Marcus D’Souza

Combined evoked potentials as markers and predictors of disability in early multiple sclerosis

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.

Quantifying Progression of Multiple Sclerosis via Classification of Depth Videos

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.

Electrophysiological markers and predictors of the disease course in primary progressive multiple sclerosis

Background: Currently no valid surrogate marker exists for primary progressive multiple sclerosis (PPMS). Objective: Our aim was to prospectively investigate multimodal evoked potentials (EPs) as markers and predictors of the disease course in PPMS. Methods: Twenty-two PPMS patients were prospectively examined with visual, somatosensory and motor EPs and Expanded Disability Status Scale (EDSS) assessments at baseline (T0) and at six-month intervals over three years. Spearman rank correlation was used to determine the relationship between EP measures and EDSS. The relationship between disease evolution and a numerical score derived from z-transformed EP-latencies (s-EP-Q) and baseline characteristics was further assessed using multivariable linear regression analysis. Results: s-EP-Q correlated with EDSS score at all points in time in cross-sectional comparison (0.53≤rs ≤0.68; 0.0007≤p≤0.0232) and also longitudinally by trend (rs=0.46, p=0.0740). The s-EP-QT0 correlated with the EDSS score at year 3 (T6) (rs=0.77, p<0.0001). The s-EP-Q changes became statistically significant six months before corresponding changes were seen in the EDSS score. EDSST6 as predicted by EDSST6= −1.027+0.037* age+0.217* s-EP-QT0 + 0.695* EDSST0 correlated with the observed values (rs=0.92, p<0.0001). Conclusions: Multimodal EPs correlate well with disability in PPMS, and allow some prediction of the disease course over three years. These findings support a role of EPs as surrogate markers in clinical trials in PPMS.

On the origin of Neurostatus

In his commentary (Kurtzke, 2015) Dr. Kurztke recapitulates the rationale and the underlying evidence for the development of the Functional Systems (FS), the Disability Status Scale (DSS) and the Expanded Disability Status Scale (EDSS). This commentary and several of the authors previous publications on this topic (Kurtzke, 1955, 1965, 1970, 1983, 1989, 2007, 2008) underline his unique and widely appreciated contribution: Dr. Kurtzke created a scale that was a major step in comprehensively assessing neurologic impairment and disability in people with MS in the course of their disease. Although frequently criticized and challenged by other scales, the (E)DSS and its FS have persisted and hold a central role as an assessment tool in MS observational and therapeutic studies and have also – with some caveats – entered daily practice for the description and communication about the status of individual patients. Reemphasizing a statement from a previous review (Kurtzke, 2008), Dr. Kurtzke acknowledges that following his publications, the (E)DSS and FS entered the public domain and started being used in variable contexts all over the world. With increasing experience it was inevitable that investigators would also realize the scales limitations. Many peer reviewed original publications, reviews and consensus statements (Willoughby

Neurostatus e-Scoring improves consistency of Expanded Disability Status Scale assessments: A proof of concept study:

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.

Monitoring multiple sclerosis by multimodal evoked potentials: Numerically versus ordinally scaled scoring systems

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.

Lesion-to-ventricle distance and other risk factors for the persistence of newly formed black holes in relapsing–remitting multiple sclerosis

Background: Progenitor cells from the subventricular zone (SVZ) of the lateral ventricles are assumed to contribute to remyelination and resolution of black holes (BHs) in multiple sclerosis (MS). This process may depend on the distance between the lesion and the SVZ. Objective: The objective of this paper is to investigate the relationship between lesion-to-ventricle (LV) distance and persistence of new BHs. Methods: We analysed the magnetic resonance images (MRIs) of 289 relapsing–remitting (RR) MS patients, obtained during a multi-centre, placebo-controlled phase II trial over one year. Results: Overall, 112/289 patients showed 367 new BHs at the beginning of the trial. Of these, 225 were located in 94/112 patients at the level of the lateral ventricles on axial MRIs and included in this analysis. In total, 86/225 (38%) BHs persisted at month 12. LV distance in persistent BHs (PBHs) was not longer than in transient BHs. In fact PBHs tended to be closer to the SVZ than transient BHs. A generalised linear mixed multivariate model adjusted for BHs clustered within a patient and including patient- as well as lesion-specific factors revealed size, ring contrast enhancement, and shorter LV distance as independent predictors for BH persistence. Conclusion: Location of BHs close to the lateral ventricles does not appear to favourably influence the resolution of new BHs in RRMS.

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

HIGHLIGHTSThe cerebellum is a prevalent site of Multiple Sclerosis (MS) disease pathology.Extent of cerebellar MS pathology is comparable to its related network counterparts.Proof of ubiquitous cerebellar involvement in MS dysfunction incl. cognitive decline.New technologies may overcome limitations in assessment of cerebellar dysfunction.Advanced methods are needed to characterize disease dynamics in longitudinal studies. ABSTRACT 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.

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.

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.