Faculty Bibliography

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

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: 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

BACKGROUND: Structural retinal imaging biomarkers are important for early recognition and monitoring of inflammation and neurodegeneration in multiple sclerosis. With the introduction of spectral domain optical coherence tomography (SD-OCT), supervised automated segmentation of individual retinal layers is possible. We aimed to investigate which retinal layers show atrophy associated with neurodegeneration in multiple sclerosis when measured with SD-OCT. METHODS: In this systematic review and meta-analysis, we searched for studies in which SD-OCT was used to look at the retina in people with multiple sclerosis with or without optic neuritis in PubMed, Web of Science, and Google Scholar between Nov 22, 1991, and April 19, 2016. Data were taken from cross-sectional cohorts and from one timepoint from longitudinal studies (at least 3 months after onset in studies of optic neuritis). We classified data on eyes into healthy controls, multiple-sclerosis-associated optic neuritis (MSON), and multiple sclerosis without optic neuritis (MSNON). We assessed thickness of the retinal layers and we rated individual layer segmentation performance by random effects meta-analysis for MSON eyes versus control eyes, MSNON eyes versus control eyes, and MSNON eyes versus MSON eyes. We excluded relevant sources of bias by funnel plots. FINDINGS: Of 25 497 records identified, 110 articles were eligible and 40 reported data (in total 5776 eyes from patients with multiple sclerosis [1667 MSON eyes and 4109 MSNON eyes] and 1697 eyes from healthy controls) that met published OCT quality control criteria and were suitable for meta-analysis. Compared with control eyes, the peripapillary retinal nerve fibre layer (RNFL) showed thinning in MSON eyes (mean difference -20.10 mum, 95% CI -22.76 to -17.44; p<0.0001) and in MSNON eyes (-7.41 mum, -8.98 to -5.83; p<0.0001). The macula showed RNFL thinning of -6.18 mum (-8.07 to -4.28; p<0.0001) in MSON eyes and -2.15 mum (-3.15 to -1.15; p<0.0001) in MSNON eyes compared with control eyes. Atrophy of the macular ganglion cell layer and inner plexiform layer (GCIPL) was -16.42 mum (-19.23 to -13.60; p<0.0001) for MSON eyes and -6.31 mum (-7.75 to -4.87; p<0.0001) for MSNON eyes compared with control eyes. A small degree of inner nuclear layer (INL) thickening occurred in MSON eyes compared with control eyes (0.77 mum, 0.25 to 1.28; p=0.003). We found no statistical difference in the thickness of the combined outer nuclear layer and outer plexiform layer when we compared MSNON or MSON eyes with control eyes, but we found a small degree of thickening of the combined layer when we compared MSON eyes with MSNON eyes (1.21 mum, 0.24 to 2.19; p=0.01). INTERPRETATION: The largest and most robust differences between the eyes of people with multiple sclerosis and control eyes were found in the peripapillary RNFL and macular GCIPL. Inflammatory disease activity might be captured by the INL. Because of the consistency, robustness, and large effect size, we recommend inclusion of the peripapillary RNFL and macular GCIPL for diagnosis, monitoring, and research. FUNDING: None.

This article consists of a Letter to the Editor regarding Post-traumatic headache: the use of the sport concussion assessment tool (SCAT-3) as a predictor of post-concussion recovery, recently published in The Journal of Headache and Pain, along with a response from the original authors.

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