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Objective: To explore associations of the main component (P100) of visual evoked potentials (VEP) to pre- and postchiasmatic damage in multiple sclerosis (MS)., Methods: 31 patients (median EDSS: 2.5), 13 with previous optic neuritis (ON), and 31 healthy controls had VEP, optical coherence tomography and magnetic resonance imaging. We tested associations of P100-latency to the peripapillary retinal nerve fiber layer (pRNFL), ganglion cell/inner plexiform layers (GCIPL), lateral geniculate nucleus volume (LGN), white matter lesions of the optic radiations (OR-WML), fractional anisotropy of non-lesional optic radiations (NAOR-FA), and to the mean thickness of primary visual cortex (V1). Effect sizes are given as marginal R 2 (mR 2 )., Results: P100-latency, pRNFL, GCIPL and LGN in patients differed from controls. Within patients, P100-latency was significantly associated with GCIPL (mR 2  = 0.26), and less strongly with OR-WML (mR 2  = 0.17), NAOR-FA (mR 2  = 0.13) and pRNFL (mR 2  = 0.08). In multivariate analysis, GCIPL and NAOR-FA remained significantly associated with P100-latency (mR 2  = 0.41). In ON-patients, P100-latency was significantly associated with LGN volume (mR 2  = -0.56)., Conclusions: P100-latency is affected by anterior and posterior visual pathway damage. In ON-patients, damage at the synapse-level (LGN) may additionally contribute to latency delay., Significance: Our findings corroborate post-chiasmatic contributions to the VEP-signal, which may relate to distinct pathophysiological mechanisms in MS., (Copyright © 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background and Objectives: Histopathologic studies have identified immunoglobulin (Ig) deposition and complement activation as contributors of CNS tissue damage in multiple sclerosis (MS). Intrathecal IgM synthesis is associated with higher MS disease activity and severity, and IgM is the strongest complement-activating immunoglobulin. In this study, we investigated whether complement components (CCs) and complement activation products (CAPs) are increased in persons with MS, especially in those with an intrathecal IgM synthesis, and whether they are associated with disease severity and progression., Methods: CC and CAP levels were quantified in plasma and CSF of 112 patients with clinically isolated syndrome (CIS), 127 patients with MS (90 relapsing-remitting, 14 primary progressive, and 23 secondary progressive), 31 inflammatory neurologic disease, and 44 symptomatic controls from the Basel CSF databank study. Patients with CIS/MS were followed in the Swiss MS cohort study (median 6.3 years). Levels of CC/CAP between diagnosis groups were compared; in CIS/MS, associations of CC/CAP levels with intrathecal Ig synthesis, baseline Expanded Disability Status Scale (EDSS) scores, MS Severity Score (MSSS), and neurofilament light chain (NfL) levels were investigated by linear regression, adjusted for age, sex, and albumin quotient., Results: CSF (but not plasma) levels of C3a, C4a, Ba, and Bb were increased in patients with CIS/MS, being most pronounced in those with an additional intrathecal IgM production. In CIS, doubling of C3a and C4a in CSF was associated with 0.31 (CI 0.06-0.56; p = 0.016) and 0.32 (0.02-0.62; p = 0.041) increased EDSS scores at lumbar puncture. Similarly, doubling of C3a and Ba in CIS/MS was associated with 0.61 (0.19-1.03; p < 0.01) and 0.74 (0.18-1.31; p = 0.016) increased future MSSS. In CIS/MS, CSF levels of C3a, C4a, Ba, and Bb were associated with increased CSF NfL levels, e.g., doubling of C3a was associated with an increase of 58% (Est. 1.58; CI 1.37-1.81; p < 0.0001)., Discussion: CNS-compartmentalized activation of the classical and alternative pathways of complement is increased in CIS/MS and associated with the presence of an intrathecal IgM production. Increased complement activation within the CSF correlates with EDSS, future MSSS, and NfL levels, supporting the concept that complement activation contributes to MS pathology and disease progression. Complement inhibition should be explored as therapeutic target to attenuate disease severity and progression in MS.

Background and Objectives: Progression independent of relapse activity (PIRA) is a crucial determinant of overall disability accumulation in multiple sclerosis (MS). Accelerated brain atrophy has been shown in patients experiencing PIRA. In this study, we assessed the relation between PIRA and neurodegenerative processes reflected by (1) longitudinal spinal cord atrophy and (2) brain paramagnetic rim lesions (PRLs). Besides, the same relationship was investigated in progressive MS (PMS). Last, we explored the value of cross-sectional brain and spinal cord volumetric measurements in predicting PIRA., Methods: From an ongoing multicentric cohort study, we selected patients with MS with (1) availability of a susceptibility-based MRI scan and (2) regular clinical and conventional MRI follow-up in the 4 years before the susceptibility-based MRI. Comparisons in spinal cord atrophy rates (explored with linear mixed-effect models) and PRL count (explored with negative binomial regression models) were performed between: (1) relapsing-remitting (RRMS) and PMS phenotypes and (2) patients experiencing PIRA and patients without confirmed disability accumulation (CDA) during follow-up (both considering the entire cohort and the subgroup of patients with RRMS). Associations between baseline MRI volumetric measurements and time to PIRA were explored with multivariable Cox regression analyses., Results: In total, 445 patients with MS (64.9% female; mean [SD] age at baseline 45.0 [11.4] years; 11.2% with PMS) were enrolled. Compared with patients with RRMS, those with PMS had accelerated cervical cord atrophy (mean difference in annual percentage volume change [MD-APC] -1.41; p = 0.004) and higher PRL load (incidence rate ratio [IRR] 1.93; p = 0.005). Increased spinal cord atrophy (MD-APC -1.39; p = 0.0008) and PRL burden (IRR 1.95; p = 0.0008) were measured in patients with PIRA compared with patients without CDA; such differences were also confirmed when restricting the analysis to patients with RRMS. Baseline volumetric measurements of the cervical cord, whole brain, and cerebral cortex significantly predicted time to PIRA (all p ≤ 0.002)., Discussion: Our results show that PIRA is associated with both increased spinal cord atrophy and PRL burden, and this association is evident also in patients with RRMS. These findings further point to the need to develop targeted treatment strategies for PIRA to prevent irreversible neuroaxonal loss and optimize long-term outcomes of patients with MS.

Importance: Mechanisms contributing to disability accumulation in multiple sclerosis (MS) are poorly understood. Blood neurofilament light chain (NfL) level, a marker of neuroaxonal injury, correlates robustly with disease activity in people with MS (MS); however, data on the association between NfL level and disability accumulation have been conflicting., Objective: To determine whether and when NfL levels are elevated in the context of confirmed disability worsening (CDW)., Design, Setting, and Participants: This study included 2 observational cohorts: results from the Expression, Proteomics, Imaging, Clinical (EPIC) study at the University of California San Francisco (since 2004) were confirmed in the Swiss Multiple Sclerosis Cohort (SMSC), a multicenter study in 8 centers since 2012. Data were extracted from EPIC in April 2022 (sampling July 1, 2004, to December 20, 2016) and SMSC in December 2022 (sampling June 6, 2012, to September 2, 2021). The study included 2 observational cohorts in tertiary MS centers. All participants of both cohorts with available NfL results were included in the study, and no eligible participants were excluded or declined to participate., Exposure: Association between NfL z scores and CDW., Main Outcome Measures: CDW was defined as Expanded Disability Status Scale (EDSS) worsening that was confirmed after 6 or more months and classified into CDW associated with clinical relapses (CDW-R) or independent of clinical relapses (CDW-NR). Visits were classified in relation to the disability worsening events into CDW(-2) for 2 visits preceding event, CDW(-1) for directly preceding event, CDW(event) for first diagnosis of EDSS increase, and the confirmation visit. Mixed linear and Cox regression models were used to evaluate NfL dynamics and to assess the association of NfL with future CDW, respectively., Results: A total of 3906 EPIC visits (609 participants; median [IQR] age, 42.0 [35.0-50.0] years; 424 female [69.6%]) and 8901 SMSC visits (1290 participants; median [IQR] age, 41.2 [32.5-49.9] years; 850 female [65.9%]) were included. In CDW-R (EPIC, 36 events; SMSC, 93 events), NfL z scores were 0.71 (95% CI, 0.35-1.07; P < .001) units higher at CDW-R(-1) in EPIC and 0.32 (95% CI, 0.14-0.49; P < .001) in SMSC compared with stable MS samples. NfL elevation could be detected preceding CDW-NR (EPIC, 191 events; SMSC, 342 events) at CDW-NR(-2) (EPIC: 0.23; 95% CI, 0.01-0.45; P = .04; SMSC: 0.28; 95% CI, 0.18-0.37; P < .001) and at CDW-NR(-1) (EPIC: 0.27; 95% CI, 0.11-0.44; P < .001; SMSC: 0.09; 95% CI, 0-0.18; P = .06). Those findings were replicated in the subgroup with relapsing-remitting MS. Time-to-event analysis confirmed the association between NfL levels and future CDW-R within approximately 1 year and CDW-NR (in approximately 1-2 years)., Conclusions and Relevance: This cohort study documents the occurrence of NfL elevation in advance of clinical worsening and may hint to a potential window of ongoing dynamic central nervous system pathology that precedes the diagnosis of CDW.

Background: Retinal degeneration leading to optical coherence tomography (OCT) changes is frequent in patients with multiple sclerosis (PwMS)., Objective: To investigate associations among OCT changes, MRI measurements of global and regional brain volume loss, and physical and cognitive impairment in PwMS., Methods: 95 PwMS and 52 healthy controls underwent OCT and MRI examinations. Mean peripapillary retinal nerve fiber layer (pRNFL) thickness and ganglion cell/inner plexiform layer (GCIPL) volume were measured. In PwMS disability was quantified with the Expanded Disability Status Scale (EDSS) and Symbol Digit Modalities Test (SDMT). Associations between OCT, MRI, and clinical measures were investigated with multivariable regression models., Results: In PwMS, pRNFL and GCIPL were associated with the volume of whole brain (p < 0.04), total gray matter (p < 0.002), thalamus (p ≤ 0.04), and cerebral cortex (p ≤ 0.003) -both globally and regionally-, but not white matter. pRNFL and GCIPL were also inversely associated with T2-lesion volume (T2LV), especially in the optic radiations (p < 0.0001). The brain volumes associated with EDSS and SDMT significantly overlapped with those correlating with pRNFL and GCIPL., Conclusions: In PwMS, pRNFL and GCIPL reflect the integrity of clinically-relevant gray matter structures, underling the value of OCT measures as markers of neurodegeneration and disability in multiple sclerosis., (© 2023. The Author(s).)

Importance: There is a lack of validated biomarkers for disability progression independent of relapse activity (PIRA) in multiple sclerosis (MS)., Objective: To determine how serum glial fibrillary acidic protein (sGFAP) and serum neurofilament light chain (sNfL) correlate with features of disease progression vs acute focal inflammation in MS and how they can prognosticate disease progression., Design, Setting, and Participants: Data were acquired in the longitudinal Swiss MS cohort (SMSC; a consortium of tertiary referral hospitals) from January 1, 2012, to October 20, 2022. The SMSC is a prospective, multicenter study performed in 8 centers in Switzerland. For this nested study, participants had to meet the following inclusion criteria: cohort 1, patients with MS and either stable or worsening disability and similar baseline Expanded Disability Status Scale scores with no relapses during the entire follow-up; and cohort 2, all SMSC study patients who had initiated and continued B-cell-depleting treatment (ie, ocrelizumab or rituximab)., Exposures: Patients received standard immunotherapies or were untreated., Main Outcomes and Measures: In cohort 1, sGFAP and sNfL levels were measured longitudinally using Simoa assays. Healthy control samples served as the reference. In cohort 2, sGFAP and sNfL levels were determined cross-sectionally., Results: This study included a total of 355 patients (103 [29.0%] in cohort 1: median [IQR] age, 42.1 [33.2-47.6] years; 73 female patients [70.9%]; and 252 [71.0%] in cohort 2: median [IQR] age, 44.3 [33.3-54.7] years; 156 female patients [61.9%]) and 259 healthy controls with a median [IQR] age of 44.3 [36.3-52.3] years and 177 female individuals (68.3%). sGFAP levels in controls increased as a function of age (1.5% per year; P < .001), were inversely correlated with BMI (-1.1% per BMI unit; P = .01), and were 14.9% higher in women than in men (P = .004). In cohort 1, patients with worsening progressive MS showed 50.9% higher sGFAP levels compared with those with stable MS after additional sNfL adjustment, whereas the 25% increase of sNfL disappeared after additional sGFAP adjustment. Higher sGFAP at baseline was associated with accelerated gray matter brain volume loss (per doubling: 0.24% per year; P < .001) but not white matter loss. sGFAP levels remained unchanged during disease exacerbations vs remission phases. In cohort 2, median (IQR) sGFAP z scores were higher in patients developing future confirmed disability worsening compared with those with stable disability (1.94 [0.36-2.23] vs 0.71 [-0.13 to 1.73]; P = .002); this was not significant for sNfL. However, the combined elevation of z scores of both biomarkers resulted in a 4- to 5-fold increased risk of confirmed disability worsening (hazard ratio [HR], 4.09; 95% CI, 2.04-8.18; P < .001) and PIRA (HR, 4.71; 95% CI, 2.05-9.77; P < .001)., Conclusions and Relevance: Results of this cohort study suggest that sGFAP is a prognostic biomarker for future PIRA and revealed its complementary potential next to sNfL. sGFAP may serve as a useful biomarker for disease progression in MS in individual patient management and drug development.

Standardization is necessary to ensure the reliability of clinical data and to enable longitudinal and cross-sectional comparisons of data obtained in different centres and countries. In patients with multiple sclerosis (MS), standardized clinical data are needed for monitoring of disability and for collecting real-world evidence for use in research. This Perspective describes attempts to improve the standardization and digitization of clinical data in MS, including digital electronic health recording systems and applications that attempt to offer a comprehensive assessment of patients' neurological deficits and their effects on daily life. Despite the challenges raised by regulatory, ethical and data-privacy considerations, the standardization and digitization of clinical data in MS is expected to generate new insights into the pathophysiology of the disease and to contribute to personalized patient care.

Purpose: Clinical ordinal rating scales of movements, e.g., the Expanded Disability Status Scale, have poor intra- and interrater reliability, are insensitive to subtle differences and result in coarse-grained ratings compared to relative comparative rating methods. We therefore established video-based setwise comparison as a fine-grained, reliable and efficient rating method of motor dysfunction using algorithmic support. Materials and methods: Eight neurologists rated a set of 40 multiple sclerosis patient videos of the Finger-to-Nose-Test using both the newly developed setwise comparison and the established pairwise comparison techniques, which result in a continuous rating scale. Reliability was assessed by the intra-class correlation coefficient. Construct validity was estimated as Pearson's correlation between the continuous scale and severity ratings according to the Neurostatus scale for upper-extremity tremor/dysmetria and the Nine-hole-peg-test. Comparing the time needed for ratings assessed efficiency. Results: Intra-class correlation coefficient was 0.83 for setwise and 0.7 for pairwise comparison. Correlation to the tremor/dysmetria score of the Neurostatus was 0.86 for both rating procedures and correlation to the Nine-hole-peg-test was 0.64 (setwise) and 0.66 (pairwise). The time needed to rate 40 videos was 22.9 ± 6.9 minutes (setwise) and 77.8 ± 14.5 minutes (pairwise). Conclusions: Setwise comparison is an efficient, valid and reliable method for fine-grained rating of motor dysfunction that can be applied to larger datasets. It is substantially more efficient than pairwise comparison.Implications for rehabilitationDisability rating is crucial in clinical neurorehabilitation and in clinical trials.Humans are naturally inconsistent in rating items on ordinal scales leading to poor intra- and interrater reliability, insensitivity to subtle differences and coarse-grained ratings.Video-based setwise comparison is a new rating method enabling fine-grained, reliable and efficient ratings of motor dysfunction using algorithmic support.

Background: The Neurostatus-eEDSS is an electronic tool providing automated real-time feedback on inconsistencies of Neurostatus-EDSS calculations., Objective: To analyze the performance of the Neurostatus-eEDSS in two multicenter phase 3 multiple sclerosis (MS) trials., Methods: All assessments captured with the Neurostatus-eEDSS web service during a period of 2.5 years were analyzed., Results: Of the total 10,789 assessments, 40.1% had inconsistencies after first entry, reduced to 22.1% due to the real-time feedback. The entire checking process resulted in a change of the expanded disability status scale (EDSS) score in 14.8% of the assessments., Conclusion: The Neurostatus-eEDSS can increase consistency and reliability of EDSS assessments in clinical MS trials.

Objectives: To examine the feasibility, reliability, granularity, and convergent validity of a video-based pairwise comparison technique that uses algorithmic support to enable automated rating of motor dysfunction in patients with multiple sclerosis (MS)., Design: Feasibility and larger cross-sectional cohort study., Setting: The outpatient clinic of 2 specialist university medical centers., Participants: Selected sample from a cohort of patients with MS participating in the Assess MS study (N=42). Videos were randomly drawn from each strata of the ataxia severity-degrees as defined in the Expanded Disability Status Scale (EDSS). In Basel: 19 videos of 17 patients (mean age, 43.4±11.6y; 10 women). In Amsterdam: 50 videos of 25 patients (mean age, 50.0±10.0y; 15 women)., Interventions: Not applicable., Main Outcome Measures: In each center, neurologists (n=13; n=10) viewed pairs of videos of patients performing standardized movements (eg, finger-to-nose test) to assess relative performance. A comparative assessment score was calculated for each video using the TrueSkill algorithm and analyzed for intrarater (test-retest; ratio of agreement) and interrater reliability (intraclass correlation coefficient [ICC] for absolute agreement) and convergent validity (Spearman ρ). Granularity was estimated from the average difference in comparative assessment scores at which 80% of neurologists considered performance to be different., Results: Intrarater reliability was excellent (median ratio of agreement≥0.87). The comparative assessment scores calculated from individual neurologists demonstrated good-excellent ICCs for interrater reliability (0.89; 0.71). The comparative assessment scores correlated (very) highly with their Neurostatus-EDSS equivalent (ρ=0.78, P<.001; ρ=0.91, P<.05), suggesting a more fine-grained rating., Conclusions: Video-based pairwise comparison of motor dysfunction allows for reliable and fine-grained capturing of clinical judgment about neurologic performance, which can contribute to the development of a consistent quantified metric of motor ability in MS., (Copyright © 2019 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Accurate clinical assessment in multiple sclerosis (MS) is challenging. The Assess MS system is being developed to automatically quantify motor dysfunction in MS, including upper extremity function (UEF) and mobility., Objective: To determine to what extent combinations of standardized movements included in the Assess MS system explain accepted measures of UEF and mobility., Methods: MS patients were recruited at four European MS centres. Eight movements were selected, including tasks of activities of daily living (ADL) and classical neurological tests. Movements were recorded on video and rated by experienced neurologists ( n  = 5). Subsequently, multivariate linear regression models were performed to explain the variance of the Nine-Hole Peg Test (9HPT), Arm Function in Multiple Sclerosis Questionnaire (AMSQ) and Timed-25 Foot Walk test (T25WT)., Results: In total, 257 patients were included. The movements explained 62.9% to 80.1% of the variance of the 9HPT models, 43.3% and 44.3% of the AMSQ models and 70.8% of the T25WT. In all models, tasks of ADL contributed most to the variance., Conclusion: Combinations of movements are valuable to assess UEF and mobility. Incorporating ADL tasks into daily clinical practice and clinical trials may be more valuable than the classical neurological examination of UEF and mobility.

Despite its functional importance and well known clinical impact in Multiple Sclerosis (MS), the cerebellum has only received significant attention over the past few years. It is now established that the cerebellum plays a key role not only in various sensory-motor networks, but also in cognitive-behavioural processes, domains primarily affected in patients with MS. Evidence from histopathological and magnetic resonance imaging (MRI) studies on cerebellar involvement in MS is increasingly available, however linking these pathological findings with clinical dysfunction remains challenging. There are promising advances in technology that are likely to improve the detection of pathological changes within the cerebellum, which may elucidate how pathology relates to disability., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: To improve the consistency of standardized Expanded Disability Status Scale (EDSS) assessments, an electronic data capture tool and analysis tool was developed, Neurostatus e-Scoring (NESC). This tool allows real-time feedback by comparing entries with established scoring rules., Objective: To test whether using NESC reduces inconsistencies as compared to the paper-and-pencil version of the Expanded Disability Status Scale (pEDSS)., Methods: In all, 100 multiple sclerosis (MS) patients were assessed in random order on the same day by pairs of neurologists, one using pEDSS and one NESC. We compared inter-rater reliability and frequency of inconsistencies in Neurostatus subscores, functional system (FS) scores, ambulation and EDSS steps., Results: Inconsistencies of any type were more likely to occur when using pEDSS (mean odds ratio (95% confidence interval (CI)) = 2.93 (1.62; 5.29)). This was also the case for FS score inconsistencies (2.54 (1.40; 4.61)) and more likely for patients in the lower EDSS range (⩽3.5 vs >3.5) (5.32 (1.19; 23.77)). Overall, inter-rater agreement for the assessed Neurostatus subscores was high (median and inter-quartile range = 0.84 (0.73, 0.81))., Conclusion: Our data provide class II evidence that the use of NESC increases consistency of standardized EDSS assessments, and may thus have the potential to decrease noise and increase power of MS clinical trials.

Objective: To compare the ability of different evoked potential scores (EPS) to monitor and predict the disease course in multiple sclerosis (MS)., Methods: Seventy-two patients with MS or clinically isolated syndrome were investigated by visual, motor, and somatosensory EP and expanded disability status scale (EDSS) at baseline (T0) and months 6, 12, 24, 36 (T4). EP results were rated according to ordinal (o), semi-quantitative (sq), and quantitative (q) EPS. Spearman rank correlation and multivariable linear regression were used to investigate the associations between EPS and clinical disability., Results: All EPS correlated with EDSS cross-sectionally (0.72⩽rho⩽0.87, all p<0.001) and longitudinally (0.39⩽rho⩽0.47, all p⩽0.004). EPS(T0) and EDSS(T0) together explained 85-86% of EDSS(T4) variance. A posteriori power calculation showed that the sample sizes needed to detect significant changes over 6 months in q-EPS, sq-EPS and o-EPS with 90% certainty would be 50, 129 and 222, respectively. q-EPS change(T1-T0) correlated with EDSS change(T4-T0) (rho=0.56, p<0.001), while sq-EPS and o-EPS changes(T1-T0) did not., Conclusion: All three EPS allow disease course monitoring in MS. However, the quantitative EPS detects clinically relevant short-term changes with a smaller sample size than semi-quantitative or ordinal EPS., Significance: These results underscore the potential of EPS to characterize MS disease evolution., (Copyright © 2016. Published by Elsevier Ireland Ltd.)

Objective: Little is known about optimal timing of multimodal evoked potential (EP)-investigations regarding prediction of MS disability. The aim of this study was to investigate whether timing of EP-investigations during a relapse or in the relapse-free interval influences prediction of MS disability., Methods: Two groups of MS patients with similar age and gender distributions received visual, motor and somatosensory EPs either during a relapse (Group 1) or in the relapse-free interval (Group 2). Expanded Disability Status Score (EDSS) was obtained at baseline (T0) and year 3 (T2). Linear regression analysis was performed to examine the association between EDSS(T2) and a baseline EP compound measure (s-EP-Q(T0)) for each group., Results: Median EDSS(T0) was 3.0 for Group 1 and 1.5 for Group 2. Mean disease durations were 2.0 and 2.8 years, respectively. Median EDSS(T2) was 2.0 for both groups. The s-EP-Q(T0) significantly predicted EDSS(T2) (R(2)=0.47) for patients in Group 2, but not for patients in Group 1 (R(2)=0.07)., Conclusion: In early MS the functional remnants of relapses are a better predictor for development of medium-term disability than is the extent of impulse propagation impairment measured during relapse., Significance: This suggests a role of multimodal EPs in prediction of MS disability if performed in the relapse-free interval., (Copyright © 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

This paper presents new learning-based techniques for measuring disease progression in Multiple Sclerosis (MS) patients. Our system aims to augment conventional neurological examinations by adding quantitative evidence of disease progression. An off-the-shelf depth camera is used to image the patient at the examination, during which he/she is asked to perform carefully selected movements. Our algorithms then automatically analyze the videos, assessing the quality of each movement and classifying them as healthy or non-healthy. Our contribution is three-fold: We i) introduce ensembles of randomized SVM classifiers and compare them with decision forests on the task of depth video classification; ii) demonstrate automatic selection of discriminative landmarks in the depth videos, showing their clinical relevance; iii) validate our classification algorithms quantitatively on a new dataset of 1041 videos of both MS patients and healthy volunteers. We achieve average Dice scores well in excess of the 80% mark, confirming the validity of our approach in practical applications. Our results suggest that this technique could be fruitful for depth-camera supported clinical assessments for a range of conditions.

Objective: To prospectively assess combined evoked potentials (EP) as markers and predictors of the disease course of early MS over 3 years., Methods: Fifty patients in the early phase of relapsing remitting MS prospectively received visual, somatosensory and motor EP and EDSS assessments at baseline (T1) and at 6 months intervals during 3 years. Spearman rank correlation was used to determine the relationship between z-transformed EP-latencies (z-EPL) and EDSS. Multivariable linear regression was performed to predict EDSS at year 3 (T7) in function of z-EPL(T1). Validity of the models was assessed using group cross-validation., Results: At each of the seven points in time, EDSS correlated with the sum of z-EPL (0.64 ≤ rho ≤ 0.79, p<0.001). The change of the sum of z-EPL(T7-T1) correlated with the change of EDSS(T7-T1) (rho=0.51, p=0.001). EDSS(T7) as predicted by the sum of z-scores of EP latencies or by the number of pathological EP results at baseline correlated with the observed clinical values after 3 years (rho>0.70, p<0.001, for both measures)., Conclusions: Multimodal EPs correlate well with clinical disability in cross-sectional and longitudinal comparison in early MS and allow prediction of disease evolution over 3 years., Significance: EPs seem well suited as markers of the disease course in early MS in clinical trials and bear potential for supporting decision-finding in individual patients., (Copyright © 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Background: Little is known about the predictive value of neurophysiological measures for the long-term course of multiple sclerosis (MS)., Objective: To prospectively investigate whether combined visual (VEP) and motor evoked potentials (MEP) allow prediction of disability over 14 years., Methods: A total of 30 patients with relapsing-remitting and secondary progressive MS were prospectively investigated with VEPs, MEPs and the Expanded Disability Status Scale (EDSS) at entry (T0) and after 6, 12 and 24 months, and with cranial MRI scans at entry (T2-weighted and gadolinium-enhanced T1-weighted images). EDSS was again assessed at year 14 (T4). The association between evoked potential (EP), magnetic resonance (MR) data and EDSS was measured using Spearman's rank correlation. Multivariable linear regression was performed to predict EDSS(T4) as a function of z-transformed EP-latencies(T0). The model was validated using a jack-knife procedure and the potential for improving it by inclusion of additional baseline variables was examined., Results: EDSS values(T4) correlated with the sum of z-transformed EP-latencies(T0) (rho = 0.68, p < 0.0001), but not with MR-parameters(T0). EDSS(T4) as predicted by the formula EDSS(T4) = 4.194 + 0.088 * z-score P100(T0) + 0.071 * z-score CMCT(UE, T0) correlated with the observed values (rho = 0.69, p < 0.0001)., Conclusion: Combined EPs allow prediction of long-term disability in small groups of patients with MS. This may have implications for the choice of monitoring methods in clinical trials and for daily practice decisions.

Importance of the Field: One of the disadvantages of currently available disease-modifying drugs (DMDs) for multiple sclerosis (MS) is their parenteral administration. Moreover, efficacy is only partial. Most patients treated with first-line DMDs do not remain relapse-free. There is a need for new oral drugs that are more effective than currently available compounds. Innovative oral drugs with new mechanisms of action showed promising results in clinical trials. One of these emerging drugs is BG00012 (BG-12), a fumaric acid ester (FAE). Its active agent, dimethyl fumarate had first been included in FAE treatments for psoriasis., Areas Covered in This Review: Results that highlight the potential role of BG-12 in MS treatment. We focus on findings of experimental studies and current results of clinical studies with FAE in MS., What the Reader Will Gain: An overview of the immunomodulatory and neuroprotective effects of FAE, their effect in animal models of MS and their short-term efficacy and safety profile in a Phase IIb clinical trial., Take Home Message: BG-12 is a promising emerging treatment for relapsing-remitting MS, combining anti-inflammatory and possibly clinically relevant neuroprotective effects with the convenience of oral administration. However, the future role of BG-12 in treatment of MS will have to be determined after the completion of ongoing Phase III studies.

Objective: Health-related quality of life (HRQOL) is often much reduced among individuals with multiple sclerosis (MS), and incidences of depression, fatigue, and anxiety are high. We examined effects of a mindfulness-based intervention (MBI) compared to usual care (UC) upon HRQOL, depression, and fatigue among adults with relapsing-remitting or secondary progressive MS., Methods: A total of 150 patients were randomly assigned to the intervention (n = 76) or to UC (n = 74). MBI consisted of a structured 8-week program of mindfulness training. Assessments were made at baseline, postintervention, and 6 months follow-up. Primary outcomes included disease-specific and disease-aspecific HRQOL, depression, and fatigue. Anxiety, personal goal attainment, and adherence to homework were secondary outcomes., Results: Attrition was low in the intervention group (5%) and attendance rate high (92%). Employing intention-to-treat analysis, MBI, compared with UC, improved nonphysical dimensions of primary outcomes at postintervention and follow-up (p < 0.002); effect sizes, 0.4-0.9 posttreatment and 0.3-0.5 at follow-up. When analyses were repeated among subgroups with clinically relevant levels of preintervention depression, fatigue, or anxiety, postintervention and follow-up effects remained significant and effect sizes were larger than for the total sample., Conclusions: In addition to evidence of improved HRQOL and well-being, these findings demonstrate broad feasibility and acceptance of, as well as satisfaction and adherence with, a program of mindfulness training for patients with MS. The results may also have treatment implications for other chronic disorders that diminish HRQOL., Classification of Evidence: This trial provides Class III evidence that MBI compared with UC improved HRQOL, fatigue, and depression up to 6 months postintervention.

There is an increasing number of clinical trials testing new compounds which act at different stages of Multiple Sclerosis (MS). To prove their effectiveness several clinical outcome measures are used. The overall quality of clinical trials is increasing steadily due to the growing experience in this area, the increasing awareness of quality standards in the MS community and the more stringent requirements of regulatory authorities for approval of new treatments. Each successful clinical trial provided additional information that could be incorporated into the design of subsequent studies to improve their quality. However, the choice of appropriate outcome measures still presents major challenges. For an individual patient improvement or stability of their disability and to a lesser extent the relapse rate, are the main targets of treatment. As there is yet no scale or assessment, which objectively covers all major issues, it is recommended to use multiple instruments and endpoints as secondary outcome measures.

This study was designed to examine the immunogenetic background predisposing to multiple sclerosis (MS). Three hundred fifty-eight clinically well-characterized MS patients from Germany were investigated and compared to 395 healthy control subjects. Each individual was genotyped for 22 polymorphic markers located within or close to immunorelevant candidate genes including HLA-DRB1*, T-cell receptor (TCR), cell interaction molecules, cytokines, and cytokine receptor genes. Altogether, approximately 17,000 genetic analyses were performed. Patients were grouped according to the course of MS-relapsing-remitting or chronic progressive. Most of the genetic markers were not associated with increased risk or their exact contribution was not clear (e.g., tumor necrosis factor). The relative risks for HLA-DRB1*15+ and DRB1*03+ individuals were 3.64 and 1.42, respectively. In both groups of patients, certain TCRB gene polymorphisms were risk factors. In DRB1*03+ individuals the relative risk was increased (> 22) when a specific TCRBV6S3 allele was also inherited. Furthermore, distinct linkage disequilibria of TCRBV6S1/TCRBV6S3 elements in patients and control subjects strongly suggested an additional risk factor in the TCRBV region for DRB1*15+ individuals. These findings are discussed with respect to the pathogenesis and rational approaches to the therapy of MS.

Background: Little is known about the predictive value of neurophysiological measures for the long-term course of multiple sclerosis (MS).Objective: To prospectively investigate whether combined visual (VEP) and motor evoked potentials (MEP) allow prediction of disability over 14 years.Methods: A total of 30 patients with relapsing–remitting and secondary progressive MS were prospectively investigated with VEPs, MEPs and the Expanded Disability Status Scale (EDSS) at entry (T0) and after 6, 12 and 24 months, and with cranial MRI scans at entry (T2-weighted and gadolinium-enhanced T1-weighted images). EDSS was again assessed at year 14 (T4). The association between evoked potential (EP), magnetic resonance (MR) data and EDSS was measured using Spearman’s rank correlation. Multivariable linear regression was performed to predict EDSST4 as a function of z-transformed EP-latenciesT0. The model was validated using a jack-knife procedure and the potential for improving it by inclusion of additional baseline variables was examined.Results: EDSS valuesT4 correlated with the sum of z-transformed EP-latenciesT0 (rho = 0.68, p < 0.0001), but not with MR-parametersT0. EDSST4 as predicted by the formula EDSST4 = 4.194 + 0.088 * z-score P100T0 + 0.071 * z-score CMCTUE, T0 correlated with the observed values (rho = 0.69, p < 0.0001).Conclusion: Combined EPs allow prediction of long-term disability in small groups of patients with MS. This may have implications for the choice of monitoring methods in clinical trials and for daily practice decisions. [ABSTRACT FROM AUTHOR]