Christian P. Kamm

Multiple Sclerosis: Current Knowledge and Future Outlook

Background: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by demyelination and axonal loss. The etiology of MS is unknown; however, environmental and genetic factors play a key role in the development of MS. Diagnostic criteria have been adapted to facilitate earlier diagnosis with increased sensitivity and specificity. Our understanding of the pathophysiology of MS has deepened considerably in recent years, resulting in different therapies to modify the disease course. Furthermore, several drugs have lately shown efficacy in phase III studies and their approval is expected in the near future. As treatment options expand, a future challenge will be to find the optimal treatment for the individual patient. Summary: This mini-review gives an overview of the current knowledge of MS with emphasis on the latest diagnostic criteria and both current and upcoming treatment options. Key Messages: Treatment of MS changes rapidly as the knowledge and therapeutic options in MS expand. Clinical Impact: Diagnosis of MS is based on McDonald criteria. MS therapy can be divided into relapse, disease-modifying and symptomatic treatment. Relapses are commonly treated with intravenous methylprednisolone. First-line therapy consists of either interferon-β, glatiramer acetate or teriflunomide. In general, agents used as escalation therapies (natalizumab, fingolimod and mitoxantrone) are more potent than the agents used for first-line therapy; however, these have potentially serious side effects and should be used with care.

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.

Effect of interferon-beta and atorvastatin on Th1/Th2 cytokines in multiple sclerosis.

Beneficial effects by both interferon-beta and statin treatment in patients with multiple sclerosis (MS) may be linked to interference with the Th1/Th2 cytokine balance. We determined patterns of Th1/Th2 cytokines (interleukin (IL)-1beta, IL-2, IL-6, IL-12p70, tumor-necrosis factor (TNF)-alpha and interferon-gamma, and IL-4, IL-5 and IL-10, respectively) in the serum of patients with relapsing-remitting MS treated with 250microg interferon-beta 1b or with interferon-beta plus 40mg atorvastatin. In treatment naïve patients with MS, a trend for lower TNF-alpha serum levels compared to controls was detected (P=0.08). Interferon-beta treatment increased TNF-alpha levels, while a trend for lowering of IL-5 serum levels was found (P=0.07). Addition of atorvastatin raised IL-12p70 serum levels (P<0.05). Mean levels of two Th2 cytokines (IL-4, IL-10) showed a non-significant increase after addition of atorvastatin. We conclude that interferon-beta and atorvastatin exert divergent action on Th1/Th2 serum cytokines levels in MS. Supplemental atorvastatin might promote a Th1-type response by raising IL-12p70. Further studies are required to support a Th2 cytokine shift by atorvastatin in patients with MS.

Atorvastatin Added to Interferon Beta for Relapsing Multiple Sclerosis: 12-Month Treatment Extension of the Randomized Multicenter SWABIMS Trial

Background Statins have anti-inflammatory and immunomodulatory properties in addition to lipid-lowering effects. Objectives To report the 12-month extension of a phase II trial evaluating the efficacy, safety and tolerability of atorvastatin 40 mg/d added to interferon beta-1b (IFNB-1b) in relapsing-remitting multiple sclerosis (RRMS). Methods In the randomized, multicenter, parallel-group, rater-blinded core study, 77 RRMS patients started IFNB-1b. At month three they were randomized 1∶1 to receive atorvastatin 40 mg/d or not in addition to IFNB-1b until month 15. In the subsequent extension study, patients continued with unchanged medication for another 12 months. Data at study end were compared to data at month three of the core study. Results 27 of 72 patients that finished the core study entered the extension study. 45 patients were lost mainly due to a safety analysis during the core study including a recruitment stop for the extension study. The primary end point, the proportion of patients with new lesions on T2-weighted images was equal in both groups (odds ratio 1.926; 95% CI 0.265–14.0007; p = 0.51). All secondary endpoints including number of new lesions and total lesion volume on T2-weighted images, total number of Gd-enhancing lesions on T1-weighted images, volume of grey and white matter, EDSS, MSFC, relapse rate, number of relapse-free patients and neutralizing antibodies did not show significant differences either. The combination therapy was well tolerated. Conclusions Atorvastatin 40 mg/day in addition to IFNB-1b did not have any beneficial effects on RRMS compared to IFNB-1b monotherapy over a period of 24 months. Trial Registration ClinicalTrials.gov NCT01111656

Corticospinal output during muscular fatigue differs in multiple sclerosis patients compared to healthy controls

Background: In multiple sclerosis (MS), fatigue is a common and often disabling symptom. It has multiple causes with central motor fatigue playing an important role. Objective: The objective of this study was to analyse the central motor conduction changes in relation to muscle contraction force during muscle fatigue and recovery in MS patients compared to healthy controls. Methods: A total of 23 MS patients with fatigue and 13 healthy subjects were assessed during 2 minutes of fatiguing exercise of the abductor digiti minimi muscle of the hand and the subsequent 7 minutes of recovery. Central motor conduction was quantified by transcranial magnetic stimulation using the triple stimulation protocol and calculating a central conduction index (CCI). Results: Force declined to 36% of the pre-exercise level (SD 16%; p < 0.01) in MS patients and to 44% (SD 9%, p < 0.01) in healthy subjects (group differences, not statistically significant). The decline of the CCI was significantly less marked in patients (–20%, SD 26%, p < 0.05) than in healthy subjects (–57%, SD 15%, p < 0.05; group differences, p < 0.05). The decline of force and CCI were not correlated in either group. Conclusions: During a fatiguing exercise, the decline in central motor conduction is significantly less pronounced in MS patients than healthy subjects, although the reduction of force is similar.

Usability and Acceptability of ASSESS MS: Assessment of Motor Dysfunction in Multiple Sclerosis Using Depth-Sensing Computer Vision

Background Sensor-based recordings of human movements are becoming increasingly important for the assessment of motor symptoms in neurological disorders beyond rehabilitative purposes. ASSESS MS is a movement recording and analysis system being developed to automate the classification of motor dysfunction in patients with multiple sclerosis (MS) using depth-sensing computer vision. It aims to provide a more consistent and finer-grained measurement of motor dysfunction than currently possible. Objective To test the usability and acceptability of ASSESS MS with health professionals and patients with MS. Methods A prospective, mixed-methods study was carried out at 3 centers. After a 1-hour training session, a convenience sample of 12 health professionals (6 neurologists and 6 nurses) used ASSESS MS to capture recordings of standardized movements performed by 51 volunteer patients. Metrics for effectiveness, efficiency, and acceptability were defined and used to analyze data captured by ASSESS MS, video recordings of each examination, feedback questionnaires, and follow-up interviews. Results All health professionals were able to complete recordings using ASSESS MS, achieving high levels of standardization on 3 of 4 metrics (movement performance, lateral positioning, and clear camera view but not distance positioning). Results were unaffected by patients’ level of physical or cognitive disability. ASSESS MS was perceived as easy to use by both patients and health professionals with high scores on the Likert-scale questions and positive interview commentary. ASSESS MS was highly acceptable to patients on all dimensions considered, including attitudes to future use, interaction (with health professionals), and overall perceptions of ASSESS MS. Health professionals also accepted ASSESS MS, but with greater ambivalence arising from the need to alter patient interaction styles. There was little variation in results across participating centers, and no differences between neurologists and nurses. Conclusions In typical clinical settings, ASSESS MS is usable and acceptable to both patients and health professionals, generating data of a quality suitable for clinical analysis. An iterative design process appears to have been successful in accounting for factors that permit ASSESS MS to be used by a range of health professionals in new settings with minimal training. The study shows the potential of shifting ubiquitous sensing technologies from research into the clinic through a design approach that gives appropriate attention to the clinic environment.

Limb apraxia in multiple sclerosis: prevalence and impact on manual dexterity and activities of daily living

OBJECTIVE To evaluate the prevalence and impact of limb apraxia on manual dexterity and activities of daily living (ADLs) in patients with multiple sclerosis (MS). DESIGN Survey. SETTING University hospital. PARTICIPANTS Consecutive patients (N=76) with clinically isolated syndrome, relapsing-remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS) or primary progressive multiple sclerosis (PPMS), Expanded Disability Status Scale (EDSS) score from 0 to 6.5, and aged from 18 to 70 years were included. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES Apraxia was assessed by the apraxia screen of TULIA (AST). The relationship of apraxia with ADLs and manual dexterity was evaluated using a dexterity questionnaire and the coin rotation task, respectively. RESULTS Overall, limb apraxia was found in 26.3% of patients (mean AST score ± SD, 7.3±1.3; cutoff <9). Apraxia was significantly correlated with higher EDSS scores, longer disease duration, and higher age with the EDSS being predictive. Furthermore, patients with SPMS and PPMS were more apraxic than patients with RRMS. Finally, limb apraxia was significantly associated with impaired ADLs and manual dexterity. CONCLUSIONS Limb apraxia is a frequent and clinically significant symptom contributing to disability in MS. It should therefore be evaluated and possibly treated, particularly in patients with MS reporting manual difficulties in everyday life.

Interdisciplinary cardiovascular and neurologic outpatient rehabilitation in patients surviving transient ischemic attack or stroke with minor or no residual deficits.

OBJECTIVE To evaluate the feasibility and effectiveness of a comprehensive outpatient rehabilitation program combining secondary prevention and neurorehabilitation to improve vascular risk factors, neurologic functions, and health-related quality of life (HRQOL) in patients surviving a transient ischemic attack (TIA) or stroke with minor or no residual deficits. DESIGN Prospective interventional single-center cohort study. SETTING University hospital. PARTICIPANTS Consecutive consenting patients having sustained a TIA or stroke with 1 or more vascular risk factors (N=105) were included. INTERVENTIONS Three-month hospital-based secondary prevention and neurorehabilitation outpatient program with therapeutic and educational sessions twice a week. Patients were evaluated at entry and program end. MAIN OUTCOME MEASURES Impact on vascular risk factors, neurological outcome, and HRQOL. RESULTS A total of 105 patients entered the program and 95 patients completed it. Exercise capacity (P<.000), smoking status (P=.001), systolic (P=.001) and diastolic (P=.008) blood pressure, body mass index (P=.005), low-density lipoprotein cholesterol (P=.03), and triglycerides (P=.001) improved significantly. Furthermore, the 9-Hole-Peg-Test (P<.000), Six-minute Walking Test (P<.000), and One Leg Stand Test (P<.011) values as well as HRQOL improved significantly. The program could be easily integrated into an existing cardiovascular prevention and rehabilitation center and was feasible and highly accepted by patients. CONCLUSIONS Comprehensive combined cardiovascular and neurologic outpatient rehabilitation is feasible and effective to improve vascular risk factors, neurologic functions, and HRQOL in patients surviving TIA or stroke with minor or no residual deficits.

SWiss Atorvastatin and Interferon Beta-1b Trial In Multiple Sclerosis (SWABIMS) - rationale, design and methodology

BackgroundStatins have anti-inflammatory and immunomodulatory properties in addition to their lipid-lowering effects. Currently, the effects of statins on multiple sclerosis are still controversial. Therefore, randomized clinical trials are needed to provide better evidence on the therapeutic potential of statins in multiple sclerosis. The SWiss Atorvastatin and Interferon Beta-1b trial in Multiple Sclerosis (SWABIMS) evaluates the efficacy, safety and tolerability of atorvastatin 40 mg per os daily and subcutaneous interferon beta-1b every other day compared to monotherapy with subcutaneous interferon beta-1b every other day in patients with relapsing-remitting multiple sclerosis.Methods/DesignSWABIMS is a multi-centre, randomized, parallel-group, rater-blinded, Phase IIb-study conducted in eight hospitals in Switzerland. 80 treatment naïve patients with relapsing-remitting forms of multiple sclerosis will receive subcutaneous interferon beta-1b for three months. Afterwards, they are randomized into two equal-sized parallel arms, receiving atorvastatin 40 mg/d or not in addition to interferon beta-1b for another 12 months. Disease activity measured by the proportion of patients with new T2 lesions is the primary endpoint.DiscussionSWABIMS is designed to give further information about the therapeutic effect of atorvastatin 40 mg per os daily as add-on therapy to interferon beta-1b in patients with relapsing-remitting multiple sclerosis. Furthermore important safety and tolerability data will be generated.Trial Registrationhttp://www.clinicaltrials.gov. Identifier: NCT00942591; Swissmedic reference number: 2005DR2119

Setwise Comparison: Consistent, Scalable, Continuum Labels for Computer Vision

A growing number of domains, including affect recognition and movement analysis, require a single, real number ground truth label capturing some property of a video clip. We term this the provision of continuum labels. Unfortunately, there is often an uncacceptable trade-off between label consistency and the efficiency of the labelling process with current tools. We present a novel interaction technique, setwise comparison, which leverages the intrinsic human capability for consistent relative judgements and the TrueSkill algorithm to solve this problem. We describe SorTable, a system demonstrating this technique. We conducted a real-world study where clinicians labelled videos of patients with multiple sclerosis for the ASSESS MS computer vision system. In assessing the efficiency-consistency trade-off of setwise versus pairwise comparison, we demonstrated that not only is setwise comparison more efficient, but it also elicits more consistent labels. We further consider how our findings relate to the interactive machine learning literature.