Faculty Bibliography

BACKGROUND:The International Multiple Sclerosis Visual System Consortium (IMSVISUAL) was formed in November 2014 with the primary goal of improving research, care, and education regarding the role of the visual system in multiple sclerosis (MS) and related disorders. METHODS:In this review, we describe the formation, goals, activities, and structure of IMSVISUAL, as well as the relationship of IMSVISUAL with the Americas Committee for Treatment and Research in MS (ACTRIMS). Finally, we provide an overview of the work IMSVISUAL has completed to date, as well as an outline of research projects ongoing under the auspices of IMSVISUAL. RESULTS:IMSVISUAL has 140 members worldwide and continues to grow. Through IMSVISUAL-related research, optical coherence tomography (OCT)-derived peripapillary retinal nerve fiber layer (pRNFL) thinning has been established as a predictor of future disability in MS. IMSVISUAL has also developed guidelines for reporting OCT studies in MS. Moreover, a systematic review performed by IMSVISUAL found that not only are pRNFL and ganglion cell + inner plexiform layer (GCIPL) thicknesses reduced in patients with MS (particularly in eyes with prior optic neuritis [ON]), but that inner nuclear layer measures may be higher among MS ON eyes, relative to healthy control eyes. Currently, there are several ongoing IMSVISUAL projects that will establish a role for visual outcomes in diagnosing MS and quantifying the effects of emerging therapies in clinical trials. CONCLUSIONS:The development of IMSVISUAL represents a major collaborative commitment to defining the role of visual outcomes in high-quality, large-scale studies that generate definitive and instructive findings in the field of MS. As a consortium, IMSVISUAL has completed several international collaborative projects, is actively engaged in numerous ongoing research studies, and is committed to expanding the role of vision research in MS and related disorders.

OBJECTIVE:The Mobile Universal Lexicon Evaluation System (MULES) is a test of rapid picture naming that is under investigation for concussion. MULES captures an extensive visual network, including pathways for eye movements, color perception, memory and object recognition. The purpose of this study was to introduce the MULES to visual assessment of patients with MS, and to examine associations with other tests of afferent and efferent visual function. METHODS:We administered the MULES in addition to binocular measures of low-contrast letter acuity (LCLA), high-contrast visual acuity (VA) and the King-Devick (K-D) test of rapid number naming in an MS cohort and in a group of disease-free controls. RESULTS:Among 24 patients with MS (median age 36 years, range 20-72, 64% female) and 22 disease-free controls (median age 34 years, range 19-59, 57% female), MULES test times were greater (worse) among the patients (60.0 vs. 40.0 s). Accounting for age, MS vs. control status was a predictor of MULES test times (P = .01, logistic regression). Faster testing times were noted among patients with MS who had greater (better) performance on binocular LCLA at 2.5% contrast (P < .001, linear regression, accounting for age), binocular high-contrast VA (P < .001), and K-D testing (P < .001). Both groups demonstrated approximately 10-s improvements in MULES test times between trials 1 and 2 (P < .0001, paired t-tests). CONCLUSION/CONCLUSIONS:The MULES test, a complex task of rapid picture naming involves an extensive visual network that captures eye movements, color perception and the characterization of objects. Color recognition, a key component of this novel assessment, is early in object processing and requires area V4 and the inferior temporal projections. MULES scores reflect performance of LCLA, a widely-used measure of visual function in MS clinical trials. These results provide evidence that the MULES test can add efficient visual screening to the assessment of patients with MS.

On average, African Americans with multiple sclerosis demonstrate higher inflammatory disease activity, faster disability accumulation, greater visual dysfunction, more pronounced brain tissue damage and higher lesion volume loads compared to Caucasian Americans with multiple sclerosis. Neurodegeneration is an important component of multiple sclerosis, which in part accounts for the clinical heterogeneity of the disease. Brain atrophy appears to be widespread, although it is becoming increasingly recognized that regional substructure atrophy may be of greater clinical relevance. Patient race (within the limitations of self-identified ancestry) is regarded as an important contributing factor. However, there is a paucity of studies examining differences in neurodegeneration and brain substructure volumes over time in African Americans relative to Caucasian American patients. Optical coherence tomography is a non-invasive and reliable tool for measuring structural retinal changes. Recent studies support its utility for tracking neurodegeneration and disease progression in vivo in multiple sclerosis. Relative to Caucasian Americans, African American patients have been found to have greater retinal structural injury in the inner retinal layers. Increased thickness of the inner nuclear layer and the presence of microcystoid macular pathology at baseline predict clinical and radiological inflammatory activity, although whether race plays a role in these changes has not been investigated. Similarly, assessment of outer retinal changes according to race in multiple sclerosis remains incompletely characterized. Twenty-two African Americans and 60 matched Caucasian Americans with multiple sclerosis were evaluated with brain MRI, and 116 African Americans and 116 matched Caucasian Americans with multiple sclerosis were monitored with optical coherence tomography over a mean duration of 4.5 years. Mixed-effects linear regression models were used in statistical analyses. Grey matter (-0.9%/year versus -0.5%: P =0.02), white matter (-0.7%/year versus -0.3%: P =0.04) and nuclear thalamic (-1.5%/year versus -0.7%/year: P =0.02) atrophy rates were approximately twice as fast in African Americans. African Americans also exhibited higher proportions of microcystoid macular pathology (12.1% versus 0.9%, P =0.001). Retinal nerve fibre layer (-1.1% versus -0.8%: P =0.02) and ganglion cell+ inner plexiform layer (-0.7%/year versus -0.4%/year: P =0.01) atrophy rates were faster in African versus Caucasian Americans. African Americans on average exhibited more rapid neurodegeneration than Caucasian Americans and had significantly faster brain and retinal tissue loss. These results corroborate the more rapid clinical progression reported to occur, in general, in African Americans with multiple sclerosis and support the need for future studies involving African Americans in order to identify individual differences in treatment responses in multiple sclerosis.

Objective/UNASSIGNED:The objective of this study was to evaluate prespecified and post hoc analyses in RENEW subgroups to identify participants more likely to benefit from opicinumab. Methods/UNASSIGNED:RENEW assessed the efficacy/safety of opicinumab versus placebo in participants with a first unilateral acute optic neuritis (AON) episode. Difference in visual evoked potential (VEP) latency of the affected eye at 24 weeks versus the fellow eye at baseline was the primary endpoint. Interactions between the primary endpoint and prespecified baseline variables (including age, timing of treatment initiation, and visual impairment) using the median as cut-off were evaluated in the per protocol population using analysis of covariance (ANCOVA); subgroups based on preexisting brain T2 lesion volume were also analyzed. Interactions between the primary endpoint and retinal ganglion cell layer/inner plexiform layer (RGCL/IPL) and retinal nerve fiber layer (RNFL) thickness were assessed post hoc as was weight gain by treatment. Results/UNASSIGNED:0.0164), occurring early on. Interpretation/UNASSIGNED:Age was the strongest prespecified baseline characteristic associated with a treatment effect of opicinumab. A strong association between VEP latency recovery at week 24 and early RGCL/IPL preservation was observed.

BACKGROUND: The Multiple Sclerosis Outcome Assessments Consortium (MSOAC) was formed by the National MS Society to develop improved measures of multiple sclerosis (MS)-related disability. OBJECTIVES: (1) To assess the current literature and available data on functional performance outcome measures (PerfOs) and (2) to determine suitability of using PerfOs to quantify MS disability in MS clinical trials. METHODS: (1) Identify disability dimensions common in MS; (2) conduct a comprehensive literature review of measures for those dimensions; (3) develop an MS Clinical Data Interchange Standards Consortium (CDISC) data standard; (4) create a database of standardized, pooled clinical trial data; (5) analyze the pooled data to assess psychometric properties of candidate measures; and (6) work with regulatory agencies to use the measures as primary or secondary outcomes in MS clinical trials. CONCLUSION: Considerable data exist supporting measures of the functional domains ambulation, manual dexterity, vision, and cognition. A CDISC standard for MS ( http://www.cdisc.org/therapeutic#MS ) was published, allowing pooling of clinical trial data. MSOAC member organizations contributed clinical data from 16 trials, including 14,370 subjects. Data from placebo-arm subjects are available to qualified researchers. This integrated, standardized dataset is being analyzed to support qualification of disability endpoints by regulatory agencies.

Background: Central nervous system inflammation may lead to alterations in vascular function. Studies of the cerebral microvasculature in multiple sclerosis (MS) reveal hypoperfusion in gray and white matter. MS lesions also exhibit elevated hypoxia inducible factors. Retinal vasculature may be altered in MS, and can be evaluated with optical coherence tomography angiography (OCT-A). Goals: To (1) compare retinal vascular plexus densities in relapsing remitting MS (RRMS) and healthy controls (HCs), and (2) examine the relationships of these measurements with retinal layer thicknesses, visual function and global disability.
Method(s): In this cross-sectional study, 116 people with RRMS [225 eyes; 98 eyes with a history of optic neuritis (ON)] and 50 HCs (97 eyes) underwent Heidelberg Spectralis OCT-A and spectral- domain OCT (with automated segmentation of retinal layer thicknesses). Superficial vascular plexus (SVP) and deep vascular plexus (DVP) densities were quantified using ImageJ software, and poor quality OCT-A images were excluded. People with RRMS also underwent assessment of visual function and expanded disability status scale (EDSS) scores. Multivariate linear regression models were adjusted for age, sex and ON history. Mixed-effects models were additionally adjusted for within-subject inter-eye correlations.
Result(s): Mean SVP density was 24.4% (SD 5.5%) in RRMS eyes [26.2% (SD 4.7%) in non-ON eyes vs. 22.4% (SD 5.6%) in ON eyes, p< 0.001], as compared to 29.2% (SD 3.3%) in HC eyes (all RRMS, non-ON, and ON eyes vs. HC eyes; p< 0.001 for all). DVP density did not differ significantly between groups. In individual RRMS eyes, lower SVP density was associated with lower peripapillary retinal nerve fiber layer (pRNFL) thickness (R²=0.53, p< 0.001), lower ganglion cell + inner plexiform layer (GCIP) thickness (R²=0.75, p< 0.001) and lower letter acuity (R²=0.22 for 100%-contrast, R²=0.36 for 2.5%-contrast, R²=0.26 for 1.25%-contrast; p< 0.001 for all). Using mixed-effects regression, lower SVP density, pRNFL and GCIP thickness were independently associated with longer disease duration (p=0.02, p=0.03 and p=0.008, respectively) and higher EDSS (p=0.04, p=0.05 and p=0.04, respectively).
Conclusion(s): RRMS eyes, both with and without a history of ON, demonstrate reduced retinal SVP density as compared to HCs. Furthermore, lower SVP density in RRMS correlates with lower retinal layer thicknesses, poorer visual function and higher levels of global disability

Introduction: Natalizumab treatment early in the relapsingremitting multiple sclerosis (RRMS) disease course may improve clinical outcomes. STRIVE is a multicentre, observational, openlabel, single-arm study of anti-JC virus antibody negative patients starting natalizumab < 3 years after RRMS diagnosis.
Objective(s): To examine no evidence of disease activity (NEDA) status, cognitive function, and health-related quality of life (HRQoL) over 3 years of natalizumab treatment in patients with early RRMS.
Method(s): NEDA was defined as no Expanded Disability Status Scale (EDSS) worsening (a score increase of >=1.5 from a baseline [BL] of 0, >=1.0 from a BL of 1.0-5.5, or >=0.5 from a BL >=6.0, confirmed over >=24 weeks), relapses, gadolinium-enhancing lesions, or new/enlarging T2-hyperintense lesions. Clinical NEDA was defined as no 24-week-confirmed EDSS worsening or relapses. The Kaplan-Meier method was used to estimate time to 24-week-confirmed EDSS worsening and improvement (a score decrease of >=1.0 from a BL >=2.0). The Symbol Digit Modalities Test (SDMT) and the Multiple Sclerosis Impact Scale-29 (MSIS- 29) were assessed at BL and yearly thereafter. Changes from BL (CFBs) to year 3 were analysed via Wilcoxon signed-rank tests.
Result(s): At BL, the intent-to-treat population (N=222) had early RRMS with a mean (standard deviation [SD]) time since diagnosis of 1.6 (0.8) years, a mean (SD) EDSS score of 2.0 (1.1), and a mean (SD) of 1.4 (1.2) relapses in the prior year. A total of 50% of the patients had not used prior disease-modifying therapies. At year 3, 55 of 164 patients (33.5%) maintained NEDA (95% CI: 26.3%, 40.8%) and 107 of 171 patients (62.6%) maintained clinical NEDA (95% CI: 55.3%, 69.8%). At year 3, the cumulative probabilities of 24-week-confirmed EDSS worsening and improvement were 19.5% and 36.2%, respectively. From BL to year 3, patients exhibited significant improvements in SDMT score (n=153; mean CFB [95% CI]: 3.6 [2.0, 5.2]; P< 0.001) and in MSIS-29 (n=147) physical score (mean CFB [95% CI]: -4.8 [-7.1, -2.5]; P< 0.001), psychological score (mean CFB [95% CI]: -2.2 [-3.5, -0.9]; P=0.001), and quality-of-life score (mean CFB [95% CI]: -7.0 [-10.3, -3.7]; P< 0.001).
Conclusion(s): In patients with early RRMS, natalizumab treatment over 3 years was associated with NEDA maintenance and improved cognitive and HRQoL outcomes. These results are consistent with previous work showing natalizumab's effectiveness when initiated early in the RRMS disease course

Objective: To determine optimal thresholds for inter-eye differences in retinal nerve fiber (RNFL) and ganglion cell+inner plexiform (GCIP) layer thicknesses that are predictive of a unilateral optic nerve lesion in multiple sclerosis (MS).
Background(s): The optic nerve is a frequent site for involvement in MS. Current international diagnostic criteria for MS do not include the optic nerve as a lesion site despite the high prevalence of acute optic neuritis (ON). Spectral-domain optical coherence tomography (SD-OCT) detects thinning of RNFL and GCIP in MS.
Method(s): In this multi-center international study at 9 sites, SD-OCT, high-contrast visual acuity (VA), low-contrast letter acuity (LCLA), and vision-specific quality of life (QOL) were measured for MS patients and healthy controls as part of the International Multiple Sclerosis Visual System Consortium (IMSVISUAL). QOL was measured using the NEI-VFQ-25 and 10-item Neuro-Ophthalmic Supplement (NOS). Presence of an optic nerve lesion was defined as history of acute unilateral ON.
Result(s): Among healthy controls (n=348), the 95th percentile value for inter-eye difference (upper boundary of expected) was 7.0 microns; for GCIP, the 95th percentile was 3.0 microns. These values were applied to the MS cohort (n=1,346), and were associated with worse vision-specific QOL for inter-eye differences above the threshold values (P<=0.04, linear regression, accounting for age). Greater inter-eye differences in VA and LCLA were associated with greater inter-eye RNFL differences (P< 0.001) and GCIP (P<=0.002). Receiver operating characteristic (ROC) curve analysis demonstrated an optimal RNFL inter-eye difference threshold of 5 microns for identifying patients with unilateral ON (n=404) in the MS cohort (point on ROC curve where sensitivity and specificity are both optimized). For GCIP, the threshold was 4 microns.
Conclusion(s): Optimal inter-eye differences of 5 microns for peripapillary RNFL and 4 microns for macular GCIP thickness are robust thresholds for identifying unilateral optic nerve lesions based on analyses of an international MS cohort

BACKGROUND:Vision-based measures have been shown to be useful markers in multiple sclerosis (MS), Alzheimer and Parkinson disease. Therefore, these testing paradigms may have applications to populations explaining repetitive head trauma that has been associated with long-term neurodegenerative sequelae. We investigated retinal structure and visual function in professional collision sport athletes compared to age- and race-matched control participants. METHODS:In this cross-sectional study, participants underwent spectral-domain optical coherence tomography (OCT) measurements of peripapillary retinal nerve fiber layer (RNFL) and macular ganglion cell complex (GCC = ganglion cell + inner plexiform layers) thickness. High-contrast visual acuity (100% level), low-contrast letter acuity (LCLA) (1.25% and 2.5% levels), and King-Devick Test of rapid number naming performance were administered. Vision-specific quality of life (QOL) measures were assessed. RESULTS:Among 46 collision sport athletes (boxing, n = 14; football, n = 29; ice hockey, n = 3) and 104 control participants, average RNFL thickness was a significant predictor of athlete vs control status with athletes demonstrating 4.8-μm of thinning compared to controls (P = 0.01, generalized estimating equation [GEE] models accounting for age and within-subject, intereye correlations). Athlete vs control status was not a predictor of RNFL thickness for the subgroup of football players in this cohort (P = 0.60). Binocular (P = 0.001) and monocular (P = 0.02) LCLA at 2.5% contrast and vision-specific QOL (P = 0.04) were significant predictors of athlete vs control status (GEE models accounting for age and within-subject, intereye correlations). Rapid number naming performance times were not significantly different between the control and athlete groups. CONCLUSIONS:This study showed that retinal axonal and neuronal loss is present among collision sport athletes, with most notable differences seen in boxers. These findings are accompanied by reductions in visual function and QOL, similar to patterns observed in multiple sclerosis, Alzheimer and Parkinson diseases. Vision-based changes associated with head trauma exposure that have the potential to be detected in vivo represent a unique opportunity for further study to determine if these changes in collision sport athletes are predictive of future neurodegeneration.

PURPOSE/OBJECTIVE:To determine relationships between visual function and GCIP thickness, and neuropsychological measures in MS. METHODS:Ninety-five relapsing-remitting (RRMS) and thirty-six progressive MS patients underwent 100%-contrast visual acuity (VA), 2.5%- and 1.25%-contrast letter acuity (LA) testing, Cirrus-HD OCT, and neuropsychological assessments. Mixed effects regression models were used to assess relationships. RESULTS:Across the cohort, 1.25%-contrast LA was associated with Symbol Digit Modalities Test (SDMT; β = 2.17, p = 0.005), and Brief Visuospatial Memory Test Revised (BVMT-R) Total Recall (TR) and Delayed Recall (DR) scores (β = 0.31, p < 0.001; β = 0.15, p = 0.039, respectively). 2.5%-contrast LA was associated with BVMT-R TR scores (β = 0.27, p = 0.006). In the RRMS cohort, 1.25%-contrast LA was generally more significantly associated with cognitive measures; SDMT (β = 2.97, p = 0.001), BVMT-R TR (β = 0.32, p < 0.001) and DR (β = 0.22, p = 0.012). CONCLUSION/CONCLUSIONS:This study suggests that visual pathway measures, particularly visual function measures, reflect aspects of cognitive function in MS, further supporting their roles as complementary outcomes in MS neuroprotection trials.