Faculty Bibliography

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: 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

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: This study introduces a rapid picture naming test, the Mobile Universal Lexicon Evaluation System (MULES), as a novel, vision-based performance measure for concussion screening. The MULES is a visual-verbal task that includes 54 original photographs of fruits, objects and animals. We piloted MULES in a cohort of volunteers to determine feasibility, ranges of picture naming responses, and the relation of MULES time scores to those of King-Devick (K-D), a rapid number naming test. METHODS: A convenience sample (n=20, age 34+/-10) underwent MULES and K-D (spiral bound, iPad versions). Administration order was randomized; MULES tests were audio-recorded to provide objective data on temporal variability and ranges of picture naming responses. RESULTS: Scores for the best of two trials for all tests were 40-50s; average times required to name each MULES picture (0.72+/-0.14s) was greater than those needed for each K-D number ((spiral: 0.33+/-0.05s, iPad: 0.36+/-0.06s, 120 numbers), p<0.0001, paired t-test). MULES scores showed the greatest degree of improvement between trials (9.4+/-4.8s, p<0.0001 for trials 1 vs. 2), compared to K-D (spiral 1.5+/-3.3s, iPad 1.8+/-3.4s). Shorter MULES times demonstrated moderate and significant correlations with shorter iPad but not spiral K-D times (r=0.49, p=0.03). CONCLUSION: The MULES test is a rapid picture naming task that may engage more extensive neural systems than more commonly used rapid number naming tasks. Rapid picture naming may require additional processing devoted to color perception, object identification, and categorization. Both tests rely on initiation and sequencing of saccadic eye movements.

BACKGROUND: Although patients with acute optic neuritis (ON) recover high-contrast visual acuity (HCVA) to 20/40 or better in 95% of affected eyes, patients with a history of ON continue to note subjective abnormalities of vision. Furthermore, substantial and permanent thinning of the retinal nerve fiber layer (RNFL) and the ganglion cell layer (GCL) is now known to occur early in the course of ON. We measured vision-specific quality of life (QOL) in patients with a history of acute ON and recovery of VA to 20/40 or better in their affected eyes to determine how these QOL scores relate to RNFL and GCL thickness and low-contrast letter acuity (LCLA) across the spectrum of visual recovery. METHODS: Data from an ongoing collaborative study of visual outcomes in multiple sclerosis and ON were analyzed for this cross-sectional observational cohort. Patients and disease-free control participants completed the 25-Item National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25) and 10-Item Neuro-Ophthalmic Supplement to the NEI-VFQ-25, as well as VA and LCLA testing for each eye separately and binocularly. Optical coherence tomography measures for each eye included peripapillary RNFL thickness and macular GCL + inner plexiform layer (GCL + IPL) thickness. RESULTS: Patients with a history of acute ON and recovery to 20/40 or better VA (n = 113) had significantly reduced scores for the NEI-VFQ-25 (83.7 +/- 15.4) and 10-Item Neuro-Ophthalmic Supplement (74.6 +/- 17.4) compared with disease-free controls (98.2 +/- 2.1 and 96.4 +/- 5.2, P < 0.001, linear regression models, accounting for age and within-patient, intereye correlations). Most patients with 20/40 or better visual recovery (98/112, 88%) had monocular HCVA in their affected eye of 20/20 or better. Although patients with 20/50 or worse HCVA recovery demonstrated the worst performance on low-contrast acuity, affected eye RNFL and GCL + IPL thickness, and QOL scales, these measures were also significantly reduced among those with 20/40 or better HCVA recovery compared with controls. CONCLUSIONS: Patients with a history of ON and "good" visual recovery, defined in the literature as 20/40 or better HCVA, are left with clinically meaningful reductions in vision-specific QOL. Such patient-observed deficits reflect the underlying significant degrees of retinal axonal and neuronal loss and visual dysfunction that are now known to characterize ON even in the setting of maximal HCVA recovery. There remains an unmet therapeutic need for patients with ON.

OBJECTIVE: The King-Devick (KD) test, which is based on rapid number naming speed, is a performance measure that adds vision and eye movement assessments to sideline concussion testing. We performed a laboratory-based study to characterize ocular motor behavior during the KD test in a patient cohort with chronic concussion to identify features associated with prolonged KD reading times. METHODS: Twenty-five patients with a concussion history (mean age: 31) were compared to control participants with no concussion history (n = 42, mean age: 32). Participants performed a computerized KD test under infrared-based video-oculography. RESULTS: Average intersaccadic intervals for task-specific saccades were significantly longer among concussed patients compared to controls (324.4 +/- 85.6 msec vs. 286.1 +/- 49.7 msec, P = 0.027). Digitized KD reading times were prolonged in concussed participants versus controls (53.43 +/- 14.04 sec vs. 43.80 +/- 8.55 sec, P = 0.004) and were highly correlated with intersaccadic intervals. Concussion was also associated with a greater number of saccades during number reading and larger average deviations of saccade endpoint distances from the centers of the to-be-read numbers (1.22 +/- 0.29 degrees vs. 0.98 +/- 0.27 degrees , P = 0.002). There were no differences in saccade peak velocity, duration, or amplitude. INTERPRETATION: Prolonged intersaccadic intervals, greater numbers of saccades, and larger deviations of saccade endpoints underlie prolonged KD reading times in chronic concussion. The KD test relies upon a diffuse neurocognitive network that mediates the fine control of efferent visual function. One sequela of chronic concussion may be disruption of this system, which may produce deficits in spatial target selection and planning of eye movements.