Faculty Bibliography

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.

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: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.

: 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.

OBJECTIVE:Measures of rapid automatized naming (RAN) have been used for over 50 years to capture vision-based aspects of cognition. The Mobile Universal Lexicon Evaluation System (MULES) is a test of rapid picture naming under investigation for detection of concussion and other neurological disorders. MULES was designed as a series of 54 grouped color photographs (fruits, random objects, animals) that integrates saccades, color perception and contextual object identification. Recent changes to the MULES test have been made to improve ease of use on the athletic sidelines. Originally an 11 × 17-inch single-sided paper, the test has been reduced to a laminated 8.5 × 11-inch double-sided version. We identified performance changes associated with transition to the new, MULES, now sized for the sidelines, and examined MULES on the sideline for sports-related concussion. METHODS:We administered the new laminated MULES to a group of adult office volunteers as well as youth and collegiate athletes during pre-season baseline testing. Athletes with concussion underwent sideline testing after injury. Time scores for the new laminated MULES were compared to those for the larger version (big MULES). RESULTS:Among 501 athletes and office volunteers (age 16 ± 7 years, range 6-59, 29% female), average test times at baseline were 44.4 ± 14.4 s for the new laminated MULES (n = 196) and 46.5 ± 16.3 s for big MULES (n = 248). Both versions were completed by 57 participants, with excellent agreement (p < 0.001, linear regression, accounting for age). Age was a predictor of test times for both MULES versions, with longer times noted for younger participants (p < 0.001). Among 6 athletes with concussion thus far during the fall sports season (median age 15 years, range 11-21) all showed worsening of MULES scores from pre-season baseline (median 4.0 s, range 2.1-16.4). CONCLUSION/CONCLUSIONS:The MULES test has been converted to an 11 × 8.5-inch laminated version, with excellent agreement between versions across age groups. Feasibly administered at pre-season and in an office setting, the MULES test shows preliminary evidence of capacity to identify athletes with sports-related concussion.

BACKGROUND:The Pulfrich phenomenon (PF) is the illusory perception that an object moving linearly along a 2-D plane appears to instead follow an elliptical 3-D trajectory, a consequence of inter-eye asymmetry in the timing of visual object identification in the visual cortex; with optic neuritis as a common etiology. OBJECTIVE:We have designed an objective method to identify the presence and magnitude of the PF, in conjunction with a cooresponding strategy by which to abolish the effect; with monocular application of neutral density filters to the less affected fellow eye, in patients with MS and a history of optic neuropathy (e.g. related to acute optic neuritis or subclinical optic neuropathy). METHODS:Twenty-three MS patients with a history of acute unilateral or bilateral optic neuritis, and ten healthy control subjects (HC) were recruited to participate in a pilot study to assess our strategy. Subjects were asked to indicate whether a linearly moving pendulum ball followed a linear 2-D path versus an illusory 3-D elliptical object-motion trajectory, by reporting the ball's approximation to one of nine horizontally-oriented colored wires that were positioned parallel to one another and horizontal to the linear pendulum path. Perceived motion of the bob that moved along wires behind or in front (along the 'Z' plane) of the middle reference wire indicated an illusory elliptical trajectory of ball motion consistent with the PF. RESULTS:When the neutral density filter titration was applied to the fellow eye the severity of the PF decreased, eventually being fully abolished in all but one patient. The magnitude of neutral density filtering required correlated to the severity of the patient's initial PF magnitude (p < 0.001). CONCLUSIONS:We ascertained the magnitude of the visual illusion associated with the PF, and the corresponding magnitude of neutral density filtering necessary to abolish it.