nerve head, enough to cause axoplasmic stasis and optic disc swelling, but not sufficient to cause visual loss. In our cohort, we observed most patients with unilateral incipient NAION (9 of 10 patients) developed visual loss over time consistent with conversion to symptomatic NAION. Treatment was at the discretion of the treating physician. Some patients were treated empirically with prednisone because of suspicion for GCA, but this was discontinued after the disease was ruled out. Because there is no proven treatment for NAION at this time, it is unlikely that any intervention would have prevented visual loss in the second, initially unaffected eye. Although incipient NAION in the fellow eye may be under-recognized, it can ultimately impair patient vision. This highlights the importance of recognizing incipient NAION early to provide better prognostic information to patients, and to intervene if there are future treatment options available. Our study has several limitations, including the retrospective design. First, patients were gathered from tertiary medical centers, so the results may lack generalizability. In addition, the sample size was small given the rarity of sNAION. The sample size was further reduced for certain visual parameters, as each institution varied in devices and instrumentation. The sample size and case–control ratio could be increased in subsequent studies. However, this was an exploratory, hypothesis-generating analysis. Although increasing the case–control ratio may increase statistical power, it would not necessarily change point estimates. Thus, the estimates provided remain informative for the Chung et al: J Neuro-Ophthalmol 2023; 43: 86-90 study’s purpose. Finally, the variability in follow-up may affect final visual outcomes, as patients with NAION can have modest improvement in visual function by 6 months (16). Based on a search of the PubMed database using the terms “bilateral simultaneous nonarteritic anterior ischemic optic neuropathy,” “bilateral simultaneous NAION,” and “bilateral sequential nonarteritic anterior ischemic optic neuropathy,” we believe that this is the first case–control study of this size comparing the clinical characteristics, investigative evaluation, and visual outcomes of sNAION patients with those of uNAION patients. 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