Faculty Bibliography

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.

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:To determine if native English speakers (NES) perform differently compared to non-native English speakers (NNES) on a sideline-focused rapid number naming task. A secondary aim was to characterize objective differences in eye movement behaviour between cohorts. BACKGROUND:The King-Devick (KD) test is a rapid number-naming task in which numbers are read from left-to-right. This performance measure adds vision-based assessment to sideline concussion testing. Reading strategies differ by language. Concussion may also impact language and attention. Both factors may affect test performance. METHODS:Twenty-seven healthy  NNES and healthy NES performed a computerized KD test under high-resolution video-oculography.  NNES also performed a Bilingual Dominance Scale (BDS) questionnaire to weight linguistic preferences (i.e., reliance on non-English language(s)). RESULTS:Inter-saccadic intervals were significantly longer in  NNES (346.3 ± 78.3 ms vs. 286.1 ± 49.7 ms, p = 0.001), as were KD test times (54.4 ± 15.1 s vs. 43.8 ± 8.6 s, p = 0.002). Higher BDS scores, reflecting higher native language dominance, were associated with longer inter-saccadic intervals in  NNES. CONCLUSION/CONCLUSIONS:These findings have direct implications for the assessment of athlete performance on vision-based and other verbal sideline concussion tests; these results are particularly important given the international scope of sport. Pre-season baseline scores are essential to evaluation in the event of concussion, and performance of sideline tests in the athlete's native language should be considered to optimize both baseline and post-injury test accuracy.

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.

: BACKGROUND:: The visual pathways are increasingly recognized as an ideal model to study neurodegeneration in multiple sclerosis (MS). Low-contrast letter acuity (LCLA) and optical coherence tomography (OCT) are validated measures of function and structure in MS. In fact, LCLA was the topic of a recent review by the Multiple Sclerosis Outcome Assessments Consortium (MSOAC) to qualify this visual measure as a primary or secondary clinical trial endpoint with the Food and Drug Administration (FDA) and other regulatory agencies. This review focuses on the use of LCLA and OCT measures as outcomes in clinical trials to date of MS disease-modifying therapies.

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.