Dopamine-driven Increase in IL-1ß in Myeloid Cells is Mediated by Differential Dopamine Receptor Expression and Exacerbated by HIV.

The catecholamine neurotransmitter dopamine is classically known for regulation of central nervous system (CNS) functions such as reward, movement, and cognition. Increasing evidence also indicates that dopamine regulates critical functions in peripheral organs and is an important immunoregulatory factor. We have previously shown that dopamine increases NF-κB activity, inflammasome activation, and the production of inflammatory cytokines such as IL-1ß in human macrophages. As myeloid lineage cells are central to the initiation and resolution of acute inflammatory responses, dopamine-mediated dysregulation of these functions could both impair the innate immune response and exacerbate chronic inflammation. However, the exact pathways by which dopamine drives myeloid inflammation are not well defined, and studies in both rodent and human systems indicate that dopamine can impact the production of inflammatory mediators through both D1-like dopamine receptors (DRD1, DRD5) and D2-like dopamine receptors (DRD2, DRD3, and DRD4). Therefore, we hypothesized that dopamine-mediated production of IL-1ß in myeloid cells is regulated by the ratio of different dopamine receptors that are activated. Our data in primary human monocyte-derived macrophages (hMDM) indicate that DRD1 expression is necessary for dopamine-mediated increases in IL-1ß, and that changes in the expression of DRD2 and other dopamine receptors can alter the magnitude of the dopamine-mediated increase in IL-1ß. Mature hMDM have a high D1-like to D2-like receptor ratio, which is different relative to monocytes and peripheral blood mononuclear cells (PBMCs). We further confirm in human microglia cell lines that a high ratio of D1-like to D2-like receptors promotes dopamine-induced increases in IL-1ß gene and protein expression using pharmacological inhibition or overexpression of dopamine receptors. RNA-sequencing of dopamine-treated microglia shows that genes encoding functions in IL-1ß signaling pathways, microglia activation, and neurotransmission increased with dopamine treatment. Finally, using HIV as an example of a chronic inflammatory disease that is substantively worsened by comorbid substance use disorders (SUDs) that impact dopaminergic signaling, we show increased effects of dopamine on inflammasome activation and IL-1ß in the presence of HIV in both human macrophages and microglia. These data suggest that use of addictive substances and dopamine-modulating therapeutics could dysregulate the innate inflammatory response and exacerbate chronic neuroimmunological conditions like HIV. Thus, a detailed understanding of dopamine-mediated changes in inflammation, in particular pathways regulating IL-1ß, will be critical to effectively tailor medication regimens.

Equivalent processing of facial expression and identity by macaque visual system and task-optimized neural network.

Both the primate visual system and artificial deep neural network (DNN) models show an extraordinary ability to simultaneously classify facial expression and identity. However, the neural computations underlying the two systems are unclear. Here, we developed a multi-task DNN model that optimally classified both monkey facial expressions and identities. By comparing the fMRI neural representations of the macaque visual cortex with the best-performing DNN model, we found that both systems: (1) share initial stages for processing low-level face features which segregate into separate branches at later stages for processing facial expression and identity respectively, and (2) gain more specificity for the processing of either facial expression or identity as one progresses along each branch towards higher stages. Correspondence analysis between the DNN and monkey visual areas revealed that the amygdala and anterior fundus face patch (AF) matched well with later layers of the DNN's facial expression branch, while the anterior medial face patch (AM) matched well with later layers of the DNN's facial identity branch. Our results highlight the anatomical and functional similarities between macaque visual system and DNN model, suggesting a common mechanism between the two systems.

Paraquat exposure produces sex-dependent reduction in binge-like alcohol drinking in high alcohol-preferring mice.

Parkinson's Disease (PD) and Alcohol Use Disorder (AUD) are disorders that involve similar dopaminergic neurobiological pathways and dysregulations in motivation- and reward-related behaviors. This study explored whether exposure to a PD-related neurotoxicant, paraquat (PQ), alters binge-like alcohol drinking and striatal monoamines in mice selectively bred for high alcohol preference (HAP), and whether these effects are sex-dependent. Previous studies found female mice are less susceptible to PD-related toxicants compared to male mice. Mice were treated with PQ or vehicle over 3 weeks (10 mg/kg, i.p. once per week) and binge-like alcohol [20% (v/v)] drinking was assessed. Mice were euthanized and brains were microdissected for monoamine analyses by high performance liquid chromatography with electrochemical detection (HPLC-ECD). PQ-treated HAP male mice showed significantly decreased binge-like alcohol drinking and ventral striatal 3,4-Dihydroxyphenylacetic acid (DOPAC) levels compared to vehicle-treated HAP mice. These effects were absent in female HAP mice. These findings suggest that male HAP mice may be more susceptible than female mice to PQ's disruptive effects on binge-like alcohol drinking and associated monoamine neurochemistry and may be relevant for understanding neurodegenerative processes implicated in PD and AUD.

Functional characterization of the biogenic amine transporters on human macrophages.

Monocyte-derived macrophages (MDMs) are key players in tissue homeostasis and diseases regulated by a variety of signaling molecules. Recent literature has highlighted the ability for biogenic amines to regulate macrophage functions, but the mechanisms governing biogenic amine signaling in and around immune cells remain nebulous. In the CNS, biogenic amine transporters are regarded as the master regulators of neurotransmitter signaling. While we and others have shown that macrophages express these transporters, relatively little is known of their function in these cells. To address these knowledge gaps, we investigated the function of norepinephrine transporter (NET) and dopamine transporter (DAT) on human MDMs. We found that both NET and DAT are present and can uptake substrate from the extracellular space at baseline. Not only was DAT expressed in cultured MDMs, but it was also detected in a subset of intestinal macrophages in situ. Surprisingly, we discovered a NET-independent, DAT-mediated immunomodulatory mechanism in response to LPS. LPS induced reverse transport of dopamine through DAT, engaging an autocrine/paracrine signaling loop that regulated the macrophage response. Removing this signaling loop enhanced the proinflammatory response to LPS. Our data introduce a potential role for DAT in the regulation of innate immunity.

Protocol for a prospective, international cohort study on the Management and Outcomes of Perioperative Care among European Diabetic Patients (MOPED).

INTRODUCTION: Diabetes is common (about 20 million patients in Europe) and patients with diabetes have more surgical interventions than the general population. There are plausible pathophysiological and clinical mechanisms suggesting that patients with diabetes are at an increased risk of postoperative complications. When postoperative complications occur in the general population, they increase major adverse events and subsequently increase 1-year mortality. This is likely to be worse in patients with diabetes. There is variation in practice guidelines in different countries in the perioperative management of patients with diabetes undergoing major surgery and whether this may affect postoperative outcome has not been investigated on a large scale. Neither is it known whether different strata of preoperative glycaemic control affects outcome. METHODS AND ANALYSIS: A prospective, observational, international, multicentre cohort study, recruiting 5000 patients with diabetes undergoing elective or emergency surgery in at least n=50 centres. Inclusion criteria are any patient with diabetes undergoing surgery under any substantive anaesthetic technique. Exclusion criteria are not being a confirmed diabetic patient and patients with diabetes undergoing procedures under monitored sedation or local anaesthetic infiltration only. Follow-up duration is 30 days after surgery. Primary outcome is days at home at 30 days. Secondary outcomes are Comprehensive Complications Index, Quality of Recovery (QoR-15) score on Day 1 postoperatively, 30-day mortality, length of hospital stay and incidence of specific major adverse events (Myocardial Infarction (MI), Myocardial Injury after Non-cardiac Surgery (MINS), Acute Kidney Injury (AKI), Postoperative Pulmonary Complications (PPC), Cerebrovascular Accident (CVA), Pulmonary Embolism (PE), DVT, surgical site infection, postoperative pulmonary infection). Tertiary outcomes include time to resumption of normal diabetes therapy, incidence of diabetic ketoacidosis or hypoglycaemia, incidence and duration of use of intravenous insulin infusion therapy and change in diabetic management at 30 days. ETHICS AND DISSEMINATION: This study will adhere to the principles of the Declaration of Helsinki (amendment 2013) by the World Medical Association and the ICH-Good Clinical Practice (GCP) Guidelines E6(R2). Specific national and local regulatory authority requirements will be followed as applicable. Ethical approval has been granted by the Institutional Review Board of the Mater Misericordiae University Hospital, Dublin, Ireland (Reference: 1/378/2167). As enrolment for this study is ongoing, ethical approval from additional centres is being added continuously. The main results of Management and Outcomes of Perioperative Care among European Diabetic Patients and its substudies will be published in peer-reviewed international medical journals and presented at Euroanaesthesia congress and other international and national meetings. TRIAL REGISTRATION NUMBER: NCT04511312.

Retinal inner nuclear layer volume reflects inflammatory disease activity in multiple sclerosis; a longitudinal OCT study.

BACKGROUND: The association of peripapillary retinal nerve fibre layer (pRNFL) and ganglion cell-inner plexiform layer (GCIPL) thickness with neurodegeneration in multiple sclerosis (MS) is well established. The relationship of the adjoining inner nuclear layer (INL) with inflammatory disease activity is less well understood. OBJECTIVE: The objective of this paper is to investigate the relationship of INL volume changes with inflammatory disease activity in MS.Methods In this longitudinal, multi-centre study, optical coherence tomography (OCT) and clinical data (disability status, relapses and MS optic neuritis (MSON)) were collected in 785 patients with MS (68.3% female) and 92 healthy controls (63.4% female) from 11 MS centres between 2010 and 2017 and pooled retrospectively. Data on pRNFL, GCIPL and INL were obtained at each centre. RESULTS: There was a significant increase in INL volume in eyes with new MSON during the study (N = 61/1562, ß = 0.01 mm3, p < .001). Clinical relapses (other than MSON) were significantly associated with increased INL volume (ß = 0.005, p = .025). INL volume was independent of disease progression (ß = 0.002 mm3, p = .474). CONCLUSION: Our data demonstrate that an increase in INL volume is associated with MSON and the occurrence of clinical relapses. Therefore, INL volume changes may be useful as an outcome marker for inflammatory disease activity in MSON and MS treatment trials.

The International Multiple Sclerosis Visual System Consortium: Advancing Visual System Research in Multiple Sclerosis.

BACKGROUND: The International Multiple Sclerosis Visual System Consortium (IMSVISUAL) was formed in November 2014 with the primary goal of improving research, care, and education regarding the role of the visual system in multiple sclerosis (MS) and related disorders. METHODS: In this review, we describe the formation, goals, activities, and structure of IMSVISUAL, as well as the relationship of IMSVISUAL with the Americas Committee for Treatment and Research in MS (ACTRIMS). Finally, we provide an overview of the work IMSVISUAL has completed to date, as well as an outline of research projects ongoing under the auspices of IMSVISUAL. RESULTS: IMSVISUAL has 140 members worldwide and continues to grow. Through IMSVISUAL-related research, optical coherence tomography (OCT)-derived peripapillary retinal nerve fiber layer (pRNFL) thinning has been established as a predictor of future disability in MS. IMSVISUAL has also developed guidelines for reporting OCT studies in MS. Moreover, a systematic review performed by IMSVISUAL found that not only are pRNFL and ganglion cell + inner plexiform layer (GCIPL) thicknesses reduced in patients with MS (particularly in eyes with prior optic neuritis [ON]), but that inner nuclear layer measures may be higher among MS ON eyes, relative to healthy control eyes. Currently, there are several ongoing IMSVISUAL projects that will establish a role for visual outcomes in diagnosing MS and quantifying the effects of emerging therapies in clinical trials. CONCLUSIONS: The development of IMSVISUAL represents a major collaborative commitment to defining the role of visual outcomes in high-quality, large-scale studies that generate definitive and instructive findings in the field of MS. As a consortium, IMSVISUAL has completed several international collaborative projects, is actively engaged in numerous ongoing research studies, and is committed to expanding the role of vision research in MS and related disorders.

Mobile Universal Lexicon Evaluation System (MULES) in MS: Evaluation of a new visual test of rapid picture naming.

OBJECTIVE: The Mobile Universal Lexicon Evaluation System (MULES) is a test of rapid picture naming that is under investigation for concussion. MULES captures an extensive visual network, including pathways for eye movements, color perception, memory and object recognition. The purpose of this study was to introduce the MULES to visual assessment of patients with MS, and to examine associations with other tests of afferent and efferent visual function. METHODS: We administered the MULES in addition to binocular measures of low-contrast letter acuity (LCLA), high-contrast visual acuity (VA) and the King-Devick (K-D) test of rapid number naming in an MS cohort and in a group of disease-free controls. RESULTS: Among 24 patients with MS (median age 36 years, range 20-72, 64% female) and 22 disease-free controls (median age 34 years, range 19-59, 57% female), MULES test times were greater (worse) among the patients (60.0 vs. 40.0 s). Accounting for age, MS vs. control status was a predictor of MULES test times (P = .01, logistic regression). Faster testing times were noted among patients with MS who had greater (better) performance on binocular LCLA at 2.5% contrast (P < .001, linear regression, accounting for age), binocular high-contrast VA (P < .001), and K-D testing (P < .001). Both groups demonstrated approximately 10-s improvements in MULES test times between trials 1 and 2 (P < .0001, paired t-tests). CONCLUSION: The MULES test, a complex task of rapid picture naming involves an extensive visual network that captures eye movements, color perception and the characterization of objects. Color recognition, a key component of this novel assessment, is early in object processing and requires area V4 and the inferior temporal projections. MULES scores reflect performance of LCLA, a widely-used measure of visual function in MS clinical trials. These results provide evidence that the MULES test can add efficient visual screening to the assessment of patients with MS.

Evolution of Visual Outcomes in Clinical Trials for Multiple Sclerosis Disease-Modifying Therapies.

: BACKGROUND:: The visual pathways are increasingly recognized as an ideal model to study neurodegeneration in multiple sclerosis (MS). Low-contrast letter acuity (LCLA) and optical coherence tomography (OCT) are validated measures of function and structure in MS. In fact, LCLA was the topic of a recent review by the Multiple Sclerosis Outcome Assessments Consortium (MSOAC) to qualify this visual measure as a primary or secondary clinical trial endpoint with the Food and Drug Administration (FDA) and other regulatory agencies. This review focuses on the use of LCLA and OCT measures as outcomes in clinical trials to date of MS disease-modifying therapies. METHODS: A Pubmed search using the specific key words "optical coherence tomography," "low-contrast letter acuity," "multiple sclerosis," and "clinical trials" was performed. An additional search on the clinicaltrials.gov website with the same key words was used to find registered clinical trials of MS therapies that included these visual outcome measures. RESULTS: As demonstrated by multiple clinical trials, LCLA and OCT measures are sensitive to treatment effects in MS. LCLA has been used in many clinical trials to date, and findings suggest that 7 letters of LCLA at the 2.5% contrast level are meaningful change. Few clinical trials using the benefits of OCT have been performed, although results of observational studies have solidified the ability of OCT to assess change in retinal structure. Continued accrual of clinical trial and observational data is needed to validate the use of OCT in clinical trials, but preliminary work suggests that an intereye difference in retinal nerve fiber layer thickness of 5-6 µm is a clinically meaningful threshold that identifies an optic nerve lesion in MS. CONCLUSIONS: Visual impairment represents a significant component of overall disability in MS. LCLA and OCT enhance the detection of visual pathway injury and can be used as measures of axonal and neuronal integrity. Continued investigation is ongoing to further incorporate these vision-based assessments into clinical trials of MS therapies.

Multicenter reliability of semiautomatic retinal layer segmentation using OCT.

OBJECTIVE: To evaluate the inter-rater reliability of semiautomated segmentation of spectral domain optical coherence tomography (OCT) macular volume scans. METHODS: Macular OCT volume scans of left eyes from 17 subjects (8 patients with MS and 9 healthy controls) were automatically segmented by Heidelberg Eye Explorer (v1.9.3.0) beta-software (Spectralis Viewing Module v6.0.0.7), followed by manual correction by 5 experienced operators from 5 different academic centers. The mean thicknesses within a 6-mm area around the fovea were computed for the retinal nerve fiber layer, ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer, outer plexiform layer (OPL), and outer nuclear layer (ONL). Intraclass correlation coefficients (ICCs) were calculated for mean layer thickness values. Spatial distribution of ICC values for the segmented volume scans was investigated using heat maps. RESULTS: Agreement between raters was good (ICC > 0.84) for all retinal layers, particularly inner retinal layers showed excellent agreement across raters (ICC > 0.96). Spatial distribution of ICC showed highest values in the perimacular area, whereas the ICCs were poorer for the foveola and the more peripheral macular area. The automated segmentation of the OPL and ONL required the most correction and showed the least agreement, whereas differences were less prominent for the remaining layers. CONCLUSIONS: Automated segmentation with manual correction of macular OCT scans is highly reliable when performed by experienced raters and can thus be applied in multicenter settings. Reliability can be improved by restricting analysis to the perimacular area and compound segmentation of GCL and IPL.

The new Mobile Universal Lexicon Evaluation System (MULES): A test of rapid picture naming for concussion sized for the sidelines.

OBJECTIVE: Measures of rapid automatized naming (RAN) have been used for over 50 years to capture vision-based aspects of cognition. The Mobile Universal Lexicon Evaluation System (MULES) is a test of rapid picture naming under investigation for detection of concussion and other neurological disorders. MULES was designed as a series of 54 grouped color photographs (fruits, random objects, animals) that integrates saccades, color perception and contextual object identification. Recent changes to the MULES test have been made to improve ease of use on the athletic sidelines. Originally an 11 × 17-inch single-sided paper, the test has been reduced to a laminated 8.5 × 11-inch double-sided version. We identified performance changes associated with transition to the new, MULES, now sized for the sidelines, and examined MULES on the sideline for sports-related concussion. METHODS: We administered the new laminated MULES to a group of adult office volunteers as well as youth and collegiate athletes during pre-season baseline testing. Athletes with concussion underwent sideline testing after injury. Time scores for the new laminated MULES were compared to those for the larger version (big MULES). RESULTS: Among 501 athletes and office volunteers (age 16 ±â€¯7 years, range 6-59, 29% female), average test times at baseline were 44.4 ±â€¯14.4 s for the new laminated MULES (n = 196) and 46.5 ±â€¯16.3 s for big MULES (n = 248). Both versions were completed by 57 participants, with excellent agreement (p < 0.001, linear regression, accounting for age). Age was a predictor of test times for both MULES versions, with longer times noted for younger participants (p < 0.001). Among 6 athletes with concussion thus far during the fall sports season (median age 15 years, range 11-21) all showed worsening of MULES scores from pre-season baseline (median 4.0 s, range 2.1-16.4). CONCLUSION: The MULES test has been converted to an 11 × 8.5-inch laminated version, with excellent agreement between versions across age groups. Feasibly administered at pre-season and in an office setting, the MULES test shows preliminary evidence of capacity to identify athletes with sports-related concussion.

Optimal Intereye Difference Thresholds in Retinal Nerve Fiber Layer Thickness for Predicting a Unilateral Optic Nerve Lesion in Multiple Sclerosis.

BACKGROUND: The optic nerve is a frequent site for involvement in multiple sclerosis (MS). Optical coherence tomography (OCT) detects thinning of the retinal nerve fiber layer (RNFL) in eyes of patients with MS and in those meeting criteria for clinically or radiologically isolated demyelinating syndromes. Current international diagnostic criteria for MS do not include the optic nerve as an imaging lesion site despite the high prevalence of acute optic neuritis (ON), or occult optic neuropathy, among early MS and clinically isolated syndrome patients; as well as most MS patients over the course of the disease. We sought to determine optimal thresholds for intereye difference in peripapillary RNFL thickness that are most predictive of a unilateral optic nerve lesion. METHODS: We analyzed spectral domain OCT data of 31 healthy volunteers and 124 patients with MS at a single center as part of an ongoing collaborative investigation of visual outcomes. Intereye differences in peripapillary (360°) RNFL thickness were calculated as the absolute value of the difference. First, we determined the 95th percentile value of intereye difference for the healthy volunteers. This value was applied to the convenience sample group of MS patients as a validation cohort determining how well this threshold could distinguish patients with vs without a history of unilateral ON. The relation of intereye differences in peripapillary RNFL thickness to binocular low-contrast letter acuity scores was also examined. RESULTS: Among healthy volunteer participants (n = 31), the 95th percentile value for intereye difference (upper boundary of expected for normal controls) was 6.0 µm. This value was applied to the convenience sample group of MS patients (n = 124, validation cohort). Positive predictive value, negative predictive value, sensitivity, and specificity for identifying MS patients with a history of unilateral ON were calculated for the 6-µm threshold value in a 2 × 2 table analysis with the application of χ tests (P < 0.0001). The 6-µm threshold was predictive of worse binocular low-contrast acuity scores at 2.5% (P = 0.03) and 1.25% (P = 0.002 by linear regression analyses). A receiver operating characteristic curve analysis demonstrated an optimal intereye difference threshold of 5 µm for identifying unilateral ON in the MS cohort. CONCLUSIONS: An intereye difference of 5-6 µm in RNFL thickness is a robust structural threshold for identifying the presence of a unilateral optic nerve lesion in MS.

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.

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.

Capturing saccades in multiple sclerosis with a digitized test of rapid number naming.

The King-Devick (K-D) test of rapid number naming is a visual performance measure that captures saccadic eye movements. Patients with multiple sclerosis (MS) have slowed K-D test times associated with neurologic disability and reduced quality of life. We assessed eye movements during the K-D test to identify characteristics associated with slowed times. Participants performed a computerized K-D test with video-oculography. The 25-Item National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25) and its 10-Item Neuro-Ophthalmic Supplement measured vision-specific quality of life (VSQOL). Among 25 participants with MS (age 37 ± 10 years, range 20-59) and 42 controls (age 33 ± 9 years, range 19-54), MS was associated with significantly longer (worse) K-D times (58.2 ± 19.8 vs. 43.8 ± 8.6 s, P = 0.001, linear regression models, accounting for age). In MS, test times were slower among patients with higher (worse) Expanded Disability Status Scale scores (P = 0.01). Average inter-saccadic intervals (ISI) were significantly longer in MS participants compared to controls (362 ± 103 vs. 286 ± 50 ms, P = 0.001), and were highly associated with prolonged K-D times in MS (P = 0.006). MS participants generated greater numbers of saccades (P = 0.007). VSQOL scores were reduced in MS patients with longer (worse) K-D times (P = 0.04-0.001) and longer ISI (P = 0.002-0.001). Patients with MS have slowed K-D times that may be attributable to prolonged ISI and greater numbers of saccades. The K-D test and its requisite eye movements capture VSQOL and make rapid number naming a strong candidate efferent visual performance measure in MS.

Monitoring the Course of MS With Optical Coherence Tomography.

OPINION STATEMENT: Retinae of patients with multiple sclerosis (MS), as part of the central nervous system (CNS), display inflammatory and neurodegenerative changes. There is increasing evidence suggesting that retinal changes, and in particular neurodegeneration, mirror global CNS alterations in MS. Spectral domain optical coherence tomography (SD-OCT) is an inexpensive, rapid, non-invasive, and reproducible imaging technique that generates high-resolution images of tissues such as the retina. An advantage of SD-OCT over magnetic resonance imaging techniques in the assessment of neurodegeneration may be its sensitivity to capture changes at the individual patient level. Several studies demonstrate that changes within the inner retina (primarily as a reflection of optic neuropathy), as assessed by OCT, correlate with reduced quality of life, visual dysfunction, and global disability in MS. Moreover, longitudinal studies suggest that inner retinal thinning is an early phenomenon in MS and that retinal thinning may occur independent of previous symptomatic episodes of optic neuritis, significantly correlating with inflammatory disease. Preliminary studies suggest that MS disease-modifying therapies may have differential effects on OCT-determined rates of retinal atrophy, supporting a potential utility for OCT to investigate the neuroprotective benefits of disease-modifying therapies in MS, as well as an outcome in trials of putatively neuroprotective strategies.

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.

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.

20/40 or Better Visual Acuity After Optic Neuritis: Not as Good as We Once Thought?

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.