Faculty Bibliography

BACKGROUND:STRIVE is a multicenter, observational, open-label, single-arm study of natalizumab in anti-JC virus (JCV) seronegative patients with early relapsing-remitting multiple sclerosis (RRMS). The objective of this prespecified 2-year interim analysis was to determine the effectiveness of natalizumab in establishing and maintaining no evidence of disease activity (NEDA) in early RRMS. METHODS:Patients aged 18-65 years had an RRMS diagnosis < 3 years prior to screening, an Expanded Disability Status Scale (EDSS) score ≤ 4.0, and anti-JCV antibody negative status. Magnetic resonance imaging was performed at baseline and yearly thereafter. Cumulative probabilities of 24-week-confirmed EDSS worsening and improvement were evaluated at 2 years. NEDA (no 24-week-confirmed EDSS worsening, no relapses, no gadolinium-enhancing lesions, and no new/newly enlarging T2-hyperintense lesions) was evaluated over 2 years. The Symbol Digit Modalities Test (SDMT) and Multiple Sclerosis Impact Score (MSIS-29) were assessed at baseline and 1 and 2 years. Statistical analysis used summary statistics and frequency distributions. RESULTS:The study population (N = 222) had early RRMS, with mean (standard deviation [SD]) time since diagnosis of 1.6 (0.77) years and mean (SD) baseline EDSS score of 2.0 (1.13). NEDA was achieved in 105 of 187 patients (56.1%) during year 1 and 120 of 163 (73.6%) during year 2. Over 2 years, 76 of 171 patients (44.4%) attained overall NEDA. Probabilities of 24-week-confirmed EDSS worsening and improvement were 14.1% and 28.4%, respectively. After 2 years, patients exhibited significant improvements from baseline in SDMT (n = 158; mean [SD]: 4.3 [11.8]; p < 0.001) and MSIS-29 physical (n = 153; mean [SD]: - 3.9 [14.7]; p = 0.001), psychological (n = 152; mean [SD]: - 2.0 [7.9]; p < 0.001), and quality-of-life (n = 153; mean [SD]: - 6.0 [21.3]; p < 0.001) scores. CONCLUSIONS:These results support natalizumab's effectiveness over 2 years, during which nearly half of early RRMS patients achieved NEDA. During year 2, nearly 75% of patients exhibited NEDA. Over 2 years, patients continued to experience significant cognitive and quality-of-life benefits. These results are limited by the lack of a comparator group to determine the extent of a placebo effect. TRIAL REGISTRATION/BACKGROUND:clinicaltrials.gov, NCT01485003 , registered 5 December 2011.

BACKGROUND:Leucine-rich repeat and immunoglobulin domain-containing Nogo receptor-interacting protein 1(LINGO-1 is a key suppressor of oligodendrocyte differentiation and axonal remyelination and regeneration. This analysis evaluated the potential benefit of opicinumab, a human monoclonal antibody against LINGO-1, vs placebo on exploratory clinical endpoints of patient-reported vision-related functioning and high-contrast visual acuity (HCVA) in RENEW participants with acute optic neuritis (AON). METHODS:Participants were randomized to 100 mg/kg opicinumab intravenous or placebo every 4 weeks (6 infusions). Assessments were conducted in the per-protocol (PP) population and included: 25-item National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25), 10-item Neuro-Ophthalmic Supplement (NOS-10), and HCVA. RESULTS:The opicinumab group (n = 33) had worse mean (SD) baseline patient-reported vision-related functioning scores vs placebo (n = 36): NEI-VFQ-25 composite, 75.5 (17.6) vs 79.0 (16.6); NOS-10 composite, 63.6 (19.8) vs 69.8 (21.2), respectively. By Week 24, the placebo and opicinumab groups experienced substantial mean improvements from baseline (NEI-VFQ-25 composite, 15.17 vs 13.51 [difference (95% CI): -1.66 (-5.11 to 1.78)]; NOS-10 composite, 17.40 vs 16.04 [difference (95% CI): -1.35 (-7.38 to 4.67)]). Between-treatment differences in mean change from baseline were not significantly different at any time point. Analysis of covariance-adjusted mean recovery from baseline in HCVA at Week 24 for the affected eyes was 11.8 and 8.7 letters for placebo and opicinumab, respectively (P = 0.202). CONCLUSIONS:Most participants in the RENEW PP population demonstrated substantial recovery from baseline in patient-reported vision-related functioning and HCVA, regardless of treatment and structural damage. Average scores after recovery remained lower than those of published disease-free control groups. These results provide important information on visual function recovery in patients with AON, as measured by NEI-VFQ-25 and NOS-10.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Background/UNASSIGNED:The association of peripapillary retinal nerve fibre layer (pRNFL) and ganglion cell-inner plexiform layer (GCIPL) thickness with neurodegeneration in multiple sclerosis (MS) is well established. The relationship of the adjoining inner nuclear layer (INL) with inflammatory disease activity is less well understood. Objective/UNASSIGNED:In this longitudinal, multi-centre study, optical coherence tomography (OCT) and clinical data (disability status, relapses and MS optic neuritis (MSON)) were collected in 785 patients with MS (68.3% female) and 92 healthy controls (63.4% female) from 11 MS centres between 2010 and 2017 and pooled retrospectively. Data on pRNFL, GCIPL and INL were obtained at each centre. Results/UNASSIGNED: = .474). Conclusion/UNASSIGNED:Our data demonstrate that an increase in INL volume is associated with MSON and the occurrence of clinical relapses. Therefore, INL volume changes may be useful as an outcome marker for inflammatory disease activity in MSON and MS treatment trials.

BACKGROUND/UNASSIGNED:The retinal vasculature may be altered in multiple sclerosis (MS), potentially acting as a biomarker of disease processes. OBJECTIVE/UNASSIGNED:To compare retinal vascular plexus densities in people with MS (PwMS) and healthy controls (HCs), and examine correlations with visual function and global disability. METHODS/UNASSIGNED:In this cross-sectional study, 111 PwMS (201 eyes) and 50 HCs (97 eyes) underwent optical coherence tomography angiography (OCTA). Macular superficial vascular plexus (SVP) and deep vascular plexus (DVP) densities were quantified, and poor quality images were excluded according to an artifact-rating protocol. RESULTS/UNASSIGNED: = 0.31; p < 0.001 for all). CONCLUSIONS/UNASSIGNED:Retinal SVP density measured by OCTA is reduced across MS eyes, and correlates with visual function, EDSS, and MSFC scores.

OBJECTIVE:To determine the optimal thresholds for inter-eye differences in retinal nerve fiber and ganglion cell+inner plexiform layer thicknesses for identifying unilateral optic nerve lesions in multiple sclerosis. BACKGROUND:Current international diagnostic criteria for multiple sclerosis do not include the optic nerve as a lesion site despite frequent involvement. Optical coherence tomography detects retinal thinning associated with optic nerve lesions. METHODS:In this multi-center international study at 11 sites, optical coherence tomography was measured for patients and healthy controls as part of the International Multiple Sclerosis Visual System Consortium. High- and low-contrast acuity were also collected in a subset of participants. Presence of an optic nerve lesion for this study was defined as history of acute unilateral optic neuritis. RESULTS:Among patients (n=1,530), receiver operating characteristic curve analysis demonstrated an optimal peripapillary retinal nerve fiber layer inter-eye difference threshold of 5 microns and ganglion cell+inner plexiform layer threshold of 4 microns for identifying unilateral optic neuritis (n=477). Greater inter-eye differences in acuities were associated with greater inter-eye retinal layer thickness differences (p≤0.001). INTERPRETATION/CONCLUSIONS:Inter-eye differences of 5 microns for retinal nerve fiber layer and 4 microns for macular ganglion cell+inner plexiform layer are robust thresholds for identifying unilateral optic nerve lesions. These thresholds may be useful to establish the presence of asymptomatic and symptomatic optic nerve lesions in multiple sclerosis and could be useful in a new version of the diagnostic criteria. Our findings lend further validation for utilizing the visual system in a multiple sclerosis clinical trial setting.

Background and Aims: Contemplating the use of N-acetylcysteine as a neuroprotectant, with dextran as an antithrombotic for patients with NIHSS less than or equal to 5, we quantified treatment-relevant clinical characteristics of a sample of this patient population at a single stroke center over one year.
Method(s): Patients with NIHSSResult(s): One-hundred twenty-eight of 310 (41%) patients with ischemic stroke had NIHSSConclusion(s): Minor stroke symptoms may not be captured by the current NIHSS. This population rarely had renal or hepatic failure, making them good candidates for combination N-acetylcysteine and dextran

OBJECTIVE:The Mobile Universal Lexicon Evaluation System (MULES) is a test of rapid picture naming under investigation. Measures of rapid automatic naming (RAN) have been used for over 50 years to capture aspects of vision and cognition. MULES was designed as a series of 54 grouped color photographs (fruits, random objects, animals) that integrates saccades, color perception and contextual object identification. We examined MULES performance in youth, collegiate and professional athletes at pre-season baseline and at the sidelines following concussion. METHODS:Our study teams administered the MULES to youth, collegiate and professional athletes during pre-season baseline testing. Sideline post-concussion time scores were compared to pre-season baseline scores among athletes with concussion to determine degrees and directions of change. RESULTS:Among 681 athletes (age 17 ± 4 years, range 6-37, 38% female), average test times at baseline were 41.2 ± 11.2 s. The group included 280 youth, 357 collegiate and 44 professional athletes; the most common sports were ice hockey (23%), soccer (17%) and football (11%). Age was a predictor of MULES test times, with longer times noted for younger participants (P < .001, linear regression). Consistent with other timed performance measures, significant learning effects were noted for the MULES during baseline testing with trial 1 test times (mean 49.2 ± 13.1 s) exceeding those for trial 2 (mean 41.3 ± 11.2 s, P < .0001, paired t-test). Among 17 athletes with concussion during the sports seasons captured to date (age 18 ± 3 years), all showed increases (worsening) of MULES time scores from pre-season baseline (median increase 11.2 s, range 0.6-164.2, P = .0003, Wilcoxon signed-rank test). The Symptom Severity Score from the SCAT5 Symptom Evaluation likewise worsened from pre-season baseline following injury among participants with concussion (P = .002). CONCLUSIONS:Concussed athletes demonstrate worsening performance on the MULES test compared to their baseline time scores. This test samples a wide network of brain pathways and complements other vision-based measures for sideline concussion assessment. The MULES test demonstrates capacity to identify athletes with sports-related concussion.

Background: Myopia's axial elongation of the eye causes an irregularly shaped retina. Cross-sectional studies show that increasing diopters and axial lengths in myopia correlate negatively with Optical Coherence Tomography (OCT) derived measures of Retinal Nerve Fiber Layer (RNFL) thickness. This has largely precluded including OCT data from high myopia individuals in Multiple Sclerosis (MS) and other studies. OCT is a promising marker of neurodegeneration in MS. However, the impact of high myopia in longitudinal studies remains to be investigated.
Objective(s): To assess the impact of high myopia on rates of change in OCT retinal layer thicknesses in MS patients and healthy controls (HC).
Method(s): A 1:2 age and sex matching scheme was used in the MS [13 high myopia (MSHM): 26 non myopia (MSNM)] and HC [7 high myopia (HCHM): 14 non myopia (HCNM)] cohorts. OCT thickness measures of the peripapillary RNFL (pRNFL), ganglion cell+inner plexiform layer (GCIP), and other retinal layers were determined using a validated segmentation algorithm. Mixed effects linear regression was used in statistical analyses.
Result(s): Baseline MSHM eyes had lower GCIP (-4.01 mum, p = 0.06) and pRNFL thicknesses (-8.15 mum, p = 0.04), as compared to MSNM eyes. HC GCIP and pRNFL thicknesses were lower in HCHM than HCNM eyes (-4.15 mum, p = 0.01 and -0.84 mum, p = 0.83 respectively). Despite cross-sectional differences in retinal layer thicknesses in eyes stratified by myopia, longitudinal (median duration of follow-up= 4.6, 6.9, 4.0, 5.1 years in MSHM, MSNM, HCHM, and HCNM respectively) rates of retinal layer change did not differ between participants with and without high myopia. In the MS cohort, rates of thinning were significant in both groups but there was no difference between rates of GCIP and pRNFL thinning among MSHM and MSNM (DELTA0.07 mum/y, p = 0.71 and DELTA0.12 mum/y, p = 0.52 respectively) eyes. Similarly, no difference in rates of GCIP and pRNFL change was found between HCHM and HCNM (DELTA0.06 mum/y, p = 0.49 and DELTA0.21 mum/y, p = 0.22 respectively) eyes. Similar results were observed for the inner and outer nuclear layers in MS and HCs.
Conclusion(s): Although cross-sectional retinal thickness measures may vary due to myopia, longitudinal rates of retinal change appear unaffected. Therefore, despite longstanding opinion, our findings suggest high myopia may not confound longitudinal OCT analyses. Future research is needed to verify and validate our preliminary findings in larger, longitudinal studies

Background: The retinal microcirculation has been studied in various diseases including multiple sclerosis (MS). However, inter-eye correlations and potential differences of the retinal blood flow velocity (BFV) remain largely unstudied, but may be important in guiding eye selection, as well as the design and interpretation of studies assessing or utilizing retinal BFV.
Objective(s): The primary aim of this study was to determine inter-eye correlations in BFVs in healthy controls (HCs). Since prior studies raise the possibility of reduced BFV in MS eyes, a secondary aim was to compare retinal BFVs between MS eyes, grouped based on optic neuritis (ON) history, and HC eyes.
Method(s): Macular arteriole and venule BFVs were determined using a retinal function imager (RFI) in both eyes of 20 HCs. One eye from a total of 38 MS patients comprising 13 eyes with ON (MSON) and 25 eyes without ON (MSNON) history were similarly imaged with RFI.
Result(s): OD (right) and OS (left) BFVs were not significantly different in arterioles (OD: 3.95 +/- 0.59 mm/s; OS: 4.08 +/- 0.60 mm/s, P = 0.10) or venules (OD: 3.11 +/- 0.46 mm/s; OS: 3.23 +/- 0.52 mm/s, P = 0.06) in HCs. Very strong inter-eye correlations were also found between arteriolar (r = 0.84, P < 0.001) and venular (r = 0.87, P < 0.001) BFVs in HCs. Arteriolar (3.48 +/- 0.88 mm/s) and venular (2.75 +/- 0.53 mm/s) BFVs in MSNON eyes were significantly lower than in HC eyes (P = 0.009 and P = 0.005 respectively). Similarly, arteriolar (3.59 +/- 0.69 mm/s) and venular (2.80 +/- 0.45 mm/s) BFVs in MSON eyes were also significantly lower than in HC eyes (P = 0.046 and P = 0.048 respectively). Arteriolar and venular BFVs in MSON and MSNON eyes did not differ from each other (P = 0.42 and P = 0.48 respectively).
Conclusion(s): Inter-eye arteriolar and venular BFVs do not differ significantly in HCs and are strongly correlated. Our findings support prior observations that arteriolar and venular BFVs may be reduced in MS eyes. Moreover, this seems to be the case in both MS eyes with and without a history of ON, raising the possibility of global blood flow alterations in MS. Future larger studies are needed to assess differences in BFVs between MSON and MSNON eyes