Faculty Bibliography

BACKGROUND:The optic nerve is a frequent site for involvement in multiple sclerosis (MS). Optical coherence tomography (OCT) detects thinning of the retinal nerve fiber layer (RNFL) in eyes of patients with MS and in those meeting criteria for clinically or radiologically isolated demyelinating syndromes. Current international diagnostic criteria for MS do not include the optic nerve as an imaging lesion site despite the high prevalence of acute optic neuritis (ON), or occult optic neuropathy, among early MS and clinically isolated syndrome patients; as well as most MS patients over the course of the disease. We sought to determine optimal thresholds for intereye difference in peripapillary RNFL thickness that are most predictive of a unilateral optic nerve lesion. METHODS:We analyzed spectral domain OCT data of 31 healthy volunteers and 124 patients with MS at a single center as part of an ongoing collaborative investigation of visual outcomes. Intereye differences in peripapillary (360°) RNFL thickness were calculated as the absolute value of the difference. First, we determined the 95th percentile value of intereye difference for the healthy volunteers. This value was applied to the convenience sample group of MS patients as a validation cohort determining how well this threshold could distinguish patients with vs without a history of unilateral ON. The relation of intereye differences in peripapillary RNFL thickness to binocular low-contrast letter acuity scores was also examined. RESULTS:Among healthy volunteer participants (n = 31), the 95th percentile value for intereye difference (upper boundary of expected for normal controls) was 6.0 μm. This value was applied to the convenience sample group of MS patients (n = 124, validation cohort). Positive predictive value, negative predictive value, sensitivity, and specificity for identifying MS patients with a history of unilateral ON were calculated for the 6-μm threshold value in a 2 × 2 table analysis with the application of χ tests (P < 0.0001). The 6-μm threshold was predictive of worse binocular low-contrast acuity scores at 2.5% (P = 0.03) and 1.25% (P = 0.002 by linear regression analyses). A receiver operating characteristic curve analysis demonstrated an optimal intereye difference threshold of 5 μm for identifying unilateral ON in the MS cohort. CONCLUSIONS:An intereye difference of 5-6 μm in RNFL thickness is a robust structural threshold for identifying the presence of a unilateral optic nerve lesion in MS.

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.

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

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.

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

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.