Faculty Bibliography

BACKGROUND:Concussion leads to neurophysiologic changes that may result in visual symptoms and changes in ocular motor function. Vision-based testing is used increasingly to improve detection and assess head injury. This review will focus on the historical aspects and emerging data for vision tests, emphasizing rapid automatized naming (RAN) tasks and objective recording techniques, including video-oculography (VOG), as applied to the evaluation of mild traumatic brain injury. METHODS:Searches on PubMed were performed using combinations of the following key words: "concussion," "mild traumatic brain injury," "rapid automatized naming," "King-Devick," "mobile universal lexicon evaluation system," "video-oculography," and "eye-tracking." Additional information was referenced from web sites of vendors of commercial eye-tracking systems and services. RESULTS:Tests of rapid number, picture, or symbol naming, termed RAN tasks, have been used in neuropsychological studies since the early 20th century. The visual system contains widely distributed networks that are readily assessed by a variety of functionally distinct RAN tasks. The King-Devick test, a rapid number naming assessment, and several picture-naming tests, such as the Mobile Universal Lexicon Evaluation System (MULES) and the modified Snodgrass and Vanderwart image set, show capacity to identify athletes with concussion. VOG has gained widespread use in eye- and gaze-tracking studies of head trauma from which objective data have shown increased saccadic latencies, saccadic dysmetria, errors in predictive target tracking, and changes in vergence in concussed subjects. Performance impairments on RAN tasks and on tasks recorded with VOG are likely related to ocular motor dysfunction and to changes in cognition, specifically to attention, memory, and executive functioning. As research studies on ocular motor function after concussion have expanded, so too have commercialized eye-tracking systems and assessments. However, these commercial services are still investigational and all vision-based markers of concussion require further validation. CONCLUSIONS:RAN tasks and VOG assessments provide objective measures of ocular motor function. Changes in ocular motor performance after concussion reflect generalized neurophysiologic changes affecting a variety of cognitive processes. Although these tests are increasingly used in head injury assessments, further study is needed to validate them as adjunctive diagnostic aids and assessments of recovery.

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.

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

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: 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