Jenelle Raynowska

Validity of low-contrast letter acuity as a visual performance outcome measure for multiple sclerosis:

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.

Role of Metal-Dependent Regulation of ESX-3 Secretion in Intracellular Survival of Mycobacterium tuberculosis

ABSTRACT More people die every year from Mycobacterium tuberculosis infection than from infection by any other bacterial pathogen. Type VII secretion systems (T7SS) are used by both environmental and pathogenic mycobacteria to secrete proteins across their complex cell envelope. In the nonpathogen Mycobacterium smegmatis, the ESX-1 T7SS plays a role in conjugation, and the ESX-3 T7SS is involved in metal homeostasis. In M. tuberculosis, these secretion systems have taken on roles in virulence, and they also are targets of the host immune response. ESX-3 secretes a heterodimer composed of EsxG (TB9.8) and EsxH (TB10.4), which impairs phagosome maturation in macrophages and is essential for virulence in mice. Given the importance of EsxG and EsxH during infection, we examined their regulation. With M. tuberculosis, the secretion of EsxG and EsxH was regulated in response to iron and zinc, in accordance with the previously described transcriptional response of the esx-3 locus to these metals. While iron regulated the esx-3 expression in both M. tuberculosis and M. smegmatis, there is a significant difference in the dynamics of this regulation. In M. smegmatis, the esx-3 locus behaved like other iron-regulated genes such as mbtB. In M. tuberculosis, both iron and zinc modestly repressed esx-3 expression. Diminished secretion of EsxG and EsxH in response to these metals altered the interaction of M. tuberculosis with macrophages, leading to impaired intracellular M. tuberculosis survival. Our findings detail the regulatory differences of esx-3 in M. tuberculosis and M. smegmatis and demonstrate the importance of metal-dependent regulation of ESX-3 for virulence in M. tuberculosis.

Mobile Universal Lexicon Evaluation System (MULES) test: A new measure of rapid picture naming for concussion

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.

Validity of low-resolution eye-tracking to assess eye movements during a rapid number naming task: performance of the eyetribe eye tracker

ABSTRACT Objective: To evaluate the performance of the EyeTribe compared to the EyeLink for eye movement recordings during a rapid number naming test in healthy control participants. Background: With the increasing accessibility of portable, economical, video-based eye trackers such as the EyeTribe, there is growing interest in these devices for eye movement recordings, particularly in the domain of sports-related concussion. However, prior to implementation there is a primary need to establish the validity of these devices. One current limitation of portable eye trackers is their sampling rate (30–60 samples per second, or Hz), which is typically well below the benchmarks achieved by their research-grade counterparts (e.g., the EyeLink, which samples at 500–2000 Hz). Methods: We compared video-oculographic measurements made using the EyeTribe with those of the EyeLink during a digitized rapid number naming task (the King-Devick test) in a convenience sample of 30 controls. Results: EyeTribe had loss of signal during recording, and failed to reproduce the typical shape of saccadic main sequence relationships. In addition, EyeTribe data yielded significantly fewer detectable saccades and displayed greater variance of inter-saccadic intervals than the EyeLink system. Conclusion: Caution is advised prior to implementation of low-resolution eye trackers for objective saccade assessment and sideline concussion screening.

Rapid sideline performance meets outpatient clinic: Results from a multidisciplinary concussion center registry

OBJECTIVE This study investigated the utility of sideline concussion tests, including components of the Sports Concussion Assessment Tool, 3rd Edition (SCAT3) and the King-Devick (K-D), a vision-based test of rapid number naming, in an outpatient, multidisciplinary concussion center treating patients with both sports-related and non-sports related concussions. The ability of these tests to predict clinical outcomes based on the scores at the initial visit was evaluated. METHODS Scores for components of the SCAT3 and the K-D were fit into regression models accounting for age, gender, and sport/non-sport etiology in order to predict clinical outcome measures including total number of visits to the concussion center, whether the patient reached a SCAT3 symptom severity score≤7, and the total types of referrals each patient received over their course. Patient characteristics, differences between those with sport and non-sport etiologies, and correlations between the tests were also analyzed. RESULTS Among 426 patients with concussion, SCAT3 total symptom score and symptom severity score at the initial visit predicted each of the clinical outcome variables. K-D score at the initial visit predicted the total number of visits and the total number of referrals. Those with sports-related concussions were younger, had less severely-affected test scores, had fewer visits and types of referrals, and were more likely to have clinical resolution of their concussion and to reach a symptom severity score≤7. CONCLUSIONS This large-scale study of concussion patients supports the use of sideline concussion tests as part of outpatient concussion assessment, especially the total symptom and symptom severity score portions of the SCAT3 and the K-D. Women in this cohort had higher total symptom and symptom severity scores compared to men. Our data also suggest that those with non-sports-related concussions have longer lasting symptoms than those with sports-related concussions, and that these two groups should perhaps be regarded separately when assessing outcomes and needs in a multidisciplinary setting.

Rapid Number Naming and Quantitative Eye Movements May Reflect Contact Sport Exposure in a Collegiate Ice Hockey Cohort

Background: The King-Devick (K-D) test of rapid number naming is a reliable visual performance measure that is a sensitive sideline indicator of concussion when time scores worsen (lengthen) from preseason baseline. Within cohorts of youth athletes <18 years old, baseline K-D times become faster with increasing age. We determined the relation of rapid number-naming time scores on the K-D test to electronic measurements of saccade performance during preseason baseline assessments in a collegiate ice hockey team cohort. Within this group of young adult athletes, we also sought to examine the potential role for player age in determining baseline scores. Methods: Athletes from a collegiate ice hockey team received preseason baseline testing as part of an ongoing study of rapid rink-side performance measures for concussion. These included the K-D test (spiral-bound cards and tablet computer versions). Participants also performed a laboratory-based version of the K-D test with simultaneous infrared-based video-oculographic recordings using an EyeLink 1000+. This allowed measurement of the temporal and spatial characteristics of eye movements, including saccadic velocity, duration, and intersaccadic interval (ISI). Results: Among 13 male athletes, aged 18–23 years (mean 20.5 ± 1.6 years), prolongation of the ISI (a combined measure of saccade latency and fixation duration) was the measure most associated with slower baseline time scores for the EyeLink-paired K-D (mean 38.2 ± 6.2 seconds, r = 0.88 [95% CI 0.63–0.96], P = 0.0001), the K-D spiral-bound cards (36.6 ± 5.9 seconds, r = 0.60 [95% CI 0.08–0.87], P = 0.03), and K-D computerized tablet version (39.1 ± 5.4 seconds, r = 0.79 [95% CI 0.42–0.93], P = 0.001). In this cohort, older age was a predictor of longer (worse) K-D baseline time performance (age vs EyeLink-paired K-D: r = 0.70 [95% CI 0.24–0.90], P = 0.008; age vs K-D spiral-bound cards: r = 0.57 [95% CI 0.03–0.85], P = 0.04; age vs K-D tablet version: r = 0.59 [95% CI 0.06–0.86], P = 0.03) as well as prolonged ISI (r = 0.62 [95% CI 0.11–0.87], P = 0.02). Slower baseline K-D times were not associated with greater numbers of reported prior concussions. Conclusions: Rapid number-naming performance using the K-D at preseason baseline in this small cohort of collegiate ice hockey players is best correlated with ISI among eye movement-recording measures. Baseline K-D scores notably worsened with increasing age, but not with numbers of prior concussions in this small cohort. While these findings require further investigation by larger studies of contact and noncontact sports athletes, they suggest that duration of contact sports exposure may influence preseason test performance.