Visual evoked potentials in multiple sclerosis: P100 latency and visual pathway damage including the lateral geniculate nucleus.

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 R2 (mR2). RESULTS: P100-latency, pRNFL, GCIPL and LGN in patients differed from controls. Within patients, P100-latency was significantly associated with GCIPL (mR2 = 0.26), and less strongly with OR-WML (mR2 = 0.17), NAOR-FA (mR2 = 0.13) and pRNFL (mR2 = 0.08). In multivariate analysis, GCIPL and NAOR-FA remained significantly associated with P100-latency (mR2 = 0.41). In ON-patients, P100-latency was significantly associated with LGN volume (mR2 = -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.

Complement Activation Is Associated With Disease Severity in Multiple Sclerosis.

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.

Association of Spinal Cord Atrophy and Brain Paramagnetic Rim Lesions With Progression Independent of Relapse Activity in People With 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.

Neurofilament Light Chain Elevation and Disability Progression in Multiple Sclerosis.

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.

Determine atrial fibrillation burden with a photoplethysmographic mobile sensor: the atrial fibrillation burden trial: detection and quantification of episodes of atrial fibrillation using a cloud analytics service connected to a wearable with photoplethysmographic sensor.

Aims: Recent studies suggest that atrial fibrillation (AF) burden (time AF is present) is an independent risk factor for stroke. The aim of this trial was to study the feasibility and accuracy to identify AF episodes and quantify AF burden in patients with a known history of paroxysmal AF with a photoplethysmography (PPG)-based wearable. Methods and results: In this prospective, single-centre trial, the PPG-based estimation of AF burden was compared with measurements of a conventional 48 h Holter electrocardiogram (ECG), which served as the gold standard. An automated algorithm performed PPG analysis, while a cardiologist, blinded for the PPG data, analysed the ECG data. Detected episodes of AF measured by both methods were aligned timewise.Out of 100 patients recruited, 8 had to be excluded due to technical issues. Data from 92 patients were analysed [55.4% male; age 73.3 years (standard deviation, SD: 10.4)]. Twenty-five patients presented AF during the study period. The intraclass correlation coefficient of total AF burden minutes detected by the two measurement methods was 0.88. The percentage of correctly identified AF burden over all patients was 85.1% and the respective parameter for non-AF time was 99.9%. Conclusion: Our results demonstrate that a PPG-based wearable in combination with an analytical algorithm appears to be suitable for a semiquantitative estimation of AF burden in patients with a known history of paroxysmal AF. Trial Registration number: NCT04563572.

Optical coherence tomography versus other biomarkers: Associations with physical and cognitive disability in multiple sclerosis.

BACKGROUND: Optical coherence tomography (OCT) is a biomarker of neuroaxonal loss in multiple sclerosis (MS). OBJECTIVE: The objective was to assess the relative role of OCT, next to magnetic resonance imaging (MRI) and serum markers of disability in MS. METHODS: A total of 100 patients and 52 controls underwent OCT to determine peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell-inner plexiform layers (GCIPL). Serum neurofilament light chain (sNfL), total lesion volume (TLV), and brain parenchymal fraction (BPF) were also assessed. The associations of OCT with disability were examined in linear regression models with correction for age, vision, and education. RESULTS: In patients, pRNFL was associated with the Symbol Digit Modalities Test (SDMT; p = 0.030). In the multivariate analysis including sNfL and MRI measures, pRNFL (ß = 0.19, p = 0.044) and TLV (ß = -0.24, p = 0.023) were the only markers associated with the SDMT. pRNFL (p < 0.001) and GCIPL (p < 0.001) showed associations with the Expanded Disability Status Scale (EDSS). In the multivariate analysis, GCIPL showed the strongest association with the EDSS (ß = -0.32, p < 0.001) followed by sNfL (ß = 0.18, p = 0.024). CONCLUSION: The associations of OCT measures with cognitive and physical disability were independent of serum and brain MRI markers of neuroaxonal loss. OCT can be an important tool for stratification in MS, while longitudinal studies using combinations of biomarkers are warranted.

Assessment of Multiple Aspects of Upper Extremity Function Independent From Ambulation in Patients With Multiple Sclerosis.

BACKGROUND: Upper extremity function (UEF) is often compromised in multiple sclerosis (MS), although its importance is regularly underrecognized relative to ambulation. We explored the concurrent presence of impairment in UEF and ambulation by examining various aspects of UEF across different levels of ambulation. METHODS: The cohort consisted of 247 patients with clinically definite MS or clinically isolated syndrome according to the revised 2010 McDonald criteria. The Nine-Hole Peg Test and the Expanded Disability Status Scale were used to stratify patients into clinically different subgroups. For UEF, cerebellar function (finger-to-nose test), pyramidal function (pronator drift test), and the ability to perform a task of activities of daily living (drinking-from-cup test) were examined. Patient-reported limitations of UEF in daily life were assessed using the Arm Function in Multiple Sclerosis Questionnaire. RESULTS: Patients in more severely impaired ambulation groups displayed poorer performance on all UEF measures. Although most patients had normal to mild (n = 147) or moderate (n = 46) ambulatory impairment, 87.7% exhibited some level of UEF impairment as defined using the Nine-Hole Peg Test. Most patients had mild UEF impairment (n = 174), accounting for the largest proportion in all ambulation groups (51.9%-77.8%). CONCLUSIONS: A distinct pattern of impairment was found for ambulation and multiple aspects of UEF. Independent assessment of multiple aspects of disability may be helpful in treatment decision-making and could support the development of rehabilitation strategies that specifically target UEF impairment.

Serum Glial Fibrillary Acidic Protein Compared With Neurofilament Light Chain as a Biomarker for Disease Progression in Multiple Sclerosis.

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.

Optical coherence tomography reflects clinically relevant gray matter damage in patients with multiple sclerosis.

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.

Improving Detection of Change in Motor Functioning in Multiple Sclerosis Using Video-Assisted Composite Measures.

BACKGROUND: Assessing motor functioning is important to monitor the disease course of multiple sclerosis (MS). Video-assisted rating of classic neurologic tests and activities of daily living may improve the detection of changes in motor functioning. We investigated the value of using video-assisted composite measures for the detection of changes in mobility and upper extremity function (UEF). METHODS: Forty-three patients with MS were recorded performing motor function tests before and during treatment with fampridine. Patients were classified as improved or not improved on mobility composite (MOB-COM) and UEF composite (UEF-COM) measures based on neurologists' ratings of the tests. The proportional agreements between the composite measures and the conventional measures-the Timed 25-Foot Walk test (T25FW) and the Nine-Hole Peg Test (NHPT)-were determined and compared with patient-perceived improvement, which was determined using patient-reported ratings of changes in mobility and UEF. RESULTS: Agreement between MOB-COM and T25FW was 79.5%, and agreement between UEF-COM and NHPT was 82.1%. Twenty-six of 39 patients (66.7%) reported mobility improvement; 6 of these reports were confirmed by both T25FW and MOB-COM, 4 were confirmed by T25FW only, and 2 were confirmed by MOB-COM only. For UEF, 13 of 39 patients (33.3%) reported improvement; 3 of these were confirmed by the NHPT and 3 were confirmed by the UEF-COM. CONCLUSIONS: Compared with the conventional NHPT measure, the video-assisted composite measure of UEF detected additional patient-perceived improvement. This was less evident for mobility measures. Video-assisted composite measures may enhance the detection of treatment effects in MS clinical practice and trials.

Standardization and digitization of clinical data in multiple sclerosis.

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.

Development and validation of the self-reported disability status scale (SRDSS) to estimate EDSS-categories.

BACKGROUND: Clinician-assessed Expanded Disease Status Scale (EDSS) is gold standard in clinical investigations but normally unavailable in population-based, patient-centred MS-studies. Our objective was to develop a self-reported gait measure reflecting EDSS-categories. METHODS: We developed the self-reported disability status scale (SRDSS) with three categories (≤3.5, 4-6.5, ≥7) based on three mobility-related questions. The SRDSS was determined for 173 persons with MS and validated against clinical EDSS to calculate sensitivity and specificity. RESULTS: Accuracy was 88.4% (153 correctly classified) and weighted kappa 0.73 (0.62-0.84). Sensitivity/specificity-pairs were 94.5%/77.8%, 69.0%/94.7% and 100%/98.2% for SRDSS ≤3.5, 4-6.5 and ≥7, respectively. CONCLUSIONS: Self-reported SRDSS approximates EDSS-categories well and fosters comparability between clinical and population-based studies.

Diagnostic procedures in suspected attacks in patients with neuromyelitis optica spectrum disorders: Results of an international survey.

BACKGROUND: Currently, there is no evidence-based definition of attacks in neuromyelitis optica spectrum disorders (NMOSD). However, to allow their stringent use as valid endpoints, recent phase III trials in NMOSD defined criteria and adjudication of these events in context of these trials. The objective of this study was to investigate diagnostic procedures currently used in routine adjudication of suspected attacks in NMOSD, and to assess whether the standardized attack-criteria from two pivotal trials may be feasible in routine clinical care. METHODS: Four global clinical networks were surveyed using an online questionnaire: NEMOS (Neuromyelitis Optica Study Group), IMSVISUAL (International Multiple Sclerosis Visual System Consortium), GJCF-ICC (Guthy Jackson Charitable Foundation-International Clinical Consortium) and NOMADMUS (Devic's neuromyelitis optica and related neurological disorders study group). RESULTS: Seventy-eight responses were received from September 2018 to February 2019. Median annual number of patients seen with suspected attacks was 10 (range 2-130). Immediate access to MRI was reported by 59.0% of all participants and the majority performs an MRI for new patients with a myelitis, optic neuritis or other symptoms. In patients with established NMOSD diagnosis presenting during routine clinical visits only 10.5% or 9.2% always perform a brain or spinal cord MRI, respectively. Digital records of patients' visits are kept by 98.7% of all participants and 88.5% have direct access to case history. An expert neurological examination is performed for 94.9% of participants reported to perform an expert neurological examination in patients with acute attacs, while only 30.8% seem to perform the assessments according to the Neurostatus-Expanded Disability Status Scale (EDSS) definitions.. The Sakura Star study criteria which are based solely on clinical assessment could be feasible in routine care, provided that more centers use the Neurostatus-EDSS, while only 9% of participants fulfill all requirements for adjudication of the N-Momentum study criteria. CONCLUSIONS: The high percentage of centers using digital records is encouraging. However, routine adjudication of clinical events in NMOSD seems highly heterogeneous. MRI is the mainstay in the majority of queried centers, but its immediate availability is limited. Only a minority of centers are equipped for trial-grade classification of attacks, if this is not solely clinically based. Thus, standard and feasible guidelines for attack adjudication are urgently needed to standardize routine care, optimize future clinical trials and allow studying long-term safety and efficacy of newly approved drugs in phase IV trials.

Autoencoder as a New Method for Maintaining Data Privacy While Analyzing Videos of Patients With Motor Dysfunction: Proof-of-Concept Study.

BACKGROUND: In chronic neurological diseases, especially in multiple sclerosis (MS), clinical assessment of motor dysfunction is crucial to monitor the disease in patients. Traditional scales are not sensitive enough to detect slight changes. Video recordings of patient performance are more accurate and increase the reliability of severity ratings. When these recordings are automated, quantitative disability assessments by machine learning algorithms can be created. Creation of these algorithms involves non-health care professionals, which is a challenge for maintaining data privacy. However, autoencoders can address this issue. OBJECTIVE: The aim of this proof-of-concept study was to test whether coded frame vectors of autoencoders contain relevant information for analyzing videos of the motor performance of patients with MS. METHODS: In this study, 20 pre-rated videos of patients performing the finger-to-nose test were recorded. An autoencoder created encoded frame vectors from the original videos and decoded the videos again. The original and decoded videos were shown to 10 neurologists at an academic MS center in Basel, Switzerland. The neurologists tested whether the 200 videos were human-readable after decoding and rated the severity grade of each original and decoded video according to the Neurostatus-Expanded Disability Status Scale definitions of limb ataxia. Furthermore, the neurologists tested whether ratings were equivalent between the original and decoded videos. RESULTS: In total, 172 of 200 (86.0%) videos were of sufficient quality to be ratable. The intrarater agreement between the original and decoded videos was 0.317 (Cohen weighted kappa). The average difference in the ratings between the original and decoded videos was 0.26, in which the original videos were rated as more severe. The interrater agreement between the original videos was 0.459 and that between the decoded videos was 0.302. The agreement was higher when no deficits or very severe deficits were present. CONCLUSIONS: The vast majority of videos (172/200, 86.0%) decoded by the autoencoder contained clinically relevant information and had fair intrarater agreement with the original videos. Autoencoders are a potential method for enabling the use of patient videos while preserving data privacy, especially when non-health-care professionals are involved.

Setwise comparison: efficient fine-grained rating of movement videos using algorithmic support - a proof of concept study.

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.

Video-Based Pairwise Comparison: Enabling the Development of Automated Rating of Motor Dysfunction in Multiple Sclerosis.

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.

Electronic Neurostatus-EDSS increases the quality of expanded disability status scale assessments: Experience from two phase 3 clinical trials.

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.

Tasks of activities of daily living (ADL) are more valuable than the classical neurological examination to assess upper extremity function and mobility in multiple sclerosis.

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.

Reference videos reduce variability of motor dysfunction assessments in multiple sclerosis.

Motor dysfunction, particularly ataxia, is one of the predominant clinical manifestations in patients with multiple sclerosis (MS). Assessment of motor dysfunction suffers from a high variability. We investigated whether the clinical rating of ataxia can be improved through the use of reference videos, covering the spectrum of severity degrees as defined in the Neurostatus-Expanded Disability Status Scale. Twenty-five neurologists participated. The variability of their assessments was significantly lower when reference videos were used (SD = 0.12; range = 0.40 vs SD = 0.26; range = 0.88 without reference videos; p = 0.013). Reference videos reduced the variability of clinical assessments and may be useful tools to improve the precision and consistency in the clinical assessment of motor functions in MS.

The role of the cerebellum in multiple sclerosis-150 years after Charcot.

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.