Faculty Bibliography

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

The King-Devick (K-D) test is a 1 to 2 minute, rapid number naming test, often used to assist with detection of concussion, but also has clinical utility in other neurological conditions (eg, Parkinson disease). The K-D involves saccadic eye and other eye movements, and abnormalities thereof may be an early indicator of Alzheimer disease (AD)-associated cognitive impairment. No study has tested the utility of the K-D in AD and we sought to do so. The sample included 206 [135 controls, 39 mild cognitive impairment (MCI), and 32 AD dementia] consecutive subjects from the Boston University Alzheimer's Disease Center registry undergoing their initial annual evaluation between March 2013 and July 2015. The K-D was administered during this period. Areas under the receiver operating characteristic curves generated from logistic regression models revealed the K-D test distinguished controls from subjects with cognitive impairment (MCI and AD dementia) [area under the curve (AUC)=0.72], MCI (AUC=0.71) and AD dementia (AUC=0.74). K-D time scores between 48 and 52 seconds were associated with high sensitivity (>90.0%) and negative predictive values (>85.0%) for each diagnostic group. The K-D correlated strongly with validated attention, processing speed, and visual scanning tests. The K-D test may be a rapid and simple effective screening tool to detect cognitive impairment associated with AD.

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

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.

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.

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.

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.