Faculty Bibliography

Mild head injury such as concussions and subconcussive repetitive impact may lead to subtle changes in brain function and it is imperative to find sensitive and reliable tests to detect such changes. Tests involving the visual system, in particular eye movements, can incorporate higher cortical functioning and involve diffuse pathways in the brain, including many areas susceptible to head impact. With concussions, the clinical neuro-ophthalmic exam is important for detecting abnormalities in vergence, saccades, pursuit, and visual fixation. On the sidelines, the King-Devick test has been used as a visual performance measure that incorporates eye movements and increases the sensitivity in detecting possible concussions in conjunction with standard sideline tests of cognition, symptom checklists, and balance. Much promise lies in the eye movement laboratory to quantitate changes in saccades and pursuit with concussions using video-oculography. A combination of eye movement tasks coupled with neuroimaging techniques and other objective biomarkers may lead to a better understanding of the anatomical and physiological consequences of concussion and to better understand the natural history of this condition.

We report four patients with monocular visual loss for whom optical coherence tomography (OCT) was helpful in distinguishing the sequelae of retinal artery occlusion from those of primary optic neuropathy. Determinations of the peripapillary retinal nerve fiber layer (RNFL) thickness as well as macular retinal layer thicknesses and architecture were used. The major findings in our patients show that changes in the inner retinal layers (including ganglion cell and inner plexiform layer) with disruption of normal macular architecture supports a diagnosis of retinal artery occlusion. Our results support the use of OCT imaging for patients with monocular visual loss of uncertain etiology; macular imaging as well as peripapillary RNFL thickness measurement can be helpful in differentiating primary retinal disease or ischemia from primary disorders of the optic nerve.

Regional gray matter (GM) atrophy in multiple sclerosis (MS) at disease onset and its temporal variation can provide objective information regarding disease evolution. An automated pipeline for estimating atrophy of various GM structures was developed using tensor based morphometry (TBM) and implemented on a multi-center sub-cohort of 1008 relapsing remitting MS (RRMS) patients enrolled in a Phase 3 clinical trial. Four hundred age and gender matched healthy controls were used for comparison. Using the analysis of covariance, atrophy differences between MS patients and healthy controls were assessed on a voxel-by-voxel analysis. Regional GM atrophy was observed in a number of deep GM structures that included thalamus, caudate nucleus, putamen, and cortical GM regions. General linear regression analysis was performed to analyze the effects of age, gender, and scanner field strength, and imaging sequence on the regional atrophy. Correlations between regional GM volumes and expanded disability status scale (EDSS) scores, disease duration (DD), T2 lesion load (T2 LL), T1 lesion load (T1 LL), and normalized cerebrospinal fluid (nCSF) were analyzed using Pearson׳s correlation coefficient. Thalamic atrophy observed in MS patients compared to healthy controls remained consistent within subgroups based on gender and scanner field strength. Weak correlations between thalamic volume and EDSS (r=-0.133; p<0.001) and DD (r=-0.098; p=0.003) were observed. Of all the structures, thalamic volume moderately correlated with T2 LL (r=-0.492; P-value<0.001), T1 LL (r=-0.473; P-value<0.001) and nCSF (r=-0.367; P-value<0.001).

A comprehensive analysis of the effect of lesion in-painting on the estimation of cortical thickness using magnetic resonance imaging was performed on a large cohort of 918 relapsing-remitting multiple sclerosis patients who participated in a phase III multicenter clinical trial. An automatic lesion in-painting algorithm was developed and implemented. Cortical thickness was measured using the FreeSurfer pipeline with and without in-painting. The effect of in-painting was evaluated using FreeSurfer's paired analysis pipeline. Multivariate regression analysis was also performed with field strength and lesion load as additional factors. Overall, the estimated cortical thickness was different with in-painting than without. The effect of in-painting was observed to be region dependent, more significant in the left hemisphere compared to the right, was more prominent at 1.5 T relative to 3 T, and was greater at higher lesion volumes. Our results show that even for data acquired at 1.5 T in patients with high lesion load, the mean cortical thickness difference with and without in-painting is ∼2%. Based on these results, it appears that in-painting has only a small effect on the estimated regional and global cortical thickness. Hum Brain Mapp 36:3749-3760, 2015. © 2015 Wiley Periodicals, Inc.

We examined the King-Devick (K-D) test, a vision-based test of rapid number naming, as a complement to components of the Sport Concussion Assessment Tool, 3rd edition (SCAT3) for diagnosis of concussion. Baseline and postconcussion data for the University of Florida men's football, women's soccer, and women's lacrosse teams were collected, including the K-D test, Standardized Assessment of Concussion (SAC), and Balance Error Scoring System (BESS). Among 30 athletes with first concussion during their athletic season (n = 217 total), differences from baseline to postinjury showed worsening of K-D time scores in 79%, while SAC showed a ≥2-point worsening in 52%. Combining K-D and SAC captured abnormalities in 89%; adding the BESS identified 100% of concussions. Adding a vision-based test may enhance the detection of athletes with concussion.

Background: Anti-LINGO-1 is a monoclonal antibody antagonist of LINGO-1, an oligodendrocyte differentiation and myelination suppressor. Objective: To determine the efficacy/safety of anti-LINGO-1 for CNS remyelination. Methods: Subjects with a first unilateral acute optic neuritis episode were treated with high-dose steroids and randomized to 100mg/kg anti-LINGO-1 IV or placebo every 4 weeks (NCT01721161). Subject and IRB approval were obtained. Nerve conduction latency recovery using full-field visual evoked potential (FF-VEP) in the affected eye over time versus unaffected eye at baseline assessed remyelination (pre-specified primary endpoint). Between-treatment comparisons were evaluated by ANCOVA and mixed-effect model repeated measure (MMRM) in subjects who completed the study and did not miss >1 study dose or receive MS modifying therapy (prespecified per-protocol population). Safety/tolerability was evaluated in those who received >1 study dose and included adverse event (AE) and clinical laboratory result assessments. Results: Anti-LINGO-1-treated subjects (n =33) showed improved latency recovery versus placebo (n=36): mean (95% confidence interval) -7.55ms (-15.12 to 0.01) at Week 24 (P=0.05); -9.13ms (-16.11 to -2.14; P=0.01) at Week 32. 54% of anti-LINGO-1 subjects had no/mild latency delay at Week 24 (affected eye FF-VEP latency <10% worse than baseline fellow eye) versus 27% of the placebo group (P=0.036). Additional subgroup analyses will be presented. 34/41 in each group experienced any AE, serious AEs occurred in 2 placebo and 5 anti-LINGO-1 subjects, and there were 3 treatment-related serious AEs. Conclusions: Improvement in FF-VEP latency is consistent with the first evidence of remyelination in a Phase 2 trial. Anti-LINGO-1 was generally well tolerated

Concussion may lead to subtle changes in brain function, and tests involving the visual system probe higher cortical functioning and increase our sensitivity in detecting these changes. Concussions are acutely and sometimes more persistently associated with abnormalities in balance, cognition, and vision. The visual system involves roughly half of the brain's circuits, including many regions susceptible to head impacts. After a concussion, the neuro-ophthalmologic exam commonly detects abnormalities in convergence, accommodation, the vestibulo-ocular reflex, ocular muscle balance, saccades, and pursuit. The King-Devick (K-D) test is a visual performance measure that may increase the sensitivity of detecting concussions on the sideline when used in combination with tests of cognition and balance that are part of the Sports Concussion Assessment Tool (3rd ed.; SCAT3). Portable eye movement trackers and pupillometry may in the future improve our neuro-ophthalmic assessment after concussions. Combining visual tasks with neuroimaging and neurophysiology has allowed subtle changes to be detected, may refine our ability to make appropriate return-to-play decisions, and could potentially determine susceptibility to long-term sequelae of concussion.

Optical coherence tomography (OCT) is a relatively new technology that is now routinely and very widely used by ophthalmologists for structural documentation of the optic nerve and retina. In neuro-ophthalmology and neurology, the value of OCT is ever expanding; its role in an increasing number of conditions is being reported in parallel with the advances of the technology. Currently, as a clinical tool, OCT is particularly useful for the structural measurement of peripapillary retinal nerve fiber layer thickness, optic nerve head volumetric analysis, and macular anatomy. Optic neuropathies of varied etiology (particularly from multiple sclerosis) may be the most common clinical indications for neurologists to obtain OCT imaging. Documentation and follow-up of disc edema of varied etiology (papilledema and idiopathic intracranial hypertension), discriminating true disc swelling from pseudopapilledema, and differentiating optic neuropathy from maculopathy are some other examples from clinical practice.