Faculty Bibliography

PURPOSE/OBJECTIVE:Optical coherence tomography (OCT) is a reliable method used to quantify discrete layers of the retina. Spectralis OCT is a device used for this purpose. Spectralis OCT macular scan imaging acquisition can be obtained on either the horizontal or vertical plane. The vertical protocol has been proposed as favorable, due to postulated reduction in confound of Henle's fibers on segmentation-derived metrics. Yet, agreement of the segmentation measures of horizontal and vertical macular scans remains unexplored. Our aim was to determine this agreement. MATERIALS AND METHODS/METHODS:Horizontal and vertical macular scans on Spectralis OCT were acquired in 20 healthy controls (HCs) and 20 multiple sclerosis (MS) patients. All scans were segmented using Heidelberg software and a Johns Hopkins University (JHU)-developed method. Agreement was analyzed using Bland-Altman analyses and intra-class correlation coefficients (ICCs). RESULTS:Using both segmentation techniques, mean differences (agreement at the cohort level) in the thicknesses of all macular layers derived from both acquisition protocols in MS patients and HCs were narrow (<1 µm), while the limits of agreement (LOA) (agreement at the individual level) were wider. Using JHU segmentation mean differences (and LOA) for the macular retinal nerve fiber layer (RNFL) and ganglion cell layer + inner plexiform layer (GCIP) in MS were 0.21 µm (-1.57-1.99 µm) and -0.36 µm (-1.44-1.37 µm), respectively. CONCLUSIONS:OCT segmentation measures of discrete retinal-layer thicknesses derived from both vertical and horizontal protocols on Spectralis OCT agree excellently at the cohort level (narrow mean differences), but only moderately at the individual level (wide LOA). This suggests patients scanned using either protocol should continue to be scanned with the same protocol. However, due to excellent agreement at the cohort level, measures derived from both acquisitions can be pooled for outcome purposes in clinical trials.

BACKGROUND: The Multiple Sclerosis Outcome Assessments Consortium (MSOAC) was formed by the National MS Society to develop improved measures of multiple sclerosis (MS)-related disability. OBJECTIVES: (1) To assess the current literature and available data on functional performance outcome measures (PerfOs) and (2) to determine suitability of using PerfOs to quantify MS disability in MS clinical trials. METHODS: (1) Identify disability dimensions common in MS; (2) conduct a comprehensive literature review of measures for those dimensions; (3) develop an MS Clinical Data Interchange Standards Consortium (CDISC) data standard; (4) create a database of standardized, pooled clinical trial data; (5) analyze the pooled data to assess psychometric properties of candidate measures; and (6) work with regulatory agencies to use the measures as primary or secondary outcomes in MS clinical trials. CONCLUSION: Considerable data exist supporting measures of the functional domains ambulation, manual dexterity, vision, and cognition. A CDISC standard for MS ( http://www.cdisc.org/therapeutic#MS ) was published, allowing pooling of clinical trial data. MSOAC member organizations contributed clinical data from 16 trials, including 14,370 subjects. Data from placebo-arm subjects are available to qualified researchers. This integrated, standardized dataset is being analyzed to support qualification of disability endpoints by regulatory agencies.

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.

Background/UNASSIGNED:Sports concussion has an annual incidence of approximately 3.8 million. Over half go unreported and a substantial number may be asymptomatic. A rapid, cost-effective, and reliable tool that facilitates diagnosis of concussion is needed. The King-Devick (K-D) test is a vision-based tool of rapid number naming for assessment of concussion. In this study, we evaluated the utility of the K-D test in real time for identification of symptomatic concussion in youth athletes and to determine if similar impairment (subclinical concussion) exists in youth athletes without an obvious head injury or symptoms. Methods/UNASSIGNED:Youth hockey players underwent K-D testing preseason, postseason, and immediately after suspected concussion. Additional testing was performed in a subgroup of nonconcussed athletes immediately before and after a game to determine effects of fatigue on K-D scores. Results/UNASSIGNED:< 0.05) and 51 nonconcussed players assessed before and after a game revealed no significant time change as a result of fatigue. Conclusions/UNASSIGNED:Rapid number naming using the K-D test accurately identifies real-time, symptomatic concussion in youth athletes. Scores in concussed players may remain abnormal over time. Athletes should undergo preseason and postseason K-D testing, with additional evaluation real time to inform the assessment of suspected concussion. Classification of Evidence/UNASSIGNED:This study provides Class III evidence that the K-D test accurately identifies real-time concussions in youth athletes.

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 potential relationship of the adjoining inner nuclear layer (INL) with inflammatory disease activity is less well understood. Objective: To investigate the longitudinal relationship of INL volume changes with inflammatory disease activity. Methods: In this longitudinal multi-center study, spectral-domain optical coherence tomography (OCT) and clinical data were collected in 821 patients with MS, from eleven MS centres between 2010 and 2017. All patients had at least two visits (minimum follow- up of 6 months). Clinical data included EDSS score, occurring of relapses, including MS-associated optic neuritis (MSON). At each centre, automated segmentation of OCT scans was performed to obtain data on the pRNFL, GCIPL and INL. Annualized changes were calculated and generalized estimation equations were used to analyze longitudinal changes and associations with clinical measures. Results: In total, 1596 eyes from 798 patients (68.2% female), with a disease duration of 9.4 (+/-8.9) years, were included. Mean follow up duration was 2.3 years (range 0.5 to 5.2 years). Microcystic macular oedema (MMO) was present in 1.3% of eyes (20/1299 eyes). Clinical relapses other than MSON were present in 24.9% of patients, and disease progression was observed in 30.1%. In eyes with an episode of MSON during follow-up (N=61/1584), INL volume showed a significant increase over time (DELTAINL=0.01 mm3, p< 0.001), whereas in eyes without MSON during followup, no significant change in INL was observed (DELTAINL=0.00, p=0.308). Increase in INL volume in MSON eyes was related to a decrease in GCIPL volume (beta=-2.6, p=0.006). In eyes with MMO, the INL volume at the last visit was 0.06 mm3 higher compared to eyes without (p=0.003). There was no significant association between clinical relapses other than MSON, and INL volume changes (DELTAINL=0.00 mm3, p=0.773). Likewise, an in-or decrease in INL volume was independent of change of the EDSS score (OR=1.16, p=0.293, 95% CI 0.88-1.52). Conclusion: Our data demonstrate that an increase of the INL volume is associated with adjacent inflammation of the optic nerve and retina, but not with global physical disability. Therefore INL volume changes may be considered as a secondary outcome measure for anti-inflammatory treatment in MSON trials

Introduction: The optic nerve and visual pathway are frequent sites for involvement in multiple sclerosis (MS). Optical coherence tomography (OCT) detects retinal nerve fiber layer (RNFL) thinning in eyes of patients with MS or in the case of clinically-or radiologically-isolated syndromes. Current diagnostic criteria do not include the optic nerve as an imaging lesion site despite a high prevalence of acute optic neuritis (ON) among early MS and clinically isolated syndrome (CIS) patients. We sought to determine optimal thresholds for inter-eye difference in RNFL thickness that are most predictive of an optic nerve lesion. Methods: Spectral-domain (SD-)OCT data from an ongoing collaborative study of visual outcomes in MS were analyzed for a single site. Median values for inter-eye difference in RNFL thickness were also calculated from the RENEW trial cohort at the 6-month endpoint. RENEW was a randomized, placebo-controlled trial of opicinumab in subjects with a first episode of acute unilateral ON, and represents the most well-characterized cohort of CIS patients with ON incorporating modern tests of visual structure and function. RENEW utilized SD-OCT with a centralized reading center. Results: Among healthy volunteer control participants in the collaborative investigation (convenience sample, n=31), the 95th percentile value for inter-eye difference (upper boundary of expected for normals) was 6.0 microns. This value, as well as median intereye differences from the RENEW cohort (8.5 microns for placebo, n=41; 13.0 microns for opicinumab, n=41), were applied to convenience sample group of MS patients (n=136) as a validation cohort. Positive predictive value, sensitivity and specificity for identifying MS patients with a history of unilateral ON were greatest for the 6-micron value compared to the RENEW medians in a 2x2 table analysis (p< 0.0001, chi-square). The 6-micron threshold was also predictive of worse binocular low-contrast acuity at 2.5% (p=0.02) and 1.25% (p=0.002, linear regression). ROC curve analysis demonstrated an optimal inter-eye difference threshold of 5 microns for identifying unilateral ON in the MS cohort. Conclusion: Inter-eye differences of 5-6 microns in RNFL thickness are thus far optimal for predicting a unilateral optic nerve lesion in MS. Larger international collaborative investigations involving 20 or more MS validation cohort sites are underway to maximize precision and generalizability for these OCT-based thresholds

Background: Retinal imaging by optical coherence tomography (OCT) has gained increasing attention in multiple sclerosis and other neuroinflammatory and neurodegenerative disorders. Ambiguous and incomplete reporting of methodology and OCT-derived data have limited the ability to compare data and to apply and generalize findings in the past. To improve this situation, the Advised Protocol for Optical coherence tomography Study Terminology and Elements (APOSTEL) recommendations have been developed to outline core information to be provided when reporting quantitative OCT studies with help of a 9-point checklist (Cruz-Herranz and Balk et al., Neurology 2016). The APOSTEL recommendations currently have the evidence level of an expert opinion (Class IV). Objective: To advance the APOSTEL recommendations for OCT reporting in a formalized procedure towards evidence-based guidelines. Methods: Studies reporting quantitative OCT results published within the last 24 months have been identified by a Pubmed search. The corresponding authors of these 1472 articles will be contacted and asked to participate in an online survey to evaluate and give feedback on the initial APOSTEL recommendations. The feedback obtained will be anonymized and distributed to a panel of international experts for evaluation and revision of the recommendations. After the initial round the corresponding authors who gave feedback will be informed about the intermediate results and asked to participate in the survey for a second time. This procedure will be repeated if necessary following the consensus-building procedure of a DELPHI process. To this end, for each round the feedback obtained as well as any revisions made to the APOSTEL recommendations will be summarized and questionnaires will be used for evaluation in order to reach consensus and to develop evidencebased guidelines for prospective OCT studies. Results: The degree of consensus of the survey's participants will be reported for the initial and the revised versions of the recommendations as well as the revisions made to the initial version. Conclusion: Formal guidelines for the reporting of quantitative OCT studies will be presented as well as the process of how they were developed