Outside the Laboratory Assessment of Upper Limb Laterality in Patients With Stroke: A Cross-Sectional Study.

BACKGROUND: The rehabilitation of upper limb sensorimotor performance after stroke requires the assessment of daily use, the identification of key levels of impairment, and monitoring the course of recovery. It needs to be answered, how laboratory-based assessments and everyday behavior are connected, which dimension of metrics, that is, volume, intensity, or quality, is most sensitive to reduced function, and what sensor, that is, gyroscope or accelerometer, is best suited to gather such data. METHODS: Performance in laboratory-based sensorimotor tests, as well as smartwatch-derived kinematic data of everyday life relative upper limb activity, during 1 day of inpatient neurorehabilitation (Germany, 2022) of 50 patients with stroke, was cross-sectionally assessed and resulting laterality indices (performance ratios) between the limbs were analyzed using ANCOVAs and principal component analysis. RESULTS: Laboratory-based tests revealed the strongest laterality indices, followed by smartwatch-based (intensity>quality>volume) metrics. Angular velocity-based metrics revealed higher laterality indices than acceleration-based ones. Laterality indices were overall well associated; however, a principal component analysis suggested upper limb impairments to be unidimensional. CONCLUSIONS: Our findings suggest that the use of sensors can deliver valid information of stroke-related laterality. It appeared that commonly used metrics that estimate the volume of use (ie, energy expenditure) are not the most sensitive. Especially reached intensities could be well used for monitoring, because they are more dependent on the performance of the sensorimotor system and less on confounders like age. The unidimensionality of the upper limb laterality suggests that an impaired limb with reduced movement quality and the inability to reach higher intensities will be used less in everyday life, especially when it is the nondominant side.

Changes in thumb tapping rates and central motor conduction times are associated in persons with multiple sclerosis.

INTRODUCTION: In persons with multiple sclerosis, nerve conductivity can be reduced. The assessment is generally performed via motor evoked potentials (MEP). So far, a strongly associated motor performance surrogate for changes in the extracted central motor conduction time (CMCT) is missing. METHODS: CMCT and performance in the nine-hole peg test and maximum thumb tapping frequencies over 10 s of 12 persons with multiple sclerosis were measured prior to and after training over 5 consecutive days. Each training consisted of 10,000 thumb taps at maximum effort with the dominant upper limb. RESULTS: The dominant upper limb improved in maximum tapping frequency over 10 s (d = 0.79) and 10,000 taps (d = 1.04), the nine-hole peg test (d = 0.60), and CMCT (d = 0.52). The nondominant upper limb only improved in the nine-hole peg test (d = 0.38). Models of multiple linear regression predicted 0.78 (model 1, tapping performance as factors) and 0.87 (model 2, patient baseline characteristics as factors) of the variance in CMCT changes. DISCUSSION: Changes in CMCT were well predictable, although the assessment of those surrogates is either not economic (model 1) or rather describing a potential of change (model 2). However, we were able to show moderate changes in CMCT within 5 days.

Benefit-risk Assessment of Cladribine Using Multi-criteria Decision Analysis (MCDA) for Patients With Relapsing-remitting Multiple Sclerosis.

PURPOSE: We applied Multi-Criteria Decision Analysis (MCDA) methods in a structured benefit-risk assessment of cladribine and newer approved disease-modifying drugs (DMDs) for patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: Decision conferencing with clinical neurologists as decision makers was used to create an MCDA model that incorporated available evidence on DMDs for RRMS and clinical judgments about the relevance of the evidence. Benefit-risk assessments were conducted for DMDs in both patients with RRMS and patients with RRMS with high disease activity (HDA; defined as ≥2 relapses in the previous year). Treatment options included cladribine and recently approved DMDs available in European Union countries at the time of assessment (December 2015): alemtuzumab, dimethyl fumarate, fingolimod, natalizumab, and teriflunomide. To account for the relative importance of DMD effects, scores for the MCDA model were weighted to ensure that the most clinically important attributes carried more weight in the final benefit-risk calculation. The neurologists weighted different efficacy and safety profile attributes without any reference to individual DMDs to disassociate the assessment of weights with any specific DMD. The neurologists did not do direct comparisons between DMDs. FINDINGS: The highest overall weighted preference value for the RRMS model was for dimethyl fumarate (63) followed closely by cladribine (62). For patients with RRMS and HDA, cladribine had the highest overall weighted preference value (76), followed by alemtuzumab (62) and natalizumab (61). The benefit-risk balance of cladribine in patients with RRMS and specifically patients with RRMS who exhibited HDA characterized by high relapse activity (≥2 relapses in the previous year) was more favorable than the other DMDs included in the model. IMPLICATIONS: The balance of high efficacy and the safety profile makes cladribine an important treatment option to consider, both in patients with RRMS and patients with HDA. Regular, single-country meetings could be organized to explore how differences in cultural values (scores and weights) and updated input data might affect the usefulness of MCDA in different, real-world, dynamic clinical settings.

Unmet needs, burden of treatment, and patient engagement in multiple sclerosis: A combined perspective from the MS in the 21st Century Steering Group.

BACKGROUND: Patient engagement is vital in multiple sclerosis (MS) in order to optimise outcomes for patients, society and healthcare systems. It is essential to involve all stakeholders in potential solutions, working in a multidisciplinary way to ensure that people with MS (PwMS) are included in shared decision-making and disease management. To start this process, a collaborative, open environment between PwMS and healthcare professionals (HCPs) is required so that similarities and disparities in the perception of key areas in patient care and unmet needs can be identified. With this patient-centred approach in mind, in 2016 the MS in the 21st Century Steering Group formed a unique collaboration to include PwMS in the Steering Group to provide a platform for the patient voice. METHODS: The MS in the 21st Century initiative set out to foster engagement through a series of open-forum joint workshops. The aims of these workshops were: to identify similarities and disparities in the perception and prioritisation in three key areas (unmet needs, the treatment burden in MS, and factors that impact patient engagement), and to provide practical advice on how the gaps in perception and understanding in these key areas could be bridged. RESULTS: Combined practical advice and direction are provided here as eight actions: 1. Improve communication to raise the quality of HCP-patient interaction and optimise the limited time available for consultations. 2. Heighten the awareness of 'hidden' disease symptoms and how these can be managed. 3. Improve the dialogue surrounding the benefit versus risk issues of therapies to help patients become fully informed and active participants in their healthcare decisions. 4. Provide accurate, lucid information in an easily accessible format from reliable sources. 5. Encourage HCPs and multidisciplinary teams to acquire and share new knowledge and information among their teams and with PwMS. 6. Foster greater understanding and awareness of challenges faced by PwMS and HCPs in treating MS. 7. Collaborate to develop local education, communication and patient-engagement initiatives. 8. Motivate PwMS to become advocates for self-management in MS care. CONCLUSION: Our study of PwMS and HCPs in the MS in the 21st Century initiative has highlighted eight practical actions. These actions identify how differences and gaps in unmet needs, treatment burden, and patient engagement between PwMS and HCPs can be bridged to improve MS disease management. Of particular interest now are patient-centred educational resources that can be used during time-limited consultations to enhance understanding of disease and improve communication. Actively bridging these gaps in a joint approach enables PwMS to take part in shared decision-making; with improved communication and reliable information, patients can make informed decisions with their HCPs, as part of their own personalised disease management.

Electrophysiological assessment of nociception in patients with Parkinson's disease: A multi-methods approach.

OBJECTIVE: Nociceptive abnormalities indicating increased pain sensitivity have been reported in patients with Parkinson's disease (PD). The disturbances are mostly responsive to dopaminergic (DA) treatment; yet, there are conflicting results. The objective of the present study was to investigate pain processing and nociception in PD patients in a more comprehensive manner than previous studies. For this purpose, a multi-methods approach was used in order to monitor different levels of the central nervous system (spinal, subcortical-vegetative, cortical). METHODS: The heat-pain threshold, contact-heat evoked brain potentials (CHEPs) and sympathetic skin responses (SSR), nociceptive flexion responses (NFR) and subjective pain ratings were measured in 23 idiopathic PD patients both in the Off-phase (without DA medication) and On-phase (after DA medication intake) as well as in 23 healthy controls. RESULTS: Compared to controls, PD patients showed decreased heat-pain thresholds only in the Off and tentatively increased NFR amplitudes in both phases. We found no between-group differences for the CHEPs, the NFR threshold/latency or the pain ratings. Yet, SSR amplitudes/frequencies were decreased and latencies were increased in PD patients in both phases. Correlations between CHEPs amplitudes and pain ratings were found only in controls. DISCUSSION: Increased pain sensitivity (heat-pain threshold) in the Off which normalizes in the On argues for DA induced dysfunctions of the nigrostriatal pain loops with the basal ganglia as main circuit in our PD sample. Dysfunctions of the subcortical-vegetative parameters despite of inconspicuous cortical nociception suggest disturbances of the central or peripheral innervation of sympathetic branches with coincidently intact ascending pathways in the PD group.

Assessment of microRNA-related SNP effects in the 3' untranslated region of the IL22RA2 risk locus in multiple sclerosis.

Recent large-scale association studies have identified over 100 MS risk loci. One of these MS risk variants is single-nucleotide polymorphism (SNP) rs17066096, located ~14 kb downstream of IL22RA2. IL22RA2 represents a compelling MS candidate gene due to the role of IL-22 in autoimmunity; however, rs17066096 does not map into any known functional element. We assessed whether rs17066096 or a nearby proxy SNP may exert pathogenic effects by affecting microRNA-to-mRNA binding and thus IL22RA2 expression using comprehensive in silico predictions, in vitro reporter assays, and genotyping experiments in 6,722 individuals. In silico screening identified two predicted microRNA binding sites in the 3'UTR of IL22RA2 (for hsa-miR-2278 and hsa-miR-411-5p) encompassing a SNP (rs28366) in moderate linkage disequilibrium with rs17066096 (r (2) = 0.4). The binding of both microRNAs to the IL22RA2 3'UTR was confirmed in vitro, but their binding affinities were not significantly affected by rs28366. Association analyses revealed significant association of rs17066096 and MS risk in our independent German dataset (odds ratio = 1.15, P = 3.48 × 10(-4)), but did not indicate rs28366 to be the cause of this signal. While our study provides independent validation of the association between rs17066096 and MS risk, this signal does not appear to be caused by sequence variants affecting microRNA function.

Reduction in healthcare and societal resource utilization associated with cladribine tablets in patients with relapsing-remitting multiple sclerosis: analysis of economic data from the CLARITY Study.

BACKGROUND: Multiple sclerosis (MS) is a common, chronic, neurodegenerative condition associated with substantial healthcare and societal economic burden. Disease-modifying MS treatments have the potential to reduce health resource utilization (HRU), thereby reducing the attendant socioeconomic burden. OBJECTIVE: This study aimed to compare health and societal resource use and productivity in patients with relapsing-remitting MS (RRMS) receiving cladribine tablets versus placebo over 96 weeks in the CLARITY study. METHODS: The CLARITY study was a 96-week, randomized, double-blind, placebo-controlled study in patients with RRMS. HRU data, societal resource use and productivity data were collected at baseline and during scheduled patient visits, at 6-month intervals. The recall period for the HRU questionnaire was 3 months. The study was carried out at 155 sites across 32 countries worldwide. The intent-to-treat population comprised 1326 patients with RRMS randomized to cladribine 3.5 mg/kg (n = 433) or 5.25 mg/kg (n = 456) tablets or placebo (n = 437). Patient subgroups with high baseline disease activity were identified based on criteria of ≥2 relapses in the previous year (n = 392); ≥1 T1 gadolinium-enhancing (Gd+) lesion (n = 413); and ≥2 relapses in the previous year plus ≥1 T1 Gd+ lesion (n = 138). Cladribine tablets were administered in two (3.5 mg/kg group) or four (5.25 mg/kg group) short courses given at 4-week intervals at the start of a 48-week treatment period, followed by another two courses at the start of a subsequent 48-week re-treatment period. Interferon-ß rescue therapy was permitted from week 24. Intravenous corticosteroids were available for the treatment of neurological relapses. HRU outcomes included mean number of hospital days and emergency room (ER), clinic and home visits during each study period. Societal resource use and productivity outcomes included mean number of hours and days of paid assistance, mean patient and carer work days missed, and self-reported productivity. RESULTS: The mean number of hospital days per patient over 96 weeks was lower in the cladribine tablets groups (3.5 mg/kg group: -3.19 days; 5.25 mg/kg group: -1.54 days [both p < 0.01]) versus placebo. Likewise the mean number of ER visits was lower in both cladribine tablet groups compared with placebo (3.5 mg/kg group: -0.09 visits; 5.25 mg/kg group: -0.11 visits [both p < 0.01]), and the mean number of clinic visits was also lower in both cladribine tablet groups (3.5 mg/kg group: -0.68 visits; 5.25 mg/kg group: -0.66 visits [both p = 0.01]). Furthermore, treatment with cladribine tablets was associated with reduced mean numbers of missed work days for patients (3.5 mg/kg group: -2.42 days [p < 0.01]; 5.25 mg/kg group: -0.60 days [p = 0.50]). Corticosteroid use was lower amongst patients in the cladribine tablet groups than in the placebo group. The reduction in hospital days following treatment with cladribine tablets was also observed in patients with high disease activity at study baseline. CONCLUSION: This study provides evidence that the efficacy of cladribine tablets observed during the CLARITY study was associated with a reduced consumption of healthcare resources and a decreased need for medical and societal support. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00213135; EudraCT number: 2004-005148-28.

Socio-economic aspects of neuroimmunological diseases.

Neuroimmunological diseases often have a chronic course and a high socio-economic impact, as most of them occur in younger patients and result in progressing disability and loss of work force. Although for many conditions different treatment strategies are available no sufficient data exist to give a reasonable account on the cost effectiveness of individual therapies. Treatment decision should primarily be guided by evidence from high quality clinical studies and-if available-from direct head-to-head trials and cost-effectiveness analysis.

Improving MS patient care.

Multiple sclerosis (MS) is a multidimensional, chronic, neurological disease affecting young people that often interferes with their life and career plans. Patient care begins at the time of diagnosis, and particular emphasis should be placed on proper education about the variable disease course and treatment options. Clinical assessment at regular intervals using quantitative measures is recommended in order to obtain important information on the effects of disease-modifying and/or symptomatic treatment. In addition to optimising therapy, it is imperative to develop effective and properly resourced care services for MS patients that will address their complex and lifelong requirements.

Health outcomes in multiple sclerosis.

PURPOSE OF REVIEW: Economic considerations are increasingly important in the evaluation of innovative medical technologies. In the past few years, evaluations of cost and cost-effectiveness analysis became a popular topic for multiple sclerosis research. Here, we review cost-of-illness and cost-utility studies in multiple sclerosis published during the past 2 years. RECENT FINDINGS: Despite differences in methodology, several cost-of-illness studies unequivocally demonstrated that indirect costs as a result of sick leave, premature retirement or loss of income made up almost half of the overall costs, and that total costs were higher in the more advanced stages of the disease. Cost-effectiveness studies of recombinant IFN-beta preparations demonstrated a marked variability in the incremental cost per quality-adjusted life-year, with amounts ranging from Euro 28 432 to US$338 738. For glatiramer acetate and mitoxantrone, only limited data are available, but even these few studies differed in their results. SUMMARY: Health outcome studies constitute a new and emerging field of multiple sclerosis research. All studies performed so far underscore the importance of indirect cost in multiple sclerosis. However, the marked differences in cost-effectiveness studies illustrate that the method of economic modeling has considerable impact on the results of these studies, which need standardization in order to evaluate properly the economic consequences of new and expensive therapies in multiple sclerosis.

Early intervention in multiple sclerosis : better outcomes for patients and society?

Multiple sclerosis (MS) is thought to be a chronic inflammatory disorder of the CNS. The past decade has seen the introduction of the new immunomodulatory drugs, interferon (IFN)-beta and glatiramer acetate, that have considerably improved the therapeutic options for this often disabling disease. The efficacy of these treatments in terms of reducing relapse rate and slowing progression has been proven in several large, multicentre, randomised, controlled trials. Similarly, early IFNbeta treatment of patients with clinically isolated syndromes suggestive of MS has been shown to lengthen time to conversion into definite MS. Cost-effectiveness has been questioned with the increasing use of these innovative and, therefore, costly therapies; however, modern studies with appropriate economic modelling suggest that treatment with IFNbeta may indeed be cost-effective. Since increasing disability is associated with increasing costs, stabilisation of the disease at low functional grades of disability should aim at not only improving quality of life for the individual patient, but provide for prospective cost-benefit analysis focussing on the socioeconomic aspects of MS.