20/40 or Better Visual Acuity After Optic Neuritis: Not; as Good as We Once Thought?

Although patients with acute optic neuritis (ON) recover high-contrast visual acuity (HCVA) to 20/40 or better in 95% of affected eyes, patients with a history of ON continue to note subjective abnormalities of vision. Furthermore, substantial and permanent thinning of the retinal nerve fiber layer (RNFL) and the ganglion cell layer (GCL) is now known to occur early in the course of ON. We measured vision-specific quality of life (QOL) in patients with a history of acute ON and recovery of VA to 20/40 or better in their affected eyes to determine how these QOL scores relate to RNFL and GCL thickness and low-contrast letter acuity (LCLA) across the spectrum of visual recovery.; Data from an ongoing collaborative study of visual outcomes in multiple sclerosis and ON were analyzed for this cross-sectional observational cohort. Patients and disease-free control participants completed the 25-Item National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25) and 10-Item Neuro-Ophthalmic Supplement to the NEI-VFQ-25, as well as VA and LCLA testing for each eye separately and binocularly. Optical coherence tomography measures for each eye included peripapillary RNFL thickness and macular GCL + inner plexiform layer (GCL + IPL) thickness.; Patients with a history of acute ON and recovery to 20/40 or better VA (n = 113) had significantly reduced scores for the NEI-VFQ-25 (83.7 ± 15.4) and 10-Item Neuro-Ophthalmic Supplement (74.6 ± 17.4) compared with disease-free controls (98.2 ± 2.1 and 96.4 ± 5.2, P < 0.001, linear regression models, accounting for age and within-patient, intereye correlations). Most patients with 20/40 or better visual recovery (98/112, 88%) had monocular HCVA in their affected eye of 20/20 or better. Although patients with 20/50 or worse HCVA recovery demonstrated the worst performance on low-contrast acuity, affected eye RNFL and GCL + IPL thickness, and QOL scales, these measures were also significantly reduced among those with 20/40 or better HCVA recovery compared with controls.; Patients with a history of ON and 'good' visual recovery, defined in the literature as 20/40 or better HCVA, are left with clinically meaningful reductions in vision-specific QOL. Such patient-observed deficits reflect the underlying significant degrees of retinal axonal and neuronal loss and visual dysfunction that are now known to characterize ON even in the setting of maximal HCVA recovery. There remains an unmet therapeutic need for patients with ON.

Original Contribution 20/40 or Better Visual Acuity After Optic Neuritis: Not as Good as We Once Thought? Sakinah B. Sabadia, BS, Rachel C. Nolan, BA, Kristin M. Galetta, MD, Kannan M. Narayana, MD, James A. Wilson, BA, Peter A. Calabresi, MD, Elliot M. Frohman, MD, Steven L. Galetta, MD, Laura J. Balcer, MD, MSCE Background: Although patients with acute optic neuritis (ON) recover high-contrast visual acuity (HCVA) to 20/40 or better in 95% of affected eyes, patients with a history of ON continue to note subjective abnormalities of vision. Furthermore, substantial and permanent thinning of the retinal nerve fiber layer (RNFL) and the ganglion cell layer (GCL) is now known to occur early in the course of ON. We measured vision-specific quality of life (QOL) in patients with a history of acute ON and recovery of VA to 20/40 or better in their affected eyes to determine how these QOL scores relate to RNFL and GCL thickness and low-contrast letter acuity (LCLA) across the spectrum of visual recovery. Methods: Data from an ongoing collaborative study of visual outcomes in multiple sclerosis and ON were analyzed for this cross-sectional observational cohort. Patients and disease-free control participants completed the 25-Item National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25) and 10-Item Neuro-Ophthalmic Supplement to the NEI-VFQ-25, as well as VA and LCLA testing for each eye separately and binocularly. Optical coherence tomography measures for each eye included peripapillary RNFL thickness and macular GCL + inner plexiform layer (GCL + IPL) thickness. Results: Patients with a history of acute ON and recovery to 20/40 or better VA (n = 113) had significantly reduced Departments of Neurology (SBS, RCN, KN, SLG, LJB), Population Health (LJB) and Ophthalmology (SLG, LJB), New York University School of Medicine, New York, New York; Department of Neurology (KMG, JAW), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; Department of Neurology (PAC), Johns Hopkins University School of Medicine, Baltimore, Maryland; and Department of Neurology (EMF), University of Texas Southwestern Medical Center, Dallas, Texas. Supported by National Multiple Sclerosis Society RG 4649A5/1. P. A. Calabresi has received consulting fees from Vertex, Abbvie, and Merck and has received research funding from Biogen, Novartis, and MedImmune; he is co-chairman of the scientific advisory board of OCTIMS study. E. M. Frohman has received consulting fees from Novartis, Genzyme, Accorda, and Teva. L. J. Balcer has received consulting fees from Biogen. S. L. Galetta has received consulting fees from Biogen. The other authors report no conflicts of interest. Address correspondence to Laura J. Balcer, MD, MSCE, Department of Neurology, NYU School of Medicine, 240 East 38th Street, 20th Floor, New York, NY 10016; E-mail: [e-mail] Sabadia et al: J Neuro-Ophthalmol 2016; 36: 369-376 scores for the NEI-VFQ-25 (83.7 ± 15.4) and 10-Item Neuro-Ophthalmic Supplement (74.6 ± 17.4) compared with disease-free controls (98.2 ± 2.1 and 96.4 ± 5.2, P , 0.001, linear regression models, accounting for age and within-patient, intereye correlations). Most patients with 20/40 or better visual recovery (98/112, 88%) had monocular HCVA in their affected eye of 20/20 or better. Although patients with 20/50 or worse HCVA recovery demonstrated the worst performance on low-contrast acuity, affected eye RNFL and GCL + IPL thickness, and QOL scales, these measures were also significantly reduced among those with 20/40 or better HCVA recovery compared with controls. Conclusions: Patients with a history of ON and "good" visual recovery, defined in the literature as 20/40 or better HCVA, are left with clinically meaningful reductions in vision-specific QOL. Such patient-observed deficits reflect the underlying significant degrees of retinal axonal and neuronal loss and visual dysfunction that are now known to characterize ON even in the setting of maximal HCVA recovery. There remains an unmet therapeutic need for patients with ON. Journal of Neuro-Ophthalmology 2016;36:369-376 doi: 10.1097/WNO.0000000000000421 © 2016 by North American Neuro-Ophthalmology Society A cute optic neuritis (ON) is a disorder characterized by demyelination and inflammation of the optic nerve resulting in subacute vision loss with pain on eye movement. Although ON can be an isolated event, it is often a presenting symptom of multiple sclerosis (MS) (1). The degree of visual loss in acute ON can range from 20/40 or better high-contrast visual acuity (HCVA), classified as minimal visual impairment, to as severe as no light perception (1,2). It has been reported that "good" recovery to 20/40 or better is often achieved after ON. However, in the Optic Neuritis Treatment Trial, vision-specific quality-of-life (QOL) scores were shown to be reduced (3). Additionally, studies have shown persistent loss of contrast sensitivity and color vision after acute ON (4). Visual impairment, therefore, persists in 369 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution many patients who have otherwise experienced what is referred to as good recovery (3,5). Spectral domain optical coherence tomography (OCT) is a reliable and accurate measure of retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL + IPL) thickness in patients with MS and ON (6-10). OCT studies have shown that RNFL and GCL + IPL thinning occurs very early in the course of acute ON (11). Such thinning is strongly associated in MS cohorts with reductions in vision-specific QOL and with functional outcomes of HCVA and low-contrast letter acuity (LCLA) (12). The purpose of this investigation was to determine degrees of residual deficit in vision-specific QOL in patients with a history of acute ON and recovery of VA to 20/40 or better, and to determine how these QOL scores relate to RNFL and GCL + IPL thickness and to LCLA across the spectrum of visual recovery. METHODS Study Participants Patients with a history of ON enrolled in an ongoing collaborative study of visual outcomes in MS were analyzed for this cross-sectional observational cohort. Exclusion criteria for analysis included any history of ocular comorbidities, including glaucoma and diabetic eye disease. Control subjects included healthy volunteers with no history of ocular or neurological disease and were recruited among staff as well as family and friends of patients. Participants were categorized into 3 groups based on visual status as follows: 1) disease-free controls, 2) patients with MS and a history of acute ON with recovery of HCVA to 20/40 or better in both eyes, and 3) patients with MS and a history of acute ON with recovery of VA to 20/50 or worse in 1 or both the eyes. All study protocols were approved by Institutional Review Boards at the collaborative centers (New York University, Johns Hopkins, University of Texas Southwestern at Dallas, and University of Pennsylvania). Written informed consent was obtained from each participant. Vision Testing Participants underwent testing both monocularly and binocularly using best-corrected vision. HCVA was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart at 3.2 m. LCLA was tested with lowcontrast Sloan letter charts (Precision Vision, LaSalle, IL) at 2.5% and 1.25% contrast at 2 m. Results were expressed as numbers of letters identified correctly, with 70 letters as the maximum possible score. Both ETDRS and Sloan letter charts are standardized with 5 letters per line, proportional spacing between lines, and equivalent levels of letter difficulty across a line. 370 Binocular summation or inhibition was quantified for HCVA and LCLA by subtracting the better monocular score from the binocular score. Binocular summation and inhibition are defined by a 7-letter threshold, as determined to be 2 SD from the interrater difference for both control and MS subjects in a previous study (13). Binocular summation was defined as a 7-letter or greater difference between binocular acuity and acuity for the better eye; inhibition was present when the binocular acuity score was 27 or less than the better eye acuity. A difference between 27 and 7 counted for neither summation nor inhibition (14). Vision-Related Quality-of-Life Measures Vision-related QOL was measured using the 25-Item National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25) (15) and the 10-Item Neuro-Ophthalmic Supplement to the NEI-VFQ-25 (16). The NEI-VFQ-25 is the standard vision-specific QOL measure used in ophthalmology and neuro-ophthalmology research and clinical trials. Scores are generated ranging from 0 to100 and include individual scores for 12 subscales and a composite score of the unweighted averages of the individual scores, excluding general health (3). The 10-Item Neuro-Ophthalmic Supplement increases the ability of the NEI-VFQ-25 to distinguish patients with neuro-ophthalmologic disorders from disease-free controls (16). This scale has been used in parallel with the NEI-VFQ-25 in many studies of MS (12,14,17-19) and in idiopathic intracranial hypertension treatment trials (20). Optical Coherence Tomography This study used spectral-domain OCT to determine peripapillary RNFL and macular GCL + IPL thickness. Using Cirrus OCT (Carl Zeiss Meditec, Dublin, CA), RNFL thickness was calculated along 2.4-mm diameter circles around the optic disc using the optic nerve head cube protocol. Macular volume was calculated with Macular Cube 200 · 200 and 512 · 128 scanning protocols, which focused on a 6 · 6 · 2 mm3 area centered on the fovea (12). Scans that were not correctly centered or segmented were either repeated or excluded. Any scans with signal strength values less than 7 (of a possible maximum of 10) were excluded. Statistical Analysis Data were analyzed using Stata statistical software, version 13.0 (Stata Corp, College Station, TX). Generalized estimating equation (GEE) regression models were used to determine associations of continuous variables; these models allow for adjustment for within-patient, intereye correlations because both eyes of each patient were included in the study. Linear regression models were used to determine associations of continuous variables for binocular measures. Patients with a history of ON were grouped Sabadia et al: J Neuro-Ophthalmol 2016; 36: 369-376 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution according to the degree(s) of visual recovery of the affected eye(s) as those with 20/40 or better HCVA in both eyes, vs 20/50 or worse in either eye after ON. Statistical significance was determined by a type I error level a = 0.05. RESULTS Data for 163 participants were analyzed in this study, with 35 controls (70 eyes), 113 patients with a history of ON and recovery of HCVA to 20/40 or better in both eyes (226 eyes), and 15 patients with HCVA 20/50 or worse in at least 1 eye (30 eyes). The MS cohort was generally representative of the US MS population, with women comprising most participants, and relapsing-remitting MS being the most common MS subtype. Both the disease-free control and 20/ 40 or better HCVA ON recovery groups had average binocular HCVA scores of 20/20 or better (Table 1). LCLA testing revealed that those patients with 20/40 or better HCVA recovery after ON still had significantly reduced binocular LCLA compared with controls at the 2.5% and 1.25% contrast levels (P , 0.001, GEE models accounting for age and within-patient, intereye correlations, Table 2). Analyses of OCT data showed statistically significant differences in RNFL thickness, macular volume, and GCL + IPL thickness between the disease-free control eyes, those with 20/40 or better HCVA recovery, and those with 20/50 or worse HCVA in 1 or both the eyes (P , 0.001, GEE models, Table 2; Fig. 1). Compared with the control group (92.2 ± 9.1 mm), the average RNFL thickness was significantly thinner even among eyes with 20/40 or better VA recovery after ON (80.0 ± 13.6 mm). Average macular volume showed similar patterns of reduction from diseasefree control eyes, even among those eyes that recovered HCVA to 20/40 or better (Table 2). RNFL and GCL + IPL thinning in ON eyes was the greatest among those with the lowest (worst) high- and low-contrast acuity scores (P , 0.001, GEE models accounting for age and within-patient, intereye correlations). Binocular inhibition (defined in Methods above) of high-contrast VA was seen in 20% of patients with ON and recovery to 20/50 or worse; inhibition was not noted in any of the control subjects (P , 0.001) or in the 20/40 or better recovery group when measuring high-contrast VA. Binocular summation of LCLA (2.5% contrast) was present in only 23% of patients with ON and recovery to 20/40 or better, whereas 53% of disease-free controls had summation (P = 0.03). Scores for the NEI-VFQ-25 and 10-Item NeuroOphthalmic Supplement were reduced among patients with a history of ON, even among those with visual recovery of VA to 20/40 or better in both the eyes (P , 0.001, linear regression models, accounting for age, Table 2; Fig. 2). Reductions in RNFL and GCL + IPL thickness in MS eyes were associated with worse QOL scores for patients, with larger percent decreases in OCT measurements correlated with lower QOL scores (Fig. 3). Although RNFL and GCL + IPL thickness decreased by 11.1% and 12.8%, respectively, in those eyes with 20/40 or better VA recovery, QOL measures were more substantially reduced when compared with controls. The 10-Item Neuro-Ophthalmic Supplement scores exhibited the most substantial reductions among patients with a history of ON. When comparing the unaffected fellow eyes of all the patients with a history of ON vs the eyes of disease-free controls, RNFL thickness (86.5 ± 12.5 vs 92.2 ± 9.1, P = 0.01), GCL + IPL thickness (75.6 ± 9.8 vs 79.8 ± 6.0, P = 0.04), HCVA (55.0 ± 7.2 vs 58.4 ± 5.6, P = 0.01), 2.5% LCLA (27.7 ± 10.7 vs 34.4 ± 6.8, P , 0.001), and 1.25% LCLA (14.7 ± 10.1 vs 19.7 ± 9.0, P = 0.01, GEE models, accounting for age and within-patient, intereye correlations) were also reduced. DISCUSSION Results of this study demonstrate that even when HCVA recovery after ON is 20/40 or better, there are clinically TABLE 1. Demographics for patients/eyes with MS and a history of acute ON, and for disease-free control participants Disease-Free Controls (n = 35, 70 Eyes) Age (mean ± SD), y Sex, n (% female) Relapsing-remitting MS, n (%) Disease duration, median (range) Binocular VA (mean ± SD), number of letters correct/70 Monocular VA (mean ± SD), number of letters correct/70 Patients With ON and Patients With ON and Recovery of VA to 20/40 or Residual VA Deficit of 20/50 Better (n = 113, 226 Eyes) or Worse (n = 15, 30 Eyes) 29.8 ± 9.5 26 (73.5) - - 62.0 ± 3.9 46.5 ± 11.4 92 (81.4) 99 (87.6) 9.1 (0.33-31) 58.5 ± 5.3 43.3 ± 11.5 10 (66.7) 14 (93.3) 12 (0.67-40) 47.3 ± 12.6 58.4 ± 5.6 54.7 ± 6.3 32.8 ± 20.9 MS, multiple sclerosis; ON, optic neuritis; SD, standard deviation; VA, visual acuity. Sabadia et al: J Neuro-Ophthalmol 2016; 36: 369-376 371 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 2. Results for LCLA testing, OCT, and vision-specific QOL scores from the NEI-VFQ-25 and 10-Item NeuroOphthalmic Supplement Binocular LCLA, 2.5% contrast (mean ± SD), number of letters correct/70 % decrease vs control mean Monocular LCLA, 2.5% contrast (mean ± SD), number of letters correct/70† % decrease vs control mean Binocular LCLA, 1.25% contrast (mean ± SD), number of letters correct/70† % decrease vs control mean Monocular LCLA, 1.25% contrast (mean ± SD), number of letters correct/70† % decrease vs control mean RNFL thickness by eye (mean ± SD), mm Macular volume by eye (mean ± SD), mm3 GCL + IPL thickness by eye (mean ± SD), mm NEI-VFQ-25 composite score (mean ± SD), best score 100 points 10-Item Neuro-Ophthalmic Supplement to the NEI-VFQ-25 (mean ± SD), best score 100 points Disease-Free Controls (n = 35, 70 Eyes) Patients With ON and Recovery of VA to 20/40 or Better (n = 113, 226 Eyes) Patients With ON and Residual VA Deficit of 20/50 or Worse (n = 15, 30 Eyes) 43.6 ± 4.2 32.4 ± 10.8 P = 0.001† 23.9 ± 13.0 P , 0.001 - 34.4 ± 6.8 225.7 25.4 ± 11.7 P , 0.001 229.9 11.4 ± 14.0 P , 0.001 - 31.8 ± 5.4 226.2 22.3 ± 11.4 P = 0.003 266.9 11.1 ± 11.7 P , 0.001 - 19.7 ± 9.0 245.2 12.7 ± 10.4 P = 0.002 265.1 5.4 ± 8.8 P , 0.001 - 92.2 ± 9.1 235.5 80.0 ± 13.6 P = 0.001 272.6 71.0 ± 15.4 P , 0.001 10.1 ± 0.4 9.7 ± 0.6 P = 0.002 9.3 ± 0.6 P , 0.001 79.8 ± 6.0 69.6 ± 10.8 P , 0.001 53.8 ± 8.7 P , 0.001 98.2 ± 2.1 83.7 ± 15.4 P , 0.001 72.8 ± 18.8 P , 0.001 96.4 ± 5.2 74.6 ± 17.4 P , 0.001 71.4 ± 18.9 P , 0.001 † P values vs controls-calculated using GEE models, accounting for age and within-patient, intereye correlations, or linear regression models, accounting for age (for QOL scores). These models determine the capacity for ON group (20/40 or better, 20/15 or worse) vs control status to predict vision test, OCT, or QOL measure, accounting for age. GCL + IPL, ganglion cell layer + inner plexiform layer; LCLA, low-contrast letter acuity; NEI-VFQ-25, 25-Item National Eye Institute Visual Functioning Questionnaire; ON, optic neuritis; RNFL, retinal nerve fiber layer; SD, standard deviation; OCT, optical coherence tomography; VA, visual acuity; QOL, quality of life; GEE, generalized estimating equation. meaningful reductions in vision-specific QOL that reflect persistent impairment of low-contrast letter acuity and losses of RNFL and GCL + IPL thickness. Such reductions are present even when recovery of HCVA is 20/20 or better in affected eyes. This is consistent with the clinical observation among neuro-ophthalmologists that patients perceive visual deficits long after the acute ON event and achievement of maximal recovery. Axonal loss undoubtedly contributes to the clinical picture and patient-reported reduced QOL in patients with ON (11,21-23). The retina is composed mainly of unmyelinated axons proximal to their entry through the lamina cribrosa and into the retrobulbar optic nerve. Because the RNFL is a unique component of the central nervous system with axons and glial cells but no myelin, OCT 372 measurements of RNFL thickness provide a unique window into the substantial and clinically significant degrees of axonal loss after an acute demyelinating event such as ON (24-27). RNFL thinning is noted as early as 1 month after acute ON (11) and is seen in 74% of affected eyes (26). The occurrence of optic disc swelling in the setting of acute ON likely influences both the proportion of eyes and the observed tempo of peripapillary RNFL thinning (12,26,28-41). Measurement of ganglion cell layer (GCL + IPL) thickness avoids the potential difficulties associated with following peripapillary RNFL thickness in the acute setting when optic disc swelling is present. Observations of early visual pathway neuronal loss in ON have substantially narrowed the potential therapeutic Sabadia et al: J Neuro-Ophthalmol 2016; 36: 369-376 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 1. Spectral domain OCT measures of RNFL and GCL + IPL thickness. Both RNFL thickness and macular GCL + IPL thickness were reduced among patients with ON and recovery to 20/40 or better VA compared with disease-free controls. Patients with ON and residual VA deficit of 20/50 or worse had even greater thinning of the RNFL and GCL + IPL layers. P values vs controls-calculated using GEE accounting for age and within-patient, intereye correlations. These models determine the capacity for ON group (20/40 or better, 20/15 or worse) vs control status to predict OCT measures, accounting for age. RNFL, retinal nerve fiber layer mean thickness; GCL + IPL, ganglion cell layer + inner plexiform layer mean thickness; OCT, optical coherence tomography; ON, optic neuritis; VA, visual acuity; GEE, generalized estimating equation. "window of opportunity" for intervention with a neurorepair or protective agent that would reduce RNFL and GCL + IPL thinning (42). This tight window, combined with the persistent deficits in visual function and QOL despite recovery of VA, confirms the unmet therapeutic needs associated with acute ON. RNFL and GCL + IPL thickness are reduced even in the absence of an acute ON history among patients with MS FIG. 2. Vision-specific QOL questionnaire scores for NEI-VFQ-25 and 10-Item Neuro-Ophthalmic Supplement to the NEI-VFQ-25. Scores for both questionnaires were reduced among patients with ON and recovery to 20/40 or better VA compared with disease-free controls. Patients with ON and residual VA deficit of 20/50 or worse had even greater reductions in questionnaire scores. P values-calculated using linear regression models, accounting for age. These models determine the capacity for ON group (20/40 or better, 20/15 or worse) vs control status to predict QOL scores, accounting for age. NEI-VFQ-25, 25-Item National Eye Institute Visual Functioning Questionnaire; ON, optic neuritis; VA, visual acuity; QOL, quality of life. Sabadia et al: J Neuro-Ophthalmol 2016; 36: 369-376 373 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 3. Percent differences from control group means for RNFL thickness, GCL + IPL thickness, NEI-VFQ-25 composite score, and 10-Item Neuro-Ophthalmic Supplement score for patients with ON and recovery to 20/40 or better VA and those with ON and residual VA deficit of 20/50 or worse. ON, optic neuritis; RNFL, retinal nerve fiber layer; GCL + IPL, ganglion cell layer + inner plexiform layer; NEI-VFQ-25, 25-Item National Eye Institute Visual Functioning Questionnaire. (9,12,29,30,37,43,44). In a cross-sectional study of GCL + IPL thickness among eyes of patients with MS (12), eyes with a history of acute ON had the greatest degrees of GCL + IPL thinning compared with MS eyes without an ON history and disease-free control eyes. This study adds to these previous findings by demonstrating that such thinning is present even among eyes of patients traditionally characterized as having good visual recovery (20/40 or better highcontrast HCVA). Furthermore, the degree of GCL + IPL thinning is correlated directly in our study with categories of HCVA, a variable that has been emphasized less in our previous investigations that have focused on LCLA as a more sensitive visual outcome. Because clinicians necessarily classify visual function using high-contrast VA, the emphasis in our study on this outcome adds clinical perspective to the findings. Fellow eyes of patients with MS and a history of ON in this study showed reductions in RNFL and GCL + IPL thickness measurements, as well as high- and low-contrast acuity scores compared with control eyes. These differences were most pronounced and significant for 2.5% lowcontrast acuity, consistent with observations in many MS studies that this particular test distinguishes MS and ON eyes from those of disease-free volunteers. In this ON study, binocular visual function was particularly affected among patients with the lowest (worst) QOL scores, consistent with previously published findings of binocular inhibition after unilateral ON (14). Binocular inhibition is a phenomenon in which binocular acuities are worse than acuities measured with either eye 374 separately. This is known to occur when patients have an interocular discrepancy in low-contrast acuity (14,45). In our study cohort, binocular inhibition in high-contrast acuity was more frequent among patients with ON and recovery to 20/50 or worse compared with controls. Measurements of low-contrast acuity demonstrated that binocular summation occurred less frequently in patients with a history of ON, even among the group with 20/40 or better visual recovery in the affected eyes. Such reductions in binocular summation likely underlie, at least in part, the observations of worse NEI-VFQ-25 and 10-Item Supplement scores in the 20/40 group despite what has been previously described in the literature as good visual recovery. One potential limitation of our study is that our ON study cohort did not include patients without an MS diagnosis. However, given the now early application of diagnostic criteria for MS (46) following a first attack of acute ON, many patients with ON have a diagnosis of MS or meet criteria at the time of first episode. The categories of HCVA recovery in our study clearly demonstrate occurrence of visual impairment and reduced QOL even when HCVA is 20/40 or even 20/20 or better. This parallels the observations for patients with MS and no history of ON, who likewise may have no HCVA deficits yet note that their vision is "not right." To the extent that RNFL and GCL + IPL thinning have been documented worldwide in MS without ON, this population also represents a group for which there are therapeutic opportunities for neuroprotection and repair. Sabadia et al: J Neuro-Ophthalmol 2016; 36: 369-376 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: S. Sabadia, R. C. Nolan, K. M. Galetta, P. A. Calabresi, and E. M. Frohman; b. Acquisition of data: S. Sabadia, R. C. Nolan, K. M. Galetta, K. Narayana, J. A. Wilson, P. A. Calabresi, E. M. Frohman, and L. J. Balcer; c. Analysis and interpretation of data: S. Sabadia, R. C. Nolan, K. M. Galetta, and L. J. Balcer. Category 2: a. Drafting the manuscript: S. Sabadia, R. C. Nolan, S. L. Galetta, and L. J. Balcer; b. Revising it for intellectual content: S. Sabadia, R. C. Nolan, K. M. Galetta, K. Narayana, J. A. Wilson, P. A. Calabresi, E. M. Frohman, S. L. Galatta, L. J. Balcer, and L. J. Balcer. Category 3: a. Final approval of the completed manuscript: S. Sabadia, R. C. Nolan, K. M. Galetta, K. Narayana, J. A. Wilson, P. A. Calabresi, E. M. Frohman, S. L. Galatta, and L. J. Balcer. 15. 16. 17. 18. REFERENCES 1. Pau D, Al Zubidi N, Yalamanchili S, Plant G, Lee A. Optic neuritis. Eye (Lond). 2011;25:833-842. 2. Colenbrander A. Aspects of vision loss-visual functions and functional vision. Vis Impair Res. 2003;5:115-136. 3. Cole SR, Beck RW, Moke PS, Gal RL, Long DT. The National Eye Institute Visual Functioning Questionnaire: experience of the ONTT. Invest Ophthalmol Vis Sci. 2000;41:1017-1021. 4. Foroozan R, Buono LM, Savino PJ, Sergott RC. Acute demyelinating optic neuritis. Curr Opin Ophthalmol. 2002;13:375-380. 5. Beck RW, Cleary PA, Backlund JC. The course of visual recovery after optic neuritis: experience of the Optic Neuritis Treatment Trial. Ophthalmology. 1994;101:1771- 1778. 6. 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