Internuclear Ophthalmoplegia Characterizes Multiple Sclerosis Rather Than Neuromyelitis Optica Spectrum Disease

Background: Neuromyelitis optica spectrum disease (NMOSD) and multiple sclerosis (MS) share clinical presentations including optic neuritis and brainstem syndromes. Internuclear ophthalmoplegia (INO) is characterized by slowed ipsilateral adduction saccades and results from a lesion in the medial longitudinal fasciculus (MLF). Although INO is a common clinical finding in MS, its prevalence in NMOSD is unknown. The objective of this work is to determine the comparative frequencies of INO in patients with NMOSD and MS and compare clinical features of both disease processes. Methods: This is a retrospective study of patients 18 years and older who have an established diagnosis of NMOSD or MS and were evaluated by both neuro-ophthalmology and neuro-immunology specialists between 2014 and 2020. Electronic medical records were screened for documentation of an acute INO at any time during follow-up. Incidence rates were calculated from number of cases of new-onset INO and patient years observed. Logistic regression was used to evaluate the likelihood of developing an INO at any time point for NMOSD vs MS patients. Multivariable analysis was performed by adjusting for age, race, gender, and length of follow-up. Results: Two hundred eighty patients (80 NMOSD, 200 MS) were included. Age range was 18-79 years with a mean age of 35.14 (SD ± 12.41 years). Average length of follow-up in MS and NMOSD patients was 4.18 years vs 3.79 years, respectively (P > 0.05), and disease duration before the start of the study in MS and NMOSD was 8.76 years vs 4.65 years, respectively (P < 0.01). Mean disease duration and follow-up time of both groups was 7.58 years and 4.07 ± 2.51 years, respectively. NMOSD patients were predominantly seropositive for AQP4 antibody (61.25%, n = 49). Individuals who had MOG antibody but also met NMOSD criteria were also included (18.75%, n = 15). The frequency of INO at any time point was 1.25% (n = 1) in NMOSD compared with 16% (n = 32) in MS. The incidence rate of new-onset INO in NMOSD (excluding MOGAD) was 3.8/1,000 person years and 23.9/1,000 person years in MS. Adjusted analysis showed that NMOSD patients were 13.89 times (odds ratio [OR] 0.07, 95% confidence interval [CI] 0.01-0.598, P = 0.015) less likely to develop an INO compared with those with MS when including MOGAD patients, 12.5 times less likely (OR 0.08, 95% CI: 0.10-0.67, P = 0.02) when excluding MOGAD patients and 9.62 times less likely (OR 0.10, 95% CI: 0.01-0.87, P = 0.036) for AQP4+ patients. Conclusions: Our study shows that the incidence of new INO (3.8 vs 23.9 per 1,000 person years), and the odds of having INO at any time point are significantly lower in NMOSD than MS. This suggests that INO and consequently MLF lesions are less common in NMOSD. The presence of an INO may help in the differentiation of NMOSD from MS and may aid in earlier implementation of disease appropriate therapy.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Internuclear Ophthalmoplegia Characterizes Multiple Sclerosis Rather Than Neuromyelitis Optica Spectrum Disease Mahmoud M. Hamza, BS, Basheer F. Alas, BS, Connie Huang, BS, Justin C. Quon, BS, Lilyana Amezcua, MD, Michael V. Robers, MD, MS, Kimberly K. Gokoffski, MD, PhD Background: Neuromyelitis optica spectrum disease (NMOSD) and multiple sclerosis (MS) share clinical presentations including optic neuritis and brainstem syndromes. Internuclear ophthalmoplegia (INO) is characterized by slowed ipsilateral adduction saccades and results from a lesion in the medial longitudinal fasciculus (MLF). Although INO is a common clinical finding in MS, its prevalence in NMOSD is unknown. The objective of this work is to determine the comparative frequencies of INO in patients with NMOSD and MS and compare clinical features of both disease processes. Methods: This is a retrospective study of patients 18 years and older who have an established diagnosis of NMOSD or MS and were evaluated by both neuro-ophthalmology and neuro-immunology specialists between 2014 and 2020. Electronic medical records were screened for documentation of an acute INO at any time during follow-up. Incidence rates were calculated from number of cases of new-onset INO and patient years observed. Logistic regression was used to evaluate the likelihood of developing an INO at any time point for NMOSD vs MS patients. Multivariable analysis was performed by adjusting for age, race, gender, and length of follow-up. Keck School of Medicine (CH, JQ), University of Southern California, Los Angeles, California; Department of Neurology (LA, MR), University of Southern California, Los Angeles, California; Department of Neurology (MR), Barrows Neurological Institute, Phoenix, Arizona; and Department of Ophthalmology (KKG), Roski Eye Institute, University of Southern California, Los Angeles, California.; and M. Hamza and B. Alas contributed equally. Supported in part by NMSS (RG-1607-25324) (Amezcua), California Community Foundation (Amezcua), Biogen, Idec (008798) (Amezcua), and NMSS Sylvia Lawry Training Grant (FP-1708-29013; M. Robers). The 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 HTML and PDF versions of this article on the journal’s Web site (www. jneuro-ophthalmology.com). Address correspondence to Kimberly Kinga Gokoffski, MD, PhD, Department of Ophthalmology, Roski Eye Institute, University of Southern California, 1450 San Pablo Street 4th Floor, Los Angeles, CA 90033; E-mail: [e-mail] Hamza et al: J Neuro-Ophthalmol 2022; 42: 239-245 Results: Two hundred eighty patients (80 NMOSD, 200 MS) were included. Age range was 18–79 years with a mean age of 35.14 (SD ± 12.41 years). Average length of follow-up in MS and NMOSD patients was 4.18 years vs 3.79 years, respectively (P . 0.05), and disease duration before the start of the study in MS and NMOSD was 8.76 years vs 4.65 years, respectively (P , 0.01). Mean disease duration and follow-up time of both groups was 7.58 years and 4.07 ± 2.51 years, respectively. NMOSD patients were predominantly seropositive for AQP4 antibody (61.25%, n = 49). Individuals who had MOG antibody but also met NMOSD criteria were also included (18.75%, n = 15). The frequency of INO at any time point was 1.25% (n = 1) in NMOSD compared with 16% (n = 32) in MS. The incidence rate of new-onset INO in NMOSD (excluding MOGAD) was 3.8/1,000 person years and 23.9/1,000 person years in MS. Adjusted analysis showed that NMOSD patients were 13.89 times (odds ratio [OR] 0.07, 95% confidence interval [CI] 0.01–0.598, P = 0.015) less likely to develop an INO compared with those with MS when including MOGAD patients, 12.5 times less likely (OR 0.08, 95% CI: 0.10– 0.67, P = 0.02) when excluding MOGAD patients and 9.62 times less likely (OR 0.10, 95% CI: 0.01–0.87, P = 0.036) for AQP4+ patients. Conclusions: Our study shows that the incidence of new INO (3.8 vs 23.9 per 1,000 person years), and the odds of having INO at any time point are significantly lower in NMOSD than MS. This suggests that INO and consequently MLF lesions are less common in NMOSD. The presence of an INO may help in the differentiation of NMOSD from MS and may aid in earlier implementation of disease appropriate therapy. Journal of Neuro-Ophthalmology 2022;42:239–245 doi: 10.1097/WNO.0000000000001534 © 2022 by North American Neuro-Ophthalmology Society N euromyelitis Optica Spectrum Disorder (NMOSD) and Multiple Sclerosis (MS) represent 2 major forms of idiopathic, autoimmune demyelinating diseases of the central nervous system. Originally described in the 19th century, NMOSD was previously believed to represent a 239 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution geographically limited form of MS (1,2). The identification of aquaporin-4 immunoglobulins (AQP-4 IgG) in patients with NMOSD, however, has led to the understanding that different pathophysiologic mechanisms underlie these 2 conditions (3,4). AQP-4 IgG mediates an astrocytopathy in NMOSD whereas MS is characterized by immunemediated destruction of the fatty myelin coat that insulates neuronal axons. Not all NMOSD patients, however, are seropositive for AQP-4 IgG. Up to 42% of patients with clinical features of NMOSD who are negative for AQP4-IgG may be found to have antimyelin oligodendrocyte glycoprotein antibodies (MOG-Ab) (1). Although MOG-associated disease (MOGAD) has become recognized as its own disease with different pathophysiology from AQP-4 (5), it does not yet have its own International Classification of Diseases diagnostic code, and not all MOG+ antibodies represent MOGAD, which makes retrospective search for these patients difficult. In addition, MOGAD patients can meet diagnostic criteria for seronegative NMOSD (6,7,8,9). Notably, NMOSD patients who are seropositive for MOG IgG antibodies have more favorable outcomes—they have fewer attacks and distinct clinical features, which are more responsive to therapy than patients with AQP4 IgG antibodies or patients who are seronegative for both (10,11).Given that 10%–40% of patients with NMOSD are sero-negative for AQP-4 IgG, differentiating MS from NMOSD can still be clinically challenging (12). Establishing clinical, laboratory, and radiographic signs that distinguish NMOSD from MS is of clinical importance. Previous studies differentiating NMOSD and MS have found adults who suffer from NMOSD-related optic neuritis are more likely to experience bilateral nerve involvement with more severe vision loss than patients with MS (13). As optic nerve atrophy sets in, severe loss of retinal ganglion cells and poorer visual recovery per inflammatory event characterizes NMOSD rather than MS (14). In addition, transverse myelitis is more complete in NMOSD patients than those who develop MS (15). Finally, radiographic findings associated with NMOSD include diencephalic and brainstem lesions, and area postrema syndrome (16,17). There are few purely clinical signs that can help differentiate NMOSD and MS. In our clinical practice, we have observed that NMOSD patients infrequently manifest internuclear ophthalmoplegia (INO), an eye coordination disorder resulting from a lesion to the medial longitudinal fasciculus (MLF) (18). To test this association, we conducted a retrospective cohort study to examine the relationship between diagnosis of NMOSD vs MS and the likelihood of developing INO during disease progression. METHODS We conducted a retrospective cohort study of individuals older than age 18 with NMOSD or MS to evaluate the 240 frequency of INO in these 2 groups. Please see Supplemental Digital Content 1 (see Methods, http://links.lww.com/ WNO/A559) for a more detailed description of our methods. Outcomes The primary outcome was the presence of INO at any time during clinic follow-up (2000–2020), reported and confirmed by neuro-ophthalmologic examination. All patients were examined by a neuro-ophthalmologist because our cohort was selected from the neuro-ophthalmology service. Secondary outcomes included incidence and timedependent hazard of new-onset INO during clinic followup, and occurrence of INO in subcategories of NMOSD (AQP4+, MOG+, and seronegative). Statistical Analysis The odds ratio (OR) of having an INO documented on examination by a neuro-ophthalmologist at any time was modelled using binomial logistic regression as a function of diagnosis (MS vs NMOSD including MOG). A variable was considered confounding if it changed the beta exponential by 15% or was of known importance in MS or NMOSD. Multivariate analysis was then performed by adjusting for the following confounding variables: age, race, gender, and length of follow-up. SPSS V.23 was used for all statistical analysis. An alpha of P = 0.05 was defined as the a priori cut off for statistical significance. Please see Supplemental Digital Content 1 (see Methods, http://links.lww. com/WNO/A559) for a more detailed description of our methods. RESULTS The demographics for the 280 patients (200 MS, 80 NMOSD) identified are provided in Table 1. The study population consisted of 38.6% (108/280) Caucasian, 35.7% (100/280) Hispanic, 11.1% (31/280) Other, 7.5% (21/280) Black, and 7.1% (20/280) Asian. A sizable minority of patients self-identified as mixed race/ ethnicity: Armenian, Iranian, or Middle Eastern and were placed in the ‟Other” category. Women comprised 72.9% (204/280) of patients. The mean age of participants at time of start of the study was 42.7 ± 13.5 years, mean length of follow-up was 4.1 ± 2.5 years, and mean disease duration was 7.6 years. The demographic characteristics of our cohort, stratified by diagnosis, is shown in Table 1. There was a significant difference in the racial make-up of MS vs NMOSD patients: Most NMOSD patients were Hispanic compared with the mostly Caucasian patients in the MS cohort. The racial breakdown of NMOSD patients by serotype can be seen in Table 2. Nearly half of the MS patients (48%) reported a history of optic neuritis, and 80% reported a history of transverse Hamza et al: J Neuro-Ophthalmol 2022; 42: 239-245 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. Descriptive statistics Variable Total, N (%) NMOSD, N (%) MOG, N (%) MS, N (%) Total (% row) 280 (100.00%) 65 (23.21%) 15 (5.36%) 200 (71.43%) Gender Male 76 (27.14%) 14 (21.54%) 2 (13.33%) 60 (30.00%) Female 204 (72.86%) 51 (78.46%) 13 (86.67%) 140 (70.00%) Race Caucasian 108 (38.57%) 13 (20.00%) 1 (6.67%) 94 (47.00%) Asian 20 (7.14%) 13 (20.00%) 0 (0.00%) 7 (3.50%) Black 21 (7.50%) 3 (4.61%) 0 (0.00%) 18 (9.00%) Hispanic 100 (35.71%) 34 (52.31%) 13 (86.67%) 53 (26.50%) Other 31 (11.07%) 2 (3.08%) 1 (6.67%) 28 (14.00%) Disease course Mean age at first symptom onset (SD) 35.14 (12.41) 40.18 (14.54) 39.47 (13.98) 33.17 (10.97) Mean disease duration (SD) 7.58 (8.73) 5.48 (7.69) 1.07 (2.09) 8.76 (9.03) Mean age at enrollment (SD) 42.72 (13.50) 45.66 (14.60) 40.53 (13.74) 41.93 (13.04) Mean enrollment duration (SD) 4.07 (2.51) 4.06 (3.27) 2.60 (1.45) 4.18 (2.25) Previously or currently on DMT 254 (90.71%) 55 (84.62%) 10 (66.67%) 189 (94.50%) Symptoms Optic neuritis 163 (58.21%) 52 (80.00%) 15 (100.00%) 96 (48.00%) Transverse myelitis 206 (73.57%) 46 (70.77%) 1 (6.67%) 159 (79.50%) Internuclear ophthalmoplegia 33 (11.79%) 1 (1.54%) 0 (0.00%) 32 (16.00%) myelitis. Significantly more people with NMOSD had a history of optic neuritis (84%), but interestingly, less had a history of transverse myelitis (59%). Within the NMOSD population, 49/80 were AQP4+, 15/80 were MOG+, and 16/80 were double antibody negative (Table 2). Of note, 65 (81.25%) NMOSD patients were on disease modifying treatment, whereas this was the case for 189 (94.50%) MS patients. One-way ANOVA was used to evaluate differences among continuous variables between MS, NMOSD (excluding MOG), and MOGAD patients (Table 1). Of the variables analyzed, age at disease onset differed significantly between the 2 groups—MS patients were, on average, younger when they experienced their first demyelinating symptoms compared with NMOSD patients (mean: 33.17 vs 40.05 years, respectively; 95% confidence interval [CI] of 3.35–10.41 years; P , 0.001). Although no difference in age at time of start of the study (41.93 vs 44.70, P . 0.05) or length of follow-up was found between P 0.192 ,0.001 ,0.001 ,0.001 0.124 0.062 ,0.001 ,0.001 ,0.001 0.002 MS and NMOSD patients (4.18 vs 3.79 years, respectively, P . 0.05), MS had significantly longer disease duration before start of the study in our study population (8.76 years vs 4.65 years, respectively, P , 0.01). When evaluating the frequency of INO, 32 MS patients (16%) had a clinically documented INO during the study whereas only one NMOSD patient, who was AQP4+, had a clinically documented INO (1.3%). For this patient, INO was noted 2 years after his initial NMOSD diagnosis. For our MS patient population, the average time of onset between initial diagnosis and INO was 12.2 years. There were no cases of INO documented in patients with MOG antibody. When considering only new cases of INO that developed during the period of observation, there was 1 INO in the NMOSD group and 19 in the MS group. Total person years observed excluding those with an INO at their first visit were 264 years in NMOSD pts (excluding MOG), 39 years in MOGAD, and 795 years of MS patients. The calculated incidence rate of INO in NMOSD was 3.3 and TABLE 2. Antibody status Variable Total (% row) Gender Male Female Race Caucasian Asian Black Hispanic Other AQP4 Ab+, N (%) Double Ab2, N (%) MOG Ab+, N (%) 49 (61.25) 16 (20.00) 15 (18.75) 42 (85.71) 7 (14.29) 7 (43.75) 9 (56.25) 2 (13.33) 13 (86.67) 12 7 2 26 2 1 (6.25) 6 (37.50) 1 (6.25) 8 (50.00) 0 (0.00) 1 (6.67) 0 (0.00) 0 (0.00) 13 (86.67) 1 (6.67) (24.49) (14.29) (4.08) (53.06) (4.08) Hamza et al: J Neuro-Ophthalmol 2022; 42: 239-245 241 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 3. Odds ratio of INO Unadjusted NMOSD, including MOGAD NMOSD, excluding MOGAD NMOSD AQP4+ Adjusted* Odds Ratio (95% Confidence Interval) P Odds Ratio (95% Confidence Interval) P 15.15 (2.02–111.11) 12.20 (1.63–90.91) 9.17 (1.22–66.67) 0.008 0.015 0.031 13.89 (1.67–111.11) 12.50 (1.49–100.0) 9.62 (1.15–76.92) 0.015 0.020 0.036 *Adjusted for treatment, disease duration, gender, race, and age at enrollment. 3.8 per 1,000 person years when including or excluding MOG patients respectively. In comparison, the incidence of INO in our MS cohort was 23.9 per 1,000 person years. Univariate analysis showed that disease duration and treatment history were significant confounders in the risk for developing an INO. Although age, race, and sex were not found to be significant confounders, we also adjusted for them in our final model because of their known influence on disease progression and severity in demyelinating diseases. Adjusting for age, gender, race, treatment history, and disease duration, our multivariable logistic regression model showed that INO is 13.89 times less likely to be observed in NMOSD (all groups, including MOGAD) compared with MS (Table 3; OR 0.072, 95% CI: 0.01–0.598; P = 0.015). Similar analysis was performed excluding MOGAD patients and showed NMOSD patients were 12.50 times less likely to develop an INO than MS; (OR: 0.08, CI: 0.1–0.67; P= 0.02). Finally, when comparing risk of developing an INO in AQP4+ vs MS patients, final adjusted analysis showed AQP4+ patients were 9.62 times less likely to develop an INO than MS patients (0.10, CI: 0.01–0.87, P = 0.036). When COX regression (Table 4) was performed to evaluate the hazard of developing a new INO by disease state, the HR showed that NMOSD patients had 6.7-fold less risk of developing INO than MS, (HR = 0.15; P =0.07) (Fig. 1). A total of 13 outcomes of interest were excluded in this analysis because they represented the cases of INO that occurred before enrollment. A second COX regression analysis was performed including these 13 cases of INO documented at the first visit and showed that NMOSD patients had 11.5 times less risk of developing an INO than MS patients (P = 0.02). CONCLUSION This retrospective cohort study of patients seen at 2 academic hospitals was performed to evaluate the possible utility of INO as a differentiating sign between NMOSD and MS. We report an incidence of INO between 3.3 and 3.8 per 1,000 person years (including or excluding MOGAD patients respectively). This is significantly less than our MS cohort, which had an incidence rate of 23.9 per 1,000 person years. Using logistic regression, we showed that compared with patients with MS, NMOSD patients 242 are 13.89 times less likely to have an INO at any point in their follow-up independent of age, gender, race, treatment status, or disease duration. This is a novel outcome that to our knowledge has not previously been described. Analysis excluding MOGAD patients or including only AQP4+ patients vs MS patients showed 12.50 and 9.62 less likelihood of developing INO, respectively. MOGAD, which is now recognized as its own disease, had no reported case with associated INO. However, as the number of MOGAD patients was low, it is difficult to determine whether this finding is inherent to the disease or not. Given that there was only one case of INO in our entire NMOSD cohort (this patient was AQP4 IgG + and presented with a unilateral INO), we were unable to perform subgroup analysis to evaluate the risk of developing INO in different serotypes of NMOSD patients. It is possible that with a larger study, the risk of developing an INO could be further stratified in NMOSD patients by sero-status. When COX regression was performed to evaluate only new cases of INO, there is clear separation in the graph between MS and NMOSD patients and the HR shows that NMOSD has 6.7-fold less risk of developing an INO than MS, but this did not reach statistical significance (P = 0.07). We suspected this loss of significance was because of a loss of power as 13 outcomes of interest had been excluded. A second COX regression analysis was performed including a case of INO documented at the first visit and this confirmed that including more outcomes increased the power and showed statistical significance. Thus, the difference in significance between the 2 COX regression analyses can be attributed to low power in the first analysis. The literature reports the prevalence of INO in MS patients to range from 15% to 55% (6,19–22), and Nij et al, argue that INO prevalence depends on the specific characteristics of the MS population that is investigated in a study. However, only a limited number of cases of INO TABLE 4. COX regression for INO risk NMOSD (excluding MOGAD) Excluding baseline INO Including baseline INO Hazard Ratio* P 7.0 11.5 0.066 0.019 *Adjusted for treatment, gender, race, and age at enrollment. Hamza et al: J Neuro-Ophthalmol 2022; 42: 239-245 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 1. Cox regression of INO-free survival by diagnosis adjusted for race, sex, and treatment status. HO = 0.15. have been documented in patients with NMOSD. For example, one case study referenced a double antibody negative 32-year-old pregnant Caucasian woman with known NMOSD who developed bilateral INO (23). A second report referenced a 19-year-old Asian woman who was AQP4+ who had wall-eyed bilateral INO (24). The frequency of INO in our MS cohort (16%) was at the low end of other published reports, possibly because of our rigorous selection process where all cases of INO were identified or confirmed by a neuro-ophthalmologist. The measured incidence during observation (excluding those present at baseline) for MS was 23.9/1,000 person years. For NMOSD, this was only 3.3 or 3.8/1,000 person years (including or excluding MOGAD, respectively). AQP4 protein is found on the foot processes of astrocytes in the optic nerves, brainstem, and spinal cord (25,26). The geographic restriction in AQP4 protein expression to these areas is believed to underlie the limitation in clinical presentation of NMOSD compared with MS. Given that histologic studies in animals have shown that AQP4 protein is found in the MLF (23,27), absence of antigen is unlikely to explain the lower incidence seen in our cohort. Others have hypothesized whether NMOSD patients can develop wall-eyed bilateral INO. The authors of one particular case report noted a patient with NMOSD who presented with both Wernekink commissure syndrome and wall-eyed bilateral INO (28). Perhaps the pathophysiologic process in the brainstem for the 2 are the same and similar to what occurred in one of our AQP4+ patients with INO. More research is needed to test whether there is a unique physiological process occurring in NMOSD, compared with MS, that limits its effects on the MLF. An interesting, unintended finding of our study was that the racial composition of the MS and NMOSD cohorts differed. The NMOSD cohort’s largest demographic was Hispanic, making up 58.75% (47/80) of patients, followed by Caucasians at 17.50% (14/80) (Table 1). This was even Hamza et al: J Neuro-Ophthalmol 2022; 42: 239-245 more pronounced in the MOGAD subgroup, where 86.67% (13/15) of the patients were Hispanic (Table 2). In the MS cohort, the largest demographic by race was Caucasian at 47.00% (94/200), followed by Hispanics at 26.50% (53/200) (Table 1). This is consistent with the long-held finding that MS prevalence is disproportionately higher in Caucasians when compared with other ethnic groups (29,30). The relatively high percentage of Hispanic patients in our NMOSD cohort may be explained by the hospital’s location, which is in a predominantly Hispanic and Spanish-speaking neighborhood. Alternatively, this could represent a true increase of NMOSD in Hispanics, a disease which is already known to affect Asians and African Americans more frequently than Caucasians (31–35). A previously published NMOSD review puts worldwide incidence of NMOSD in Afro-Caribbean populations at 0.73/ 100,000 person years and 0.037/100,000 person years in Australia/New Zealand (36); however, incidence in other ethnic groups have not been previously reported. Limitations A major strength of our study is the fact that every patients’ diagnosis of NMOSD and MS was established by a neuroimmunologist and INO was screened for by neuroophthalmologists. There are, however, a number of limitations to our study. First and foremost, although our NeuroOphthalmology service sees a large number of patients with demyelinating disease, this still represents a subset of patients served by the Neuro-immunology service. This design could have introduced a selection bias whereby only patients with visual complaints were included, leading to an overestimation of the incidence of INO. However, we know that the overall percentage of INO and incidence of new INO in our MS cohort is similar to what has been previously reported in the literature, thus reducing the possibility of selection bias for cases with INO. Second, the retrospective nature limits the causal interpretation of the study. Third, although we adjusted for confounders of known importance, it is possible that unmeasured confounders contributed to the results. Our results show that when adjusted for age, gender, race, and length of follow-up, the diagnosis of NMOSD is associated with 13.89 times less likelihood of developing an INO at any time during follow-up than MS patients. Although far from being a clinical examiation finding i.e., pathognomonic for MS, its presence can help the clinician steer their diagnosis away from that of NMOSD. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: M. Hamza, B. Alas, C. Huang, J. Quon, L. Amezcua, M. Robers, and K. K. Gokoffski; b. Acquisition of data: M. Hamza, B. Alas, C. Huang, and J. Quon; c. Analysis and interpretation of data: M. Hamza, B. Alas, C. Huang, J. Quon, L. Amezcua, M. Robers, and K. K. Gokoffski. Category 2: a. Drafting the manuscript: M. Hamza, B. Alas, C. Huang, J. Quon, L. Amezcua, M. Robers, and K. K. Gokoffski; b. Revising it for intellectual content: M. 243 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution Hamza, B. Alas, C. Huang, J. Quon, L. Amezcua, M. Robers, and K. K. Gokoffski. Category 3: a. Final approval of the completed manuscript: M. Hamza, B. Alas, C. Huang, J. Quon, L. Amezcua, M. Robers, and K. K. Gokoffski. 15. 16. REFERENCES 1. Flanagan EP. Neuromyelitis optica spectrum disorder and other non-multiple sclerosis central nervous system inflammatory diseases. Continuum (Minneap MN). 2019;25:815–844. 2. Fujihara K. Neuromyelitis optica spectrum disorders: still evolving and broadening. Curr Opin Neurol. 2019;32:385– 394. 3. Yokote H, Mizusawa H. Multiple sclerosis and neuromyelitis optica spectrum disorders: some similarities in two distinct diseases. Neural Regen Res. 2016;11:410–411. 4. Lennon VA, Wingerchuk DM, Kryzer TJ, Pittock SJ, Lucchinetti CF, Fujihara K, Nakashima I, Weinshenker BG. 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