Faculty Bibliography

Low-contrast letter acuity (LCLA) has emerged as the leading outcome measure to assess visual disability in multiple sclerosis (MS) research. As visual dysfunction is one of the most common manifestations of MS, sensitive visual outcome measures are important in examining the effect of treatment. Low-contrast acuity captures visual loss not seen in high-contrast visual acuity (HCVA) measurements. These issues are addressed by the MS Outcome Assessments Consortium (MSOAC), including representatives from advocacy organizations, Food and Drug Administration (FDA), European Medicines Agency (EMA), National Institute of Neurological Disorders and Stroke (NINDS), academic institutions, and industry partners along with persons living with MS. MSOAC goals are acceptance and qualification by regulators of performance outcomes that are highly reliable and valid, practical, cost-effective, and meaningful to persons with MS. A critical step is elucidation of clinically relevant benchmarks, well-defined degrees of disability, and gradients of change that are clinically meaningful. This review shows that MS and disease-free controls have similar median HCVA, while MS patients have significantly lower LCLA. Deficits in LCLA and vision-specific quality of life are found many years after an episode of acute optic neuritis, even when HCVA has recovered. Studies reveal correlations between LCLA and the Expanded Disability Status Score (EDSS), Multiple Sclerosis Functional Composite (MSFC), retinal nerve fiber layer (RNFL) and ganglion cell layer plus inner plexiform layer (GCL + IPL) thickness on optical coherence tomography (OCT), brain magnetic resonance imaging (MRI), visual evoked potential (VEP), electroretinogram (ERG), pupillary function, and King-Devick testing. This review also concludes that a 7-point change in LCLA is clinically meaningful. The overall goal of this review is to describe and characterize the LCLA metric for research and clinical use among persons with MS.

Objective: To assess relationships between classic saccade sequences and rapid number naming on the King Devick (K-D) test in concussion. Background: The K-D test is sensitive for concussion detection on athletic sidelines, with longer test times in concussion largely due to inter-saccadic interval (ISI) prolongation. The ISI is a measure of time between saccades that represents a combination of fixation duration and saccade latency. K-D saccade latency cannot be directly measured, as numbers are simultaneously displayed. We assessed saccade latency independent of K-D test. Design/Methods: Twenty-seven chronically concussed participants (mean age 32+/-13 years, range 17-61) and 19 healthy controls (mean age 29+/-8 years, range 19-48) performed K-D and saccade sequences: reflexive, gap, overlap, and antisaccades. Eye movements were recorded with EyeLink 1000+ video-oculography. Results: K-D test times were longer in concussion (54.6s vs 41.5s, p=0.001), as were ISIs (301.9ms vs 241.4ms, p=0.01). Longer reflexive and overlap latencies (reflexive: 198.1ms vs 176.7ms, p=0.04; overlap: 222.3ms vs 182.8ms, p=0.003) and worse accuracy were seen in concussion. Gap latencies showed no difference (160.6ms vs 148.8ms, p=0.13). Antisaccade latencies were longer in concussion (204.9ms vs 182.3ms, p=0.04) for saccades initially made in the incorrect direction, though there was no difference in error rates. Peak velocity and duration versus amplitude relationships showed no differences between groups. Conclusions: ISI prolongation during K-D performance could be due to increased saccade latencies and/or attention and cognitive impairment. In this study, saccade latency prolongation is seen in several saccade types in concussion, suggesting that it may, indeed, contribute to K-D ISI prolongation in concussion. Further, overlap saccade latency prolongation suggests that pre-saccade visual fixation disengagement is altered in concussion. These results suggest that saccade motor planning is impaired in concussion, possibly from damage to frontal lobe saccade control centers prone to traumatic injury

Objective: Speeded Saccadic Eye Movement Predicts Symbol Digit Modalities Test Performance in Multiple Sclerosis Background: Multiple sclerosis is an autoimmune demyelinating disease with estimates of cognitive impairment above 30% in pediatric and 50% in adult patients. The SDMT, a widely-used screening tool that measures speeded information processing, has been used to track cognitive decline in MS. The K-D test is a brief measure of saccadic eye movement speed using a timed number naming test, commonly used for the detection of mild traumatic brain injury. Here, we tested the sensitivity of the K-D test in MS and its association with performance on the SDMT. Design/Methods: Adult and pediatric patients with clinically-definite MS were consecutively recruited through the NYU Langone MS Comprehensive Care Center. All participants completed the SDMT and K-D at a single visit. Results: A total of 30 participants completed the assessments ranging in age from 13 to 72 years (mean 38 +/- 19 years), were 74% female, and with an EDSS range 0.0 to 6.5. Relative to age normative data, the K-D indicated greater impairment than the SDMT (74% vs. 48%, respectively). Controlling for age, both tests were significantly correlated (r=0.44, p =0.02), demonstrating a close contribution of oculomotor function to SDMT performance. Conclusions: The K-D test is sensitive to detecting impairment in MS across the lifespan. Performance on the SDMT is closely associated with oculomotor function in MS

Objective: This study introduces the Mobile Universal Lexicon Evaluation System (MULES), a new vision-based test of rapid picture naming, in a cohort of youth and collegiate athletes at pre-season concussion testing. Background: Vision-based measures of rapid number naming (King-Devick [K-D]) have improved the sensitivity of sports-related concussion screening. K-D requires saccades and vergence, measuring aspects of frontal, parietal and brainstem centers. We developed the MULES to capture a more extensive vision network, integrating saccades, color perception, and object identification. Design/Methods: We administered MULES and K-D to youth and collegiate athletes during pre-season baseline testing. Sports for 2016-17 included ice hockey, football, soccer, volleyball and wrestling. Test administration order was randomized. Results: Among 165 athletes (age 14+/-5 years, range 6-24, 25% female), average K-D times (59.9+/-29.7 seconds) were similar to MULES (57.9+/-20.4 seconds). Higher K-D times predicted greater MULES times, accounting for age (p<0.001, linear regression). Age was itself a predictor of K-D and MULES time scores, with longer times noted for younger participants (p<0.001). Faster times with increasing age were noted primarily among athletes <16 years for K-D and <15 years for MULES. MULES showed greater degrees of improvement between two baseline trials (57.9 vs. 51.2 seconds, p<0.0001, paired t-test), vs. K-D (59.9 vs. 58.3 seconds, p=0.01). Conclusions: A complex task, the MULES test of rapid picture naming involves a more extensive visual network that captures not only rapid saccades but color perception and the characterization of objects. Color recognition is early in object processing and requires area V4 and the inferior temporal projections. In contrast, rapid number naming appears to engage a specific area of the inferior temporal cortex. Both tests use the centers responsible for initiating and sequencing saccadic eye movements, and will be further examined in our youth and collegiate cohorts during this athletic season for their ability to detect concussion

Objective: To describe a case of gaze-position dependent opsoclonus and discuss potential localization. Background: Opsoclonus is characterized by bursts of involuntary, back-to-back saccades without an intersaccadic interval at frequency of 10-25 Hz in horizontal, vertical, and torsional planes. Opsoclonus with gaze-directional selectivity has been rarely described. Design/Methods: We report a 50 year-old man who sustained a concussion three years prior followed by postconcussive headaches and disequilibrium. Exam revealed very small amplitude oscillations in left gaze that could not be further characterized on clinical exam. Different larger amplitude horizontal oscillations were present with convergence. There were no other posterior fossa signs. Brain MRI was unremarkable. Results: Video-oculography demonstrated opsoclonus predominantly in left gaze [median amplitude 5 deg (range <1- 11 deg), frequency 30 Hz] and during leftward smooth pursuit, which improved [median amplitude 2 deg (range < 1-10 deg), frequency 10 Hz] as post-concussive symptoms improved. Conclusions: This case demonstrates opsoclonus with eye position selectivity in post-concussive syndrome. Various theories of opsoclonus exist, including lesions of saccade burst, omnipause, or cerebellar fastigial pause neurons which project to brainstem burst neurons. Ultimately, all of these lead to increased excitability in the inherently unstable saccade generators. Burst and omnipause neuron firing rates are not influenced by eye position. The leftward gaze-dependence in our case supports dysfunction of cerebellar dorsal vermis Purkinje cells leading to disinhibition of the fastigial ocular motor nucleus, as vermal pause neurons have gaze-directional selectivity. Vermal pause neurons exhibit a pause of discharge immediately before and during contralateral saccades. Thus, selective dysfunction, possibly related to concussion-related membrane instability, could create an imbalance in burst neuron excitability, resulting in triggering of unidirectional opsoclonus. Further, our patient's saccade system may be inherently prone to oscillations given the presence of larger amplitude horizontal oscillations consistent with 'voluntary flutter', which persisted when leftward opsoclonus improved

Objective: The Mobile Universal Lexicon Evaluation System (MULES) is a new test of rapid picture naming that is under investigation in youth, collegiate and professional athlete cohorts as a concussion screening tool. The purpose of this study is to determine the ocular motor underpinnings, including saccade characteristics, required to perform this vision-based performance measure. Background: The MULES includes 54 color photographs of fruits, objects and animals. It has demonstrated excellent feasibility for administration among adult volunteers and in cohorts of athletes of all ages at pre-season baseline. MULES likely captures a more extensive vision network in the brain compared to rapid number naming, integrating saccades, color perception and object identification. Video-oculographic studies of the King-Devick (K-D) test of rapid number naming demonstrate prolonged inter-saccadic intervals (ISI) among individuals with longer testing times. Design/Methods: Participants underwent testing with the paper-based MULES as well as the computer screen-based version (eMULES) designed for simultaneous testing with infrared-based video-oculography (Eye Link 1000+). Saccade velocity, duration and the inter-saccadic interval were measured. Results: Among adult volunteers (n=23, aged 19-45) and patients with recent concussion (n=6, aged 17-43), those with the greatest number of saccades had the longest eMULES completion times ( f0 . 48 , p=0.008). In this cohort, prolonged ISI was not associated with greater eMULES testing times (AS=0.06, p=0.76). Conclusions: Longer testing times for the MULES likely reflect greater numbers of saccades rather than prolongation of the ISI. This pattern may reflect greater degrees of cognitive activity and visual pathway complexity for picture compared to number naming. Underlying dynamics for eye movements are likely to differ between the MULES and K-D, supporting complementary roles for each in concussion assessment

Objective: To compare video-oculography performed by EyeTribe versus EyeLink during a rapid number naming task. Background: With increasing accessibility of portable, economical, video-based, infrared eye trackers, such as EyeTribe, there is growing interest in eye movement recordings, including in the setting of sports-related concussion. However, prior to implementation, there is a primary need to establish the validity of these low-resolution (30-60 Hz) eye trackers via comparison with high-resolution (500-1000 Hz) devices such as EyeLink. Design/Methods: A convenience sample of 30 controls performed a digitized version of the King-Devick (K-D) test with EyeTribe and EyeLink eye movement recordings. Results: Signal loss and tracings inconsistent with eye movement physiology were common with EyeTribe. Saccade main sequence parameters (fit to decaying exponentials) were significantly different for the two devices (reported as best-fit parameter and 95% confidence interval). Peak velocity versus amplitude relationships revealed a main sequence asymptote of 1674degree/s (CI: 1527, 1852degree/s) for EyeTribe vs. 506degree/s (CI: 499, 513degree/s) for EyeLink and a time constant of 102.9degree (CI: 93.5,115.7degree) for EyeTribe vs. 6.1degree (CI: 5.3, 6.3degree) for EyeLink. Duration versus amplitude relationships also demonstrated significant differences, with an asymptote of 62.7ms (CI: 61.0, 64.3ms) for EyeTribe vs. 83.2ms (CI: 82.2, 84.4ms) for EyeLink and time constant of 4.9degree (CI: 4.6, 5.3degree) for EyeTribe vs. 13.8degree (CI: 13.6, 14.1degree) for EyeLink. Total number of saccades to complete the K-D was significantly lower with EyeTribe, with an average of 110.2 vs. 120.5 saccades recorded by EyeTribe and EyeLink respectively (paired t-test, p=0.001). There was no significant difference in the inter-saccadic interval, despite a discrepancy of 42ms between devices. Conclusions: The EyeTribe device was unable to capture valid saccade data during rapid number naming. Caution is advised regarding the implementation of eye trackers with low temporal resolution for objective saccade assessment or sideline concussion screening

BACKGROUND: The human monoclonal antibody opicinumab (BIIB033, anti-LINGO-1) has shown remyelinating activity in preclinical studies. We therefore assessed the safety and tolerability, and efficacy of opicinumab given soon after a first acute optic neuritis episode. METHODS: This randomised, double-blind, placebo-controlled, phase 2 study (RENEW) was done at 33 sites in Australia, Canada, and Europe in participants (aged 18-55 years) with a first unilateral acute optic neuritis episode within 28 days from study baseline. After treatment with high-dose methylprednisolone (1 g/day, intravenously, for 3-5 days), participants were assigned with a computer-generated sequence with permuted block randomisation (1:1) using a centralised interactive voice and web response system to receive 100 mg/kg opicinumab intravenously or placebo once every 4 weeks (six doses) and followed up to week 32. All study participants and all study staff, including the central readers, were masked to treatment assignment apart from the pharmacist responsible for preparing the study treatments and the pharmacy monitor at each site. The primary endpoint was remyelination at 24 weeks, measured as recovery of affected optic nerve conduction latency using full-field visual evoked potential (FF-VEP) versus the unaffected fellow eye at baseline. Analysis was by intention-to-treat (ITT); prespecified per-protocol (PP) analyses were also done. This study is registered with ClinicalTrials.gov, number NCT01721161. FINDINGS: The study was done between Dec 21, 2012, and Oct 21, 2014. 82 participants were enrolled, and 41 in each group comprised the ITT population; 33 participants received opicinumab and 36 received placebo in the PP population. Adjusted mean treatment difference of opicinumab versus placebo was -3.5 ms (17.3 vs 20.8 [95% CI -10.6 to 3.7]; 17%; p=0.33) in the ITT population, and -7.6 ms in the PP population (14.7 vs 22.2 [-15.1 to 0.0]; 34%; p=0.050) at week 24 and -6.1 ms (15.1 vs 21.2 [-12.7 to 0.5]; 29%; p=0.071) in the ITT population and -9.1 ms (13.2 vs 22.4 [-16.1 to -2.1]; 41%; p=0.011) in the PP population at week 32. The overall incidence (34 [83%] of 41 in each group) and severity of adverse events (two [5%] of 41 severe adverse events with placebo vs three [7%] of 41 with opicinumab) were similar between groups and no significant effects on brain MRI measures were noted in either group (mean T2 lesion volume change, 0.05 mL [SD 0.21] for placebo vs 0.20 mL [0.52] with opicinumab; 27 [77%] of 35 participants with no change in gadolinium-enhancing [Gd+] lesion number with opicinumab vs 27 [79%] of 34 with placebo; mean 0.4 [SD 0.79 for the placebo group and 0.85 for the opicinumab group] new Gd+ lesions per participant in both groups). Treatment-related serious adverse events were reported in three (7%) of 41 participants in the opicinumab group (hypersensitivity [n=2], asymptomatic increase in transaminase concentrations [n=1]) and none of the participants in the placebo group. INTERPRETATION: Remyelination did not differ significantly between the opicinumab and placebo groups in the ITT population at week 24. However, results from the prespecified PP population suggest that enhancing remyelination in the human CNS with opicinumab might be possible and warrant further clinical investigation. FUNDING: Biogen.

While cerebral amyloid angiopathy is a common cause of lobar hemorrhage, rarely it may be associated with an inflammatory response, thought to be incited by amyloid deposits. We report a 73-year-old woman with an extensive cancer history who presented with tumor-like lesions and symptoms of homonymous hemianopia and prosopagnosia. Found to have cerebral amyloid angiopathy-related inflammation proven by brain biopsy, she was treated successfully with immunosuppression.

OBJECTIVE: To retrospectively investigate whether disease-modifying therapies (DMTs) exert differential effects on rates of retinal atrophy in relapsing-remitting multiple sclerosis (RRMS), as assessed using optical coherence tomography (OCT). METHODS: A total of 402 patients with RRMS followed at the Johns Hopkins MS Center who underwent Cirrus-HD OCT were assessed for eligibility. Inclusion criteria included at least 1 year of OCT follow-up and adherence to a single DMT during the period of follow-up. Combined thickness of the ganglion cell + inner plexiform (GCIP) and other retinal layers was computed utilizing automated macular segmentation. Retinal thickness changes were analyzed using mixed-effects linear regression. RESULTS: The effects of glatiramer acetate (GA; n = 48), natalizumab (NAT; n = 46), and interferon-beta-1a subcutaneously (IFNSC; n = 35) and intramuscularly (IFNIM; n = 28) were assessed. Baseline analyses revealed no significant differences between groups in terms of age, sex, optic neuritis history, or follow-up duration. During follow-up, relative to NAT-treated patients, IFNSC- and GA-treated patients exhibited 0.37 mum/y (p < 0.001) and 0.14 mum/y (p = 0.035) faster rates of GCIP thinning, respectively, adjusting for the interval between initiation of DMT and OCT monitoring (gap time), age, sex, relapses, and disease duration. In the IFNSC group, GCIP thinning was 1.53 mum/y faster during the first year of therapy vs during the time interval afterwards (p < 0.001). CONCLUSIONS: Rates of GCIP atrophy in patients with RRMS vary according to DMT utilization. Our findings support OCT for monitoring neurodegenerative treatment effects in the retina, an easily accessible tissue, and as a practical outcome measure in RRMS clinical trials.