Macular Ganglion Cell and Inner Plexiform Layer Thickness Is More Strongly Associated With Visual Function in Multiple Sclerosis Than Bruch Membrane Opening

Background: Optical coherence tomography (OCT) measurements of ganglion cell + inner plexiform layer (GCIPL) and peripapillary retinal nerve fiber layer (pRNFL) thicknesses are associated with visual function (VF) and disability in multiple sclerosis (MS). However, the value of measuring Bruch membrane opening-minimum rim width (BMO-MRW) thickness in MS remains unclear. Methods: Sixty-eight patients with MS and 22 healthy controls (HCs) underwent spectral domain OCT, 100%-contrast visual acuity (VA), 2.5%- and 1.25%-contrast letter acuity (LA), and Expanded Disability Status Scale (EDSS) testing. Mixed-effects linear regression models, accounting for within-subject, intereye correlations, were used to assess relationships. Results: The MS cohort exhibited significantly lower BMO-MRW (P = 0.01), pRNFL at 3.7-, 4.1-, and 4.7-mm diameters surrounding the optic disc (P < 0.001 for all), and GCIPL (P < 0.001) thicknesses than HCs. BMO-MRW thickness was associated with 100%-VA (P < 0.001, R = 0.08), 2.5%-LA (P < 0.001; R = 0.13), and 1.25%-LA (P = 0.002; R = 0.11). All measured pRNFL thicknesses were associated with high- and low-contrast VF (all: P < 0.001). GCIPL thickness was more strongly associated with 100%-VA (P < 0.001; R = 0.23), 2.5%-LA (P < 0.001; R = 0.27), and 1.25%-LA (P < 0.001; R = 0.21) than the other OCT measures assessed. All OCT measures were significantly, but weakly, associated with EDSS scores. Conclusions: BMO-MRW and pRNFL thicknesses are reduced and associated with VF and disability in MS, but GCIPL thickness is a stronger marker of visual impairment. Our findings corroborate the utility of OCT in providing valuable information regarding the MS disease process.

Clinical Research: Epidemiology Meets Neuro-Ophthalmology Section Editors: Heather E. Moss, MD, PhD Stacy L. Pineles, MD Macular Ganglion Cell and Inner Plexiform Layer Thickness Is More Strongly Associated With Visual Function in Multiple Sclerosis Than Bruch Membrane Opening–Minimum Rim Width or Peripapillary Retinal Nerve Fiber Layer Thicknesses James Nguyen, BS, Alissa Rothman, BS, Natalia Gonzalez, MD, Ama Avornu, BA, Esther Ogbuokiri, BS, Laura J. Balcer, MD, MSCE, Steven L. Galetta, MD, Elliot M. Frohman, MD, PhD, Teresa Frohman, PA-C, Ciprian Crainiceanu, PhD, Peter A. Calabresi, MD, Shiv Saidha, MBBCh, MD, MRCPI, Background: Optical coherence tomography (OCT) measurements of ganglion cell + inner plexiform layer (GCIPL) and peripapillary retinal nerve fiber layer (pRNFL) thicknesses are associated with visual function (VF) and disability in multiple sclerosis (MS). However, the value of measuring Bruch membrane opening–minimum rim width (BMO-MRW) thickness in MS remains unclear. Methods: Sixty-eight patients with MS and 22 healthy controls (HCs) underwent spectral domain OCT, 100%-contrast visual acuity (VA), 2.5%- and 1.25%-contrast letter acuity (LA), and Expanded Disability Status Scale (EDSS) testing. Mixed-effects linear regression models, accounting for within-subject, intereye correlations, were used to assess relationships. Results: The MS cohort exhibited significantly lower BMOMRW (P = 0.01), pRNFL at 3.7-, 4.1-, and 4.7-mm diameters surrounding the optic disc (P , 0.001 for all), and GCIPL (P , 0.001) thicknesses than HCs. BMO-MRW thickness was Department of Neurology (JN, AR, NG, AA, EO, PAC, and SS), Johns Hopkins University School of Medicine, Baltimore, Maryland; Departments of Neurology (LJB and SLG), Population Health (LJB and SLG), and Ophthalmology (LJB and SLG), New York University School of Medicine, New York, New York; Departments of Neurology (EMF and TF) and Ophthalmology (EMF and TF), Dell Medical School, University of Texas at Austin, Austin, Texas; and Department of Biostatistics (CC), Johns Hopkins University, Baltimore, Maryland. This study was funded by Race to Erase MS (grant number not applicable [to S.S.]); National Institute of Health (grant number 5R01NS082347-02 [to P.A.C.]); National Multiple Sclerosis Society (grant number RG-1606-08768 [to S.S.]); and Walters Foundation (grant number not applicable [to E.M.F.]). The authors report no conflicts of interest. Address correspondence to Shiv Saidha, MBBCh, MD, MRCPI, Neurology Division of Neuroimmunology and Neurological Infections, Johns Hopkins Hospital, 600N. Wolfe Street, Baltimore, MD 21287; E-mail: [e-mail] 444 associated with 100%-VA (P , 0.001, R2 = 0.08), 2.5%-LA (P , 0.001; R2 = 0.13), and 1.25%-LA (P = 0.002; R2 = 0.11). All measured pRNFL thicknesses were associated with high- and low-contrast VF (all: P , 0.001). GCIPL thickness was more strongly associated with 100%-VA (P , 0.001; R2 = 0.23), 2.5%-LA (P , 0.001; R2 = 0.27), and 1.25%-LA (P , 0.001; R2 = 0.21) than the other OCT measures assessed. All OCT measures were significantly, but weakly, associated with EDSS scores. Conclusions: BMO-MRW and pRNFL thicknesses are reduced and associated with VF and disability in MS, but GCIPL thickness is a stronger marker of visual impairment. Our findings corroborate the utility of OCT in providing valuable information regarding the MS disease process. Journal of Neuro-Ophthalmology 2019;39:444–450 doi: 10.1097/WNO.0000000000000768 © 2019 by North American Neuro-Ophthalmology Society M agnetic resonance imaging (MRI) has been the goldstandard technique for detecting inflammatory activity, as well as axonal and neuronal degeneration in multiple sclerosis (MS). Although conventional MRI markers of inflammation, including the formation of new or enlarging T2 and contrast-enhancing lesions, are used to monitor MS, such parameters only modestly correlate with disability progression (1). Nonconventional MRI measures of neurodegeneration such as brain substructure volumetric-derived gray matter volumes, for example, correlate better with disability in MS but have been difficult to implement into routine clinical practice due to cost and technical challenges. Thus, imaging techniques that allow for reliable and translatable quantification of neurodegeneration remain an unmet need. Nguyen et al: J Neuro-Ophthalmol 2019; 39: 444-450 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Research: Epidemiology Meets Neuro-Ophthalmology Optical coherence tomography (OCT) is an inexpensive, high-resolution, noninvasive imaging technique that uses nearinfrared light to reliably quantify retinal neurodegeneration (2). There is an abundance of evidence suggesting the utility of OCT in complementing MRI to monitor MS. Specifically, OCT-derived peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell + inner plexiform layer (GCIPL) thicknesses correlate with global disability and visual function (VF) in MS. GCIPL thickness may have superior structure–function relationships than pRNFL thickness, potentially related to better reproducibility and reliability (3). Moreover, rates of GCIPL atrophy correlate with rates of whole-brain and gray matter atrophy in MS and are accelerated in patients exhibiting inflammatory disease activity and/or disability progression (4). Recent advances in OCT techniques have expanded the range of OCT measures that can be measured, potentially allowing for more comprehensive retinal characterization. Novel software on Spectralis (Heidelberg Engineering, Heidelberg, Germany) spectral domain (SD) OCT now allows for the determination of Bruch membrane opening– minimum rim width (BMO-MRW) thickness, which represents the minimum width measured from Bruch membrane opening to the termination of the neuroretinal rim (Fig. 1). BMO-MRW has been suggested as an anatomical surrogate for the neuroretinal rim (5). BMO-MRW is reduced in patients with glaucoma compared to healthy controls (HCs) (6) and is believed to be more sensitive for the assessment of glaucomatous optic neuropathy (7) as well as being associated with lower VF (8). Although retinal ganglion cells represent a principal site of neurodegeneration in glaucoma as in MS (9), glaucoma likely has a different underlying pathophysiological mechanism than MS-related optic neuropathy, including neuroretinal rim degeneration and progressive optic disc cupping (10). New Spectralis OCT software allows for more comprehensive pRNFL thickness analysis at 4.1- and 4.7-mm diameters surrounding the optic disc, in addition to the traditionally used 3.5-mm diameter measurement. Whether these novel measures contribute additional utility beyond GCIPL thickness in MS remains to be examined. In this cross-sectional study, we sought to determine the relation between Spectralis OCT-derived BMO-MRW and pRNFL thicknesses at varying diameters with VF and global disability measures in MS, and compare these with GCIPL thickness structure–function correlations. We hypothesized that BMO-MRW, as well as pRNFL thicknesses at varying diameters, would be abnormal in MS but may not exhibit benefit over the robustness of GCIPL thickness measurements in MS. PATIENTS AND METHODS Patients Patients with MS and HCs were recruited by convenience sampling from the Johns Hopkins MS Center, and written informed consent was obtained from all participants. All study Nguyen et al: J Neuro-Ophthalmol 2019; 39: 444-450 protocols were approved by the Johns Hopkins University Institutional Review Board, and the study was performed in accordance with the tenets of the Declaration of Helsinki. MS diagnoses were based on the 2010 revised McDonald criteria (11). Patients were categorized according to the Lublin classification as having either relapsing remitting MS (RRMS), secondary progressive MS (SPMS), or primary progressive MS (PPMS) (12). Because the numbers of patients with SPMS and PPMS recruited were relatively small, they were combined into a single group designated progressive MS (PMS). Participants with glaucoma, diabetes, uveitis, eye trauma or surgery, hypertension, refractive errors of greater than or equal to ±6 diopters, a history of optic neuritis (ON) within 6 months of OCT acquisition, or other ophthalmological or neurological disorders were excluded. Disease duration, age, ethnicity, sex, and history, date, and side of previous ON were recorded. Optical Coherence Tomography Spectralis SD-OCT, with automated macular segmentation (model OCT2, software version 6.4.7.0; Heidelberg Engineering), as well as confocal scanning laser ophthalmoscopy that produces simultaneous high-resolution fundus images, was used to perform retinal imaging by experienced technicians. For each participant’s eye, an anatomical positioning system constructed a map of the retina using the center of the fovea and the center of Bruch membrane opening as anatomical landmarks (7). Thereafter, all scans were oriented based on this anatomical map, allowing for more precise and accurate characterization of retinal structures (13). BMOMRW and pRNFL measurements were obtained using the Optic Nerve Head—Radial, Circle scan protocol, consisting of 24 radial, 15° B-scans centered on BMO, with a radial automated real time (ART) of 25, as well as 3 circle scans at 3.5-, 4.1-, and 4.7-mm diameters surrounding the optic disc and circle ART of 100, as described elsewhere (14). GCIPL measures were derived from the Posterior Pole Horizontal scan protocol with an ART of 9, as described elsewhere (14). Mean measurements for all OCT parameters were calculated by averaging temporal, temporal superior, nasal superior, nasal, nasal inferior, and temporal inferior sectors. Each scan included in the study exhibited signal strength greater than 20 dB and were devoid of artifact, in accordance with the OSCAR-IB criteria (15), as well as microcystoid changes. Visual and Neurological Testing High-contrast (100%) visual acuity at 4 m and low-contrast letter acuity (2.5% and 1.25%) at 2 m were assessed using retroilluminated Early Treatment Diabetic Retinopathy Study and Sloan letter charts (Precision Vision, Lasalle, IL), respectively. The number of correctly identified letters was recorded for each eye (with a maximum score of 70 letters per chart). Visual assessments were administered in a darkened room by trained technicians using standard testing protocols (16). Participants used their habitual distance corrective lenses. To assess neurological function, Expanded Disability Status 445 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Research: Epidemiology Meets Neuro-Ophthalmology FIG. 1. A. Optical coherence tomography-derived fundus image shows the optic disc with corresponding retinal microvasculature, as well as 24 radial slices of the peripapillary region and 3 circular scans at 3.5-, 4.1-, and 4.7-mm diameters surrounding the optic disc. B. The corresponding OCT image demonstrates Bruch membrane opening–minimum rim width (BMO-MRW) flanking the optic cup (blue arrows). This scan was acquired from a healthy participant. Scale (EDSS) scores were determined by Neurostatus-certified examiners. Statistical Analyses Statistical analyses were performed using Stata (version 12; StataCorp LP, College Station, TX). Comparisons between MS subtypes, as well as between MS and HCs, in regard to proportions of eyes with ON history and differences in sex were performed using the chi-square (x2) test. The Wilcoxon ranksum test was used to assess differences in age and disease duration between subtypes. The Shapiro–Wilk test was used to assess normality of distributions. Associations were then determined using multilevel, mixed-effects linear regression analyses, accounting for within-subject intereye correlations, and adjusting for age, sex, disease duration, and ON history. The HC and MS cohorts were compared using mixed-effects linear regression restrictive maximum likelihood models, 446 accounting for within-subject intereye correlations, and adjusting for age and sex. Snijders/Bosker Level 1 R2 values were derived from this statistical model. Statistical significance was defined as P # 0.05. Because this study was hypothesis-driven, correction for multiple comparisons was not performed (17). RESULTS Demographics/Clinical Characteristics Sixty-eight people with MS (48 RRMS, 91 eyes; 20 PMS, 38 eyes) and 22 HCs fulfilled eligibility criteria and participated in the study. Seven eyes (5 RRMS and 2 PMS eyes) were excluded from the study due to inadequate OCT quality. Mean age, disease duration, and EDSS were significantly higher in PMS as compared to RRMS (P , 0.001 for all; Table 1). Similarly, the RRMS cohort exhibited a significantly greater proportion of Nguyen et al: J Neuro-Ophthalmol 2019; 39: 444-450 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Research: Epidemiology Meets Neuro-Ophthalmology eyes with (ON) history (45%) as compared to PMS (25%; P = 0.03). No significant differences were found between the RRMS and PMS cohorts in regards to sex or race. As compared to HCs, patients with MS were significantly older, more likely to be female, and had a lower proportion of participants with race classified as other (P , 0.001 for all). The summary of demographics and patient characteristics is outlined in Table 1. Differences in Optical Coherence Tomography Measures Between Multiple Sclerosis and Healthy Controls Adjusting for age, sex, and within-subject intereye correlations, BMO-MRW thickness was significantly lower in MS as compared to HCs (297 vs 337 mm; mean difference = 40 mm; P = 0.01) (Table 2). Similarly, pRNFL thickness at 3.5, 4.1, and 4.7 mm surrounding the optic disc was significantly lower in patients with MS relative to HCs, with mean differences between the cohorts of 17, 14, and 11 mm, respectively (P , 0.001 for all). GCIPL thickness was significantly lower in patients with MS than HCs, with a mean difference of 14 mm (P , 0.001). In MS subtype analyses, BMO-MRW, pRNFL at 3.7, 4.1, and 4.7 mm, as well as GCIPL thicknesses in RRMS and PMS were all similarly significantly lower than in HCs (data not shown). Relation Between Optical Coherence Tomography–Derived Retinal Measurements, Visual Function, and Expanded Disability Status Scale Adjusting for age, sex, disease duration, history of ON and within-subject, intereye correlations, BMO-MRW, pRNFL at 3.5, 4.1, and 4.7 mm, as well as average GCIPL thicknesses were all significantly associated with 100%VA, 2.5%- and 1.25%-letter acuity (LA), and EDSS scores across the MS cohort (Table 3). For all relationships described below, lower OCT-derived thicknesses were associated with lower VF and higher disability scores. In general, across the OCT measures assessed, R2 relationships were numerically highest with 2.5%-LA scores, which is in accordance with the previous data suggesting that 2.5%-LA may be the more sensitive for capturing visual dysfunction in MS (Fig. 2). In general, of the OCT measures analyzed, R2 relationships across VF measures were numerically highest with average GCIPL thickness. GCIPL thickness was associated with 100%-VA (P , 0.001; R2 = 0.23), 2.5%LA (P , 0.001; R2 = 0.27), and 1.25%-LA (P , 0.001; R2 = 0.21). Although the associations of BMO-MRW, pRNFL at 3.5, 4.1, and 4.7 mm, and average GCIPL thicknesses with EDSS were all significant, they were weak and similar across OCT measures. In MS subtype analyses, similar associations between BMO-MRW, pRNFL at 3.7-, 4.1-, and 4.7-mm diameters, as well as GCIPL thicknesses with VF and EDSS scores were observed in RRMS and PMS, as compared to the entire MS cohort (data not shown). DISCUSSION The results of our study suggest associations between OCTderived retinal thickness measures and disability in MS. These data illustrate new, and also confirm previously studied parameters for which OCT may be of value to track disease progression and disability in MS. Because the novel measures studied (BMO-MRW and pRNFL thicknesses at varying diameters around the optic disc) are related to TABLE 1. Demographics and clinical characteristics of patients with multiple sclerosis vs healthy controls Characteristic Mean age, yr (SD) Mean disease duration, yr (SD) Females (%) Race Caucasian African American Other Patients with ON history (%) Eyes with ON history (%) Mean EDSS Overall MS, n = 68 (Eyes = 129) RRMS, n = 48 (Eyes = 91) PMS, n = 20 (Eyes = 38) HC, n = 22 (Eyes = 44) P value RRMS vs PMS P value HC vs MS 46.5 (12.5) 13.9 (10.9) 41.6 (10.3) 11.2 (8.4) 58.5 (8.7) 20.5 (13.4) 33.4 (1.65) — ,0.001* ,0.001* ,0.001* — 81 82 80 55 0.20† ,0.001† 59 8 1 44 (65) 54 (41) 3.13 41 6 1 37 (77) 44 (47) 1.83 18 2 0 7 (35) 10 (26) 6.44 8 3 11 — — — 0.89‡ ,0.001‡ — 0.03† ,0.001* — — — Bolded values represent statistically significant results. *Computed with the Wilcoxon rank-sum test. † Computed with the chi-square test. ‡ Computed with the Fisher exact test. EDSS, Expanded Disability Status Scale; HC, healthy control; MS, multiple sclerosis; ON, optic neuritis; PMS, progressive multiple sclerosis; RRMS, relapsing–remitting multiple sclerosis; SD, standard deviation. Nguyen et al: J Neuro-Ophthalmol 2019; 39: 444-450 447 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Research: Epidemiology Meets Neuro-Ophthalmology TABLE 2. Comparison of OCT-derived measures between patients with multiple sclerosis and healthy controls HC (Eyes = 44) Mean, mm (SD) BMO-MRW pRNFL-3.5 mm pRNFL-4.1 mm pRNFL-4.7 mm GCIPL 337 105 90 78 80 MS (Eyes = 131) Mean, mm (SD) (77) (11) (8) (7) (4) 297 88 75 67 66 (66) (17) (13) (11) (11) HC vs MS Mean Difference, mm HC vs MS P value 40 17 14 11 14 0.01 ,0.001 ,0.001 ,0.001 ,0.001 P values were derived from mixed-effect linear regression restrictive maximum likelihood models, accounting for within-subject intereye correlation and adjusting for age and sex. Bolded values designate statistical significance. BMO-MRW, Bruch membrane opening–minimum rim width; GCIPL, ganglion cell + inner plexiform layer; HC, healthy control; mm, millimeters; MS, multiple sclerosis; OCT, optical coherence tomography; pRNFL, peripapillary retinal nerve fiber layer; mm, micrometers. conventional OCT measures such as standard pRNFL at 3.5 mm and GCIPL thicknesses, it is not surprising that these new measures similarly correlate with VF and disability scores in MS. However, the proposed benefit of BMO-MRW thickness in glaucoma over conventional OCT measures may not similarly be the case in MS. GCIPL thickness has previously been shown to be one of the most robust OCT measures in MS, with superior structure–function relationships, and potentially overcoming many of the known limitations of conventional pRNFL thickness measures. For example, the GCIPL may not swell during ON and may also be less prone to astrogliosis, which primarily occurs in the RNFL and may lead to false increases in RNFL thickness (3). In our study, lower GCIPL thickness seemed to explain the greatest degree of variance in reduced 100%-VA, 2.5%-LA, and 1.25%-LA scores across the MS cohort as compared to BMO-MRW and pRNFL thicknesses at various diameters. Conversely, BMO-MRW thickness may explain a smaller amount of variance in VF among patients with MS. This may simply relate to the anatomy of this measurement. The BMO-MRW includes all retinal layers, including the pRNFL and GCIPL. Thus, decreased BMO-MRW thickness and its associations with VF found in this study may be driven by retrograde neurodegeneration of the pRNFL and GCIPL layers, yet may, at the same time, be partially diluted by the inclusion of the other retinal layers intrinsic to the BMO-MRW measurement. Among the pRNFL thickness measures assessed, relationships with VF seemed to be strongest for pRNFL measurements closer to the optic disc, measured at 3.5 mm, the conventional pRNFL thickness measurement on the Spectralis OCT device. Interestingly, all the OCT measures examined in the current study similarly and only weakly explained variance in EDSS scores in participants with MS. To the best of our knowledge, this is one of the first demonstrations that BMO-MRW thickness is significantly lower in MS compared to HCs and is associated with highand low-contrast VF in MS. Analogous to studies in patients with glaucoma, BMO-MRW thickness may be a measure for the number of axons entering the optic nerve head. However, based on our findings, BMO-MRW thickness in patients with MS may be less robustly associated with VF compared to GCIPL thickness. This is likely due to retrograde degeneration of the constituent fibers of the optic nerve and a subsequent dropout of retinal ganglion cell axons (RNFL) and neurons (GCIPL) (18–21). Across all cohorts, low-contrast LA (LCLA), and in particular 2.5%-LA, generally exhibited a stronger relationship with all retinal measures examined as compared to 100% high-contrast VA (HCVA). This is consistent with TABLE 3. Relation between OCT-derived retinal measurements, visual function, and global disability scores in patients with multiple sclerosis Average BMO-MRW Scores P value R2 100%-VA 2.5%-LA 1.25%-LA EDSS ,0.001 ,0.001 0.002 0.02 0.08 0.13 0.11 0.05 pRNFL-3.5 mm pRNFL-4.1 mm pRNFL-4.7 mm P value R2 P value R2 P value R2 Average GCIPL P value R2 ,0.001 ,0.001 ,0.001 0.001 0.19 0.21 0.19 0.10 ,0.001 ,0.001 ,0.001 0.001 0.17 0.19 0.17 0.10 ,0.001 ,0.001 ,0.001 0.001 0.13 0.15 0.15 0.08 ,0.001 ,0.001 ,0.001 0.002 0.23 0.27 0.21 0.06 P values were derived from mixed-effect linear regression models, adjusting for within-subject intereye correlation, and accounting for age, sex, disease duration, and history of optic neuritis. All the values indicate statistically significant results. BMO-MRW, Bruch membrane opening–minimum rim width; EDSS, Expanded Disability Status Scale; GCIPL, ganglion cell + inner plexiform layer; LA, letter acuity; OCT, optical coherence tomography; pRNFL, peripapillary retinal nerve fiber layer; VA, visual acuity. 448 Nguyen et al: J Neuro-Ophthalmol 2019; 39: 444-450 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Research: Epidemiology Meets Neuro-Ophthalmology FIG. 2. Adjusted variable plots comparing the strength of significant associations between OCT-derived average Bruch membrane opening–minimum rim width (BMO-MRW) (A), average ganglion cell–inner plexiform layer (GCIPL) (B) and peripapillary retinal nerve fiber layer (pRNFL), thicknesses (C) with 2.5% low-contrast letter acuity in MS (accounting for age, sex, disease duration, and history of optic neuritis). Consistent with a tighter distribution fit along the linear regression line, GCIPL thickness exhibits the highest R2 value. P values and R2 values were derived from mixed-effect linear regression models, adjusting for within-subject intereye correlation and accounting for age, sex, disease duration, and history of optic neuritis. MS, multiple sclerosis; OCT, optical coherence tomography. previous findings that have shown that relative to HCVA, LCLA is more closely associated with OCT-derived measures (22), is a more sensitive measure of visual disability (23), and is more broadly associated with MS disability, as estimated by EDSS scores (22), as well as neuropsychological function (24). Our study findings, in conjunction with the previous reports, support the concept that OCT and VF, particularly LCLA, may be complementary tools in MS. Our study has several limitations. First, the study cohort was heterogeneous, and there were insufficient numbers of patients with SPMS or PPMS to examine these cohorts separately. The number of HCs included in the study was relatively low, and the HC cohort was generally younger than those in the MS cohort and more biased toward being male. There is a possibility that agerelated pRNFL reduction in the MS cohort may have affected our results; however, all our analyses were Nguyen et al: J Neuro-Ophthalmol 2019; 39: 444-450 adjusted for age and sex. Lack of obtaining bestcorrected visual acuity with refraction is another limitation (25). Since our study was cross-sectional and exploratory in nature, our results regarding the BMO-MRW thickness being decreased and associated with disability in MS are preliminary. It is likely that BMO-MRW may secondarily decrease as a result of RNFL degeneration as it does in glaucoma. To elucidate the progression of anatomical changes in MS, future studies should focus on increasing the study sample size in a longitudinal setting across MS subtypes. In summary, our findings suggest strong associations between a broad panel of OCT-derived measures and functional disability, particularly of VF in patients with MS. Although novel OCT-derived parameters, BMOMRW and pRNFL thicknesses at varying diameters surrounding the optic disc, seem to be reduced in and broadly associated with visual and global disability in MS, 449 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Research: Epidemiology Meets Neuro-Ophthalmology GCIPL thickness, in accordance with previous studies, seems to be the most accurate OCT-derived structural marker in MS. Our study findings provide further support for OCT measures: a) as outcome metrics in clinical trials of neuroprotective and/or remyelinating therapies, b) for monitoring disease progression, and c) for contributing clinically useful information regarding global aspects of the MS disease process. STATEMENT OF AUTHORSHIP Category 1: a. conception and design: S. Saidha and P. A. Calabresi; b. acquisition of data: J. Nguyen, A. Rothman, N. Gonzalez, A. Avornu, E. Ogbuokiri, P. A. Calabresi, and S. Saidha; c. analysis and interpretation of data: J. Nguyen, C. Crainiceanu, P. A. Calabresi, and S. Saidha. Category 2: a. drafting the manuscript: J. Nguyen, C. Crainiceanu, P. A. Calabresi, and S. Saidha; b. revising it for intellectual content: J. Nguyen, A. Rothman, N. Gonzalez, A. Avornu, E. Ogbuokiri, L. J. Balcer, S. L. Galetta, E. M. Frohman, T. Frohman, C. Crainiceanu, P. A. Calabresi, and S. Saidha. Category 3: a. final approval of the completed manuscript: J. Nguyen, A. Rothman, N. Gonzalez, A. Avornu, E. Ogbuokiri, L. J. Balcer, S. L. Galetta, E. M. Frohman, T. Frohman, C. Crainiceanu, P. A. Calabresi, and S. Saidha. 9. 10. 11. 12. 13. 14. 15. REFERENCES 1. Kappos L, Moeri D, Radue EW, Schoetzau A, Schweikert K, Barkhof F, Miller D, Guttmann CR, Weiner HL, Gasperini C, Filippi M. Predictive value of gadolinium-enhanced magnetic resonance imaging for relapse rate and changes in disability or impairment in multiple sclerosis: a meta-analysis. Gadolinium MRI Meta-analysis Group. Lancet. 1999;353:964–969. 2. Syc SB, Warner CV, Hiremath GS, Farrell SK, Ratchford JN, Conger A, Frohman T, Cutter G, Balcer LJ, Frohman EM, Calabresi PA. Reproducibility of high-resolution optical coherence tomography in multiple sclerosis. Mult Scler. 2010;16:829–839. 3. Saidha S, Syc BS, Durbin MK, Eckstein C, Oakley JD, Meyer SA, Conger A, Frohman TC, Newsome S, Ratchford JN, Frohman EM, Calabresi PA. Visual dysfunction in multiple sclerosis correlates better with optical coherence tomography derived estimates of macular ganglion cell layer thickness than peripapillary retinal nerve fiber layer thickness. Mult Scler. 2011;17:1449–1463. 4. Saidha Al-Louzi O, Ratchford JN, Bhargava P, Oh J, Newsome SD, Prince JL, Pham D, Roy S, van Zijl P, Balcer LJ, Frohman EM, Reich DS, Crainiceanu C, Calabresi PA. Optical coherence tomography reflects brain atrophy in multiple sclerosis: a fouryear study. Ann Neurol. 2016;78:801–813. 5. Reis AS, O’Leary N, Yang H, Sharpe GP, Nicolela MT, Burgoyne CF, Chauhan BC. Influence of clinically invisible, but optical coherence tomography detected, optic disc margin anatomy on neuroretinal rim evaluation. Invest Ophthalmol Vis Sci. 2012;53:1852–1860. 6. Park KH, Lee JW, Kim JM, Nouri-Mahdavi K, Caprioli J. Bruch’s membrane opening-minimum rim width and visual field loss in glaucoma: a broken stick analysis. Int J Ophthalmol. 2018;11:828–834. 7. Chauhan BC, O’Leary N, Almobarak FA. Enhanced detection of open-angle glaucoma with an anatomically accurate optical coherence tomography-derived neuroretinal rim parameter. Ophthalmology. 2013;120:535–543. 8. Pollet-Villard F, Chiquet C, Romanet JP, Noel C, Aptel F. Structurefunction relationships with spectral-domain optical coherence 450 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. tomography retinal nerve fiber layer and optic nerve head measurements. Invest Ophthal Vis Sci. 2014;55:2953–2962. HA, Nickells RW, Kerrigan LA, Pease ME, Thibault DJ, Zack DJ. Retinal ganglion cell death in experimental glaucoma and after axotomy occurs by apoptosis. Invest Ophthalmol Vis Sci. 1995;36:774–786. Agarwal R, Gupta SK, Agarwal P, Saxena R, Agrawal SS. Current concepts in the pathophysiology of glaucoma. Indian J Ophthalmol. 2009;57:257–266. Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, Fujihara K, Havrdova E, Hutchinson M, Kappos L, Lublin FD, Montalban X, O’Connor P, Sandberg-Wollheim M, Thompson AJ, Waubant E, Weinshenker B, Wolinsky JS. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69:292–302. Lublin FD. New multiple sclerosis phenotypic classification. Eur Neurol. 2014;72(suppl 1):1–5. Park K, Kim J, Lee J. Reproducibility of Bruch membrane opening-minimum rim width measurements with spectral domain optical coherence tomography. J Glaucoma. 2017;26:1041–1050. Gonzalez NC, Antony B, He Y, Lang A, Nguyen J, Rothman A, Ogbuokiri E, Avornu A, Balcer LJ, Frohman E, Frohman TC, Bhargava P, Prince J, Calabresi PA, Saidha S. Analysis of agreement of retinal-layer thickness measures derived from the segmentation of horizontal and vertical spectralis OCT macular scans. Curr Eye Res. 2017;43:415–423. Tewarie P, Balk L, Costello F, Green A, Martin R, Schippling S, Petzold A. The OSCAR-IB consensus criteria for retinal OCT quality assessment. PLoS One. 2012;7:e34823. Talman LS, Bisker ER, Sackel DJ, Long DA Jr, Galetta KM, Ratchford JN, Lile DJ, Farrell SK, Loguidice MJ, Remington G, Conger A, Frohman TC, Jacobs DA, Markowitz CE, Cutter GR, Ying GS, Dai Y, Maguire MG, Galetta SL, Frohman EM, Calabresi PA, Balcer LJ. Longitudinal study of vision and retinal nerve fiber layer thickness in MS. Ann Neurol. 2010;67:749–760. Bender R, Lange S. Adjusting for multiple testing—when and how? J Clin Epidemiol. 2001;54:343–349. Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mörk S, Bö L. Axonal transection in the lesions of multiple sclerosis. N Engl J Med. 1998;338:278–285. Shindler KS, Ventura E, Dutt M, Rostami A. Inflammatory demyelination induces axonal injury and retinal ganglion cell apoptosis in experimental optic neuritis. Exp Eye Res. 2008;87:208–213. Green AJ, McQuaid S, Hauser SL, Allen IV, Lyness R. Ocular pathology in multiple sclerosis: retinal atrophy and inflammation irrespective of disease duration. Brain. 2010;133:1591–1601. Kerrison JB, Flynn T, Green WR. Retinal pathologic changes in multiple sclerosis. Retina. 1994;14:445–451. Balcer LJ, Baier ML, Cohen JA, Kooijmans MF, Sandrock AW, Nano-Schiavi ML, Pfohl DC, Mills M, Bowen J, Ford C, Heidenreich FR, Jacobs DA, Markowitz CE, Stuart WH, Ying GS, Galetta SL, Maguire MG, Cutter GR. Contrast letter acuity as a visual component for the multiple sclerosis functional composite. Neurology. 2003;61:1367–1373. Ratchford JN, Saidha S, Sotirchos ES, Oh JA, Seigo MA, Eckstein C, Durbin MK, Oakley JD, Meyer SA, Conger A, Frohman TC, Newsome SD, Balcer LJ, Frohman EM, Calabresi PA. Active MS is associated with accelerated retinal ganglion cell/inner plexiform layer thinning. Neurology. 2013;80:47–54. Nguyen J, Rothman A, Fitzgerald K, Whetstone A, Syc-Mazurek S, Aquino J, Balcer LJ, Frohman EM, Frohman TC, Crainiceanu C, Beier M, Newsome SD, Calabresi PA, Saidha S. Visual pathway measures are associated with neuropsychological function in multiple sclerosis. Curr Eye Res. 2018;43:941–948. Pointer JS. Habitual vs optimal distance visual acuity. Ophthalmic Physiol Opt. 2008;28:457–466. Nguyen et al: J Neuro-Ophthalmol 2019; 39: 444-450 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.