Sensitive Identification of Asymmetries and Neuromuscular Deficits in Lower Limb Function in Early Multiple Sclerosis.

BACKGROUND: In the early stages of multiple sclerosis (MS), there are no objective sensitive functional assessments to identify and quantify early subclinical neuromuscular deficits and lower limb strength asymmetries during complex movements. Single-countermovement jumps (SLCMJ), a maximum single leg vertical jump, on a force plate allow functional evaluation of unilateral lower limb performance in performance diagnostics and could therefore provide early results on asymmetries in MS. OBJECTIVE: Objective evaluation of early lower limb neuromuscular deficits and asymmetries in people with multiple sclerosis (pwMS) using SLCMJ on a force plate. METHODS: A study was conducted with pwMS (N = 126) and healthy controls (N = 97). All participants performed 3 maximal SLCMJs on a force plate. Temporal, kinetic, and power jump parameters were collected. The Expanded Disability Status Scale (EDSS) was performed on all participants. A repeated measures analysis of covariance (ANCOVA) with age, Body-Mass-Index, and gender as covariates was used. RESULTS: PwMS with normal muscle strength according to the manual muscle tests showed significantly reduced SLCMJ performance compared to HC. In both groups, jumping performance differed significantly between the dominant and non-dominant leg, with higher effect size for pwMS. A significant interaction effect between leg dominance and group was found for propulsive time, where the pwMS showed an even higher difference between the dominant and non-dominant leg compared to HC. Furthermore, there was a significant small correlation between leg asymmetries and EDSS in pwMS. CONCLUSION: The study shows that the SLCMJ on a force plate is suitable for the early detection of subclinical lower limb neuromuscular deficits and strength asymmetries in MS.

Insights from Real-World Practice: The Dynamics of SARS-CoV-2 Infections and Vaccinations in a Large German Multiple Sclerosis Cohort.

The SARS-CoV-2 pandemic profoundly impacted people with multiple sclerosis (pwMS). Disease-related aspects and demographic factors may influence vaccination rates, infection susceptibility, and severity. Despite prior research, comprehensive real-world data obtained throughout the pandemic remain limited. We investigated SARS-CoV-2 vaccination and infection patterns in a large monocentric real-world cohort. We collected prospective data from medical visits at the MS Center Dresden, Germany, from the pandemic's beginning until 31 May 2022. Logistic regression and rank correlation analyses were used to explore associations between SARS-CoV-2 outcomes and patient characteristics. Of 2115 pwMS assessed (mean age 46.5, SD ± 12.9; median expanded disability status scale 2.5), 77.9% were under disease-modifying treatment (DMT), primarily B-cell depletion (25.4%). A total of 35.5% reported SARS-CoV-2 infections, and 77.4% were fully vaccinated. PwMS with increased disability, older age, and comorbidities were associated with higher vaccination rates, possibly due to the awareness of these populations regarding complications of SARS-CoV-2 infections. Infections were more common in younger females, people with a lower degree of disability, those with relapsing MS, and those who were not vaccinated. PwMS on B-cell depletion reported more infections than untreated pwMS and those receiving other types of disease-modifying therapy, despite higher vaccination rates. Most infections were mild, with no severity differences according to demographic or disease-related factors, except for gender. Notably, all fatal cases occurred in unvaccinated pwMS. Our studies suggest that demographic and disease-related factors, especially age and the use of B-cell depletion, significantly influenced SARS-CoV-2 vaccination and infection rates in our cohort. These factors may be considered in future preventive campaigns in further pandemics.

An audit of 1632 routinely collected cervical cancer screening smears from 398 women in Germany: Results from the TeQaZ Study.

OBJECTIVE: There is evidence in Germany that half of the cervical cancer (CC) cases had undergone screening frequently in the decade preceding their diagnosis, signaling cytology quality issues. This study investigates routine smear assessment accuracy in Germany. METHODS: Within a population-based case-control study in 9 German states, we recruited cases (women with a histologically confirmed diagnosis of CC) and population controls (women with no history of CC or hysterectomy). Two independent expert cytologists audited Pap smears taken within the 10 years preceding CC diagnosis (cases)/study entry (controls). We report the prevalence of positive results, as well as routine assessment's accuracy, as sensitivity, specificity, false-positive and false-negative rates along with 95% confidence intervals (95% CI). We also examined cases' smear history, to investigate possible false-positive recurrence. RESULTS: We audited 1632 smears of 392 women (18.9% cases, 81.1% controls). In the routine assessment, the overall prevalence of positive results was 4.5% (29.0% among cases). According to the expert audit, the overall prevalence of positive results was 7.7% (40.8% among cases). When restricting analyses to the 3 years preceding diagnosis/study entry, this prevalence increased to 11.9% overall (61.4% among cases). The overall sensitivity of the routine assessment was 54.9% (66.8% for cases). CONCLUSION: As cytology remains an important part of CC screening, quality issues must be urgently addressed in Germany. Shifting to objective methods such as primary high-risk HPV screening followed by triaging may help CC elimination in Germany.

Modelling the effect of demographic change and healthcare infrastructure on the patient structure in German hospitals - a longitudinal national study based on official hospital statistics.

BACKGROUND: Effects of demographic change, such as declining birth rates and increasing individual life expectancy, require health system adjustments offering age- and needs-based care. In addition, healthcare factors can also influence health services demand. METHODS: The official German hospital statistics database with odd-numbered years between 1995 and 2011 was analysed. This is a national comprehensive database of all general hospital inpatient services delivered. Official data from hospital statistics were linked at the district level with demographic and socio-economic data as well as population figures from the official regional statistics. Panel data regression, modelling case numbers per hospital, was performed for 13 diagnosis groups that characterised the patient structure. Socio-demographic variables included age, sex, household income, and healthcare factors included bed capacity, personnel and hospital characteristics. RESULTS: The median number of annual treatments per hospital increased from 6 015 (5th and 95th percentile [670; 24 812]) in 1995 to 7 817 in 2011 (5th and 95th percentile [301; 33 651]). We developed models characterising the patient structure of health care in Germany, considering both socio-demographic and hospital factors. Demographic factors influenced case numbers across all major diagnosis groups. For example, the age groups 65-74 and 75 + influenced cerebrovascular disease case numbers (p < 0.001). Other important factors included human and material resources of hospitals or the household income of patients. Distinct differences between the models for the individual diagnosis groups were observed. CONCLUSIONS: Hospital planning should not only consider demographic change but also hospital infrastructure and socio-economic factors.

Countermovement Jumps Detect Subtle Motor Deficits in People with Multiple Sclerosis below the Clinical Threshold.

In the early stages of multiple sclerosis (MS), there are currently no sensitive assessments to evaluate complex motor functions. The countermovement jump (CMJ), a high-challenge task in form of a maximal vertical bipedal jump, has already been investigated as a reliable assessment in healthy subjects for lower extremity motor function. The aim was to investigate whether it is possible to use CMJ to identify subthreshold motor deficits in people with multiple sclerosis (pwMS). All participants (99 pwMS and 33 healthy controls) performed three maximal CMJs on a force plate. PwMS with full motor function and healthy controls (HC) did not differ significantly in age, disease duration, Body Mass Index and the Expanded Disability Scale Score. In comparison to HC, pwMS with full motor function demonstrated a significantly decreased CMJ performance in almost all observed kinetic, temporal and performance parameters (p < 0.05). With increasing disability in pwMS, it was also observed that jump performance decreased significantly. This study showed that the CMJ, as a high challenge task, could detect motor deficits in pwMS below the clinical threshold of careful neurological examination. Longitudinal studies are pending to evaluate whether the CMJ can be used as a standardized measure of disease progression.

Acute Effects of Ocrelizumab Infusion in Multiple Sclerosis Patients.

B cell-depleting therapies such as ocrelizumab (OCR) are highly effective in people with multiple sclerosis (MS). Especially at treatment start and initial infusion, infusion-related reactions (IRR) are a common adverse event. The relevance of acute changes of cell-depleting therapies on peripheral immune compartments and routine lab testing is important for clinical practice. We systematically analyzed routine blood parameters, detailed blood immunophenotyping and serum cytokine profiles in 45 MS patients starting on OCR. Blood samples were collected before and after corticosteroid premedication and directly after each OCR infusion of the first three ocrelizumab infusions. Blood B cells were rapidly depleted and accompanied only by a mild cytokine release at the first OCR infusion. Cytokine release was not significantly detectable from a third application in line with decreasing IRRs. B cell depletion was accompanied by short-lived changes in other immune cell populations in number, activation and cytokine secretion after each OCR infusion. Standard lab parameters did not show any clinically relevant changes. Our data demonstrate only mild changes during the first OCR infusion, which are not present any more during long-term treatment.

[The Multiple Sclerosis Health Resource Utilization Survey]. / Der Multiple Sclerosis Health Resource Utilization Survey.

BACKGROUND: In health economic studies, valid and reliable cost data are essential to reach meaningful conclusions. In the case of multiple sclerosis (MS), such studies are often based on primary data for which the underlying survey instruments have not been published. In addition, heterogeneous methods make the comparability and interpretation of such study results difficult. To standardize health economic studies in MS, the Multiple Sclerosis Health Resource Utilization Survey (MS-HRS) was developed, validated and published in a freely accessible format. RESEARCH QUESTION: This review focuses on the MS-HRS. We report on the methodological background of studies on the assessment of cost of illness as well as MS-HRS-based results on the costs of disease dynamics in people with MS. METHODS: This article is based on a selective literature review on the MS-HRS as well as on health economic aspects of cost assessment. RESULTS: The MS-HRS provides a holistic assessment of direct medical, direct non-medical and indirect resource utilization. Within indirect costs, we considered absenteeism, either short term (sick leave) or long term (disability pension), but also presenteeism, which refers to impaired performance during work. Resources were valued at the societal opportunity cost or the best possible approximation. First analyses based on MS-HRS showed that, in addition to inpatient disease severity and clinical course, disease dynamics in form of relapses and progression have enormous socioeconomic implications. CONCLUSION: Valid cost data bring transparency to the economic consequences of diseases. In addition to clinical data, cost data can be used to determine cost-effectiveness and thus reveal opportunities for more efficient patient care. For the case of MS, a freely accessible tool is available for cost assessments.

Cost of illness in multiple sclerosis by disease characteristics - A review of reviews.

INTRODUCTION: In light of the increasing number of economic burden studies and heterogeneity in methodology and reporting standards, there is a need for robust evidence synthesis on an umbrella review level. AREAS COVERED: We performed the first review of reviews of cost-of-illness studies in multiple sclerosis. Focusing on disaggregated costs by disease characteristics (disability level, relapse, disease course), we also characterized the underlying methodological evidence base of individual (primary) studies. EXPERT COMMENTARY: We identified 17 reviews encompassing 111 unique primary studies, and a high degree of overlap across reviews. Costs were substantial, rising with disability level, relapse episodes, and disease progression. Disability was the key cost driver. Compared to mild disability, total costs for moderate disability were 1.4-2.3-fold higher and 1.8-2.9-fold higher for severe disability. With escalating disability, the share of costs outside the health system (indirect costs, informal care) increasingly outweighed the share of direct medical costs. Of all 111 primary studies, 72% gathered resource use/loss data by patient self-report. Associated costs were mostly reported by disability level (75%), followed by relapse (48%) and disease course (21%). In conclusion, although heterogeneity can make in-depth comparisons of costs across studies impossible, important patterns are broadly apparent.

Digital Biomarkers in Multiple Sclerosis.

For incurable diseases, such as multiple sclerosis (MS), the prevention of progression and the preservation of quality of life play a crucial role over the entire therapy period. In MS, patients tend to become ill at a younger age and are so variable in terms of their disease course that there is no standard therapy. Therefore, it is necessary to enable a therapy that is as personalized as possible and to respond promptly to any changes, whether with noticeable symptoms or symptomless. Here, measurable parameters of biological processes can be used, which provide good information with regard to prognostic and diagnostic aspects, disease activity and response to therapy, so-called biomarkers Increasing digitalization and the availability of easy-to-use devices and technology also enable healthcare professionals to use a new class of digital biomarkers-digital health technologies-to explain, influence and/or predict health-related outcomes. The technology and devices from which these digital biomarkers stem are quite broad, and range from wearables that collect patients' activity during digitalized functional tests (e.g., the Multiple Sclerosis Performance Test, dual-tasking performance and speech) to digitalized diagnostic procedures (e.g., optical coherence tomography) and software-supported magnetic resonance imaging evaluation. These technologies offer a timesaving way to collect valuable data on a regular basis over a long period of time, not only once or twice a year during patients' routine visit at the clinic. Therefore, they lead to real-life data acquisition, closer patient monitoring and thus a patient dataset useful for precision medicine. Despite the great benefit of such increasing digitalization, for now, the path to implementing digital biomarkers is widely unknown or inconsistent. Challenges around validation, infrastructure, evidence generation, consistent data collection and analysis still persist. In this narrative review, we explore existing and future opportunities to capture clinical digital biomarkers in the care of people with MS, which may lead to a digital twin of the patient. To do this, we searched published papers for existing opportunities to capture clinical digital biomarkers for different functional systems in the context of MS, and also gathered perspectives on digital biomarkers under development or already existing as a research approach.

Using Machine Learning Algorithms for Identifying Gait Parameters Suitable to Evaluate Subtle Changes in Gait in People with Multiple Sclerosis.

In multiple sclerosis (MS), gait impairment is one of the most prominent symptoms. For a sensitive assessment of pathological gait patterns, a comprehensive analysis and processing of several gait analysis systems is necessary. The objective of this work was to determine the best diagnostic gait system (DIERS pedogait, GAITRite system, and Mobility Lab) using six machine learning algorithms for the differentiation between people with multiple sclerosis (pwMS) and healthy controls, between pwMS with and without fatigue and between pwMS with mild and moderate impairment. The data of the three gait systems were assessed on 54 pwMS and 38 healthy controls. Gaussian Naive Bayes, Decision Tree, k-Nearest Neighbor, and Support Vector Machines (SVM) with linear, radial basis function (rbf) and polynomial kernel were applied for the detection of subtle walking changes. The best performance for a healthy-sick classification was achieved on the DIERS data with a SVM rbf kernel (κ = 0.49 ± 0.11). For differentiating between pwMS with mild and moderate disability, the GAITRite data with the SVM linear kernel (κ = 0.61 ± 0.06) showed the best performance. This study demonstrates that machine learning methods are suitable for identifying pathologic gait patterns in early MS.

Impact of opportunistic screening on squamous cell and adenocarcinoma of the cervix in Germany: A population-based case-control study.

BACKGROUND: We investigated the uptake of opportunistic cervical cancer screening (CCS) and other risk factors and their association with cervical cancer in Germany in a case-control study. METHODS AND FINDINGS: We recruited incident cases of cervical cancer (ICD-10 C53) diagnosed between 2012 and 2016 and matched with three population-based controls, based on age and region of residence. Cases and controls reported their CCS participation during the past ten years (frequent: every three years; no or infrequent: less than every three years) and other relevant variables. We fitted conditional logistic regression models, reporting odds ratios (OR) and 95% confidence intervals (95% CI). We report overall and stratified analyses by histologic group (squamous cell-SCC, and adenocarcinoma-AC), T category (T1 and T2+), and age (<50 and ≥50 years). We analysed 217 cases and 652 matched controls. 53.0% of cases and 85.7% of controls attended CCS frequently. In the overall adjusted model, no or infrequent participation in CCS (OR 5.63; 95% CI 3.51 to 9.04), having had more than one sexual partner (OR 2.86; 95%CI 1.50 to 5.45) and obesity (OR 1.69; 95% CI 1.01 to 2.83) were associated with cervical cancer. Twelve years of schooling (OR 0.37; 95% CI 0.23 to 0.60) and a net monthly income of €3000 or more (OR 0.50; 95% CI 0.30 to 0.82) were protective factors. In the stratified analyses, no or infrequent participation was associated with T1 (OR 4.37; 95% CI 2.48 to 7.71), T2+ (OR 10.67; 95% CI 3.83 to 29.74), SCC (OR 6.88; 95% CI 4.08 to 11.59) and AC (OR 3.95; 95% CI 1.47 to 10.63). CONCLUSION: Although women who frequently attended CCS were less likely to develop cervical cancer, especially larger tumours, the high proportion of cases who had been frequently screened prior to diagnosis underscores the need to investigate the quality of cytology and treatment of precancerous lesions in Germany.

Electronic Health Interventions in the Case of Multiple Sclerosis: From Theory to Practice.

(1) Background: eHealth interventions play a growing role in shaping the future healthcare system. The integration of eHealth interventions can enhance the efficiency and quality of patient management and optimize the course of treatment for chronically ill patients. In this integrative review, we discuss different types of interventions, standards and advantages of quality eHealth approaches especially for people with multiple sclerosis (pwMS). (2) Methods: The electronic databases PubMed, Cochrane and Web of Science were searched to identify potential articles for eHealth interventions in pwMS; based on 62 articles, we consider different ways of implementing health information technology with various designs. (3) Results: There already exist some eHealth interventions for single users with a single-use case, interventions with a social setting, as well as eHealth interventions that integrate various single and social interventions and even those that may be used additionally for complex use cases. A key determinant of consumer acceptance is a high-quality user-centric design for healthcare practitioners and pwMS. In pwMS, the different neurological disabilities should be considered, and particular attention must be paid to the course of the treatment and the safety processes of each treatment option. (4) Conclusion: Depending on the field of application and the respective users, interventions are designed for single, social, integrated or complex use. In order to be accepted by their target group, interventions must be beneficial and easy to use.

Cervical Cancer Screening: Comparison of Conventional Pap Smear Test, Liquid-Based Cytology, and Human Papillomavirus Testing as Stand-alone or Cotesting Strategies.

BACKGROUND: Some countries have implemented stand-alone human papillomavirus (HPV) testing while others consider cotesting for cervical cancer screening. We compared both strategies within a population-based study. METHODS: The MARZY cohort study was conducted in Germany. Randomly selected women from population registries aged ≥30 years (n = 5,275) were invited to screening with Pap smear, liquid-based cytology (LBC, ThinPrep), and HPV testing (Hybrid Capture2, HC2). Screen-positive participants [ASC-US+ or high-risk HC2 (hrHC2)] and a random 5% sample of screen-negatives were referred to colposcopy. Post hoc HPV genotyping was conducted by GP5+/6+ PCR-EIA with reverse line blotting. Sensitivity, specificity (adjusted for verification bias), and potential harms, including number of colposcopies needed to detect 1 precancerous lesion (NNC), were calculated. RESULTS: In 2,627 screened women, cytological sensitivities (Pap, LBC: 47%) were lower than HC2 (95%) and PCR (79%) for CIN2+. Cotesting demonstrated higher sensitivities (HC2 cotesting: 99%; PCR cotesting: 84%), but at the cost of lower specificities (92%-95%) compared with HPV stand-alone (HC2: 95%; PCR: 94%) and cytology (97% or 99%). Cotesting versus HPV stand-alone showed equivalent relative sensitivity [HC2: 1.06, 95% confidence interval (CI), 1.00-1.21; PCR: 1.07, 95% CI, 1.00-1.27]. Relative specificity of Pap cotesting with either HPV test was inferior to stand-alone HPV. LBC cotesting demonstrated equivalent specificity (both tests: 0.99, 95% CI, 0.99-1.00). NNC was highest for Pap cotesting. CONCLUSIONS: Cotesting offers no benefit in detection over stand-alone HPV testing, resulting in more false positive results and colposcopy referrals. IMPACT: HPV stand-alone screening offers a better balance of benefits and harms than cotesting.See related commentary by Wentzensen and Clarke, p. 432.

Gender disparities in health resource utilization in patients with relapsing-remitting multiple sclerosis: a prospective longitudinal real-world study with more than 2000 patients.

BACKGROUND: For the case of multiple sclerosis, research on gender differences from a health economics perspective has not received much attention. However, cost-of-illness analyses can provide valuable information about the diverse impact of the disease and thus help decision-makers to allocate scarce resources. The aim of this study was to describe healthcare resource use and associated societal costs from a gender perspective. In particular, we aimed to identify how resource utilization potentially differs in certain cost components between men and women. METHODS: Clinical and economic data were extracted from two prospective, multicentre, non-interventional, observational studies in Germany. Information on health resource use was obtained from all patients on a quarterly basis using a validated questionnaire.Cost analyses were conducted from the societal perspective including all direct (healthcare-related) and indirect (work-related) costs, regardless of who bears them. Gender-related differences were analysed by a multivariable generalized linear model with a negative binomial distribution and log link function due to the right-skewed distribution pattern of cost data. In addition, costs for men and women were descriptively analysed within subgroups of two-year disease activity. RESULTS: In total, 2095 patients (women-to-men ratio of 2.7:1) presented a mean age of 41.85 years and a median Expanded Disability Status Scale of 2 (interquartile range 1-3.5) (p > 0.30 for gender-related differences). Women and men did not statistically differ in total quarterly costs (€2329 ± €2570 versus €2361 ± €2612). For both, costs were higher with advancing disease severity and indirect costs were the main societal cost driver. Regarding healthcare-related resources, women incurred higher costs for ambulant consultations [incidence rate ratio (IRR) 1.16, confidence interval (CI) 1.04-1.31], complementary medicine (IRR 2.41, CI 1.14-5.06), medical consumables (IRR 2.53, CI 1.69-3.79) and informal care (IRR 2.79, CI 1.56-5.01). Among indirect costs, we found higher costs for men for presenteeism (IRR 0.62; CI 0.53-0.72) and higher costs for women for disability pension (IRR 1.62; CI 1.23-2.13). CONCLUSIONS: Multiple sclerosis poses a significant economic burden on patients, families and society. While the total economic burden did not differ between male and female patients, we found gender differences in specific cost items that are similar to those in the wider non-MS population.

The Dresden Protocol for Multidimensional Walking Assessment (DMWA) in Clinical Practice.

Walking impairments represent one of the most debilitating symptom areas for people with multiple sclerosis (MS). It is important to detect even slightest walking impairments in order to start and optimize necessary interventions in time to counteract further progression of the disability. For this reason, a regular monitoring through gait analysis is highly necessary. At advanced stages of MS with significant walking impairment, this assessment is also necessary to optimize symptomatic treatment, choose the most suitable walking aid and plan individualized rehabilitation. In clinical practice, walking impairment is only assessed at higher levels of the disease using e.g., the Expanded Disability Status Scale (EDSS). In contrast to the EDSS, standardized functional tests such as walking speed, walking endurance and balance as well as walking quality and gait-related patient-reported outcomes allow a more holistic and sensitive assessment of walking impairment. In recent years, the MS Center Dresden has established a standardized monitoring procedure for the routine multidimensional assessment of gait and balance disorders. In the following protocol, we present the techniques and procedures for the analysis of gait and balance of people with MS at the MS Center Dresden. Patients are assessed with a multidimensional gait analysis at least once a year. This enables long-term monitoring of walking impairment, which allows early active intervention regarding further progression of disease and improves the current standard clinical practice.

Health-Related Quality of Life and the Relationship to Treatment Satisfaction in Patients with Multiple Sclerosis: Insights from a Large Observational Study.

INTRODUCTION: In patients with multiple sclerosis (MS), fatigue, depression, and physical disability are important determinants that negatively affect health-related quality of life (HRQoL). In studies about MS, HRQoL and treatment satisfaction are emerging endpoints representing the patients' perspective. However, the association of HRQoL and MS treatment satisfaction has not been evaluated so far. PURPOSE: Our objective was to evaluate the relationship of different dimensions of HRQoL and treatment satisfaction (effectiveness, side effects, convenience), and to assess which factors of treatment satisfaction, besides disease-related and sociodemographic explanatory factors, can best describe HRQoL. PATIENTS AND METHODS: We analyzed data from a cross-sectional, observational multicenter study in Germany (THEPA-MS, N=2990 eligible patients for first-line treatment). The instruments used were the SF-36 for HRQoL and the TSQM for treatment satisfaction. Correlation analyses, classification and regression trees and multivariate linear regression with the least absolute shrinkage and selection operator (LASSO) for global variable selection were used to analyze explanatory factors of HRQoL. RESULTS: The SF-36 physical summary score was 45.49 ±12.03 and mental component summary score 42.87 ±12.12, with currently untreated patients (N=250) reporting lower HRQoL than patients under first-line treatment (N=2740) (p<0.001). Physical disability (standardized beta (b)=0.408) was the strongest cross-sectional predictor for physical health, followed by employment status (b=0.163), age (b=0.159) and treatment satisfaction in terms of side effects (b=0.146) and effectiveness (b=0.137). For the mental summary health dimension, presence of a major depressive episode (b=0.234) had the greatest impact, followed by satisfaction with side effects (b=0.152) and effectiveness (b=0.131). CONCLUSION: Satisfaction with the effectiveness and side effects of treatment was part of the main independent explanatory variables for mental and physical HRQoL in patients with MS. To improve HRQoL, patients' needs and satisfaction measures may be integral part of disease management beyond treatment of physical disability, depression or fatigue.

Visual Feedback and Postural Control in Multiple Sclerosis.

As people with multiple sclerosis (pwMS) manifest heterogeneous demyelinating lesions that could affect somatosensory or vestibular ways, visual stimulus as feedback could be especially relevant to achieve postural control. This has clinical importance for the development of preventive measures and rehabilitation therapies in order to avoid falls and accidents in this group. In our study, we objectively evaluated the influence of visual feedback on the stabilization of balance in pwMS versus healthy controls (HC) and its potential utility in clinical evaluation. Static posturography tests were performed in 99 pwMS and 30 HC. Subjects stood on a force platform with open and closed eyes. During this procedure, three balance parameters were obtained for both vision conditions: average sway, average speed, and average speed of sway. Neurostatus-Expanded Disease Disability Score (EDSS) and Multiple Sclerosis Functional Composite (MSFC) were performed in parallel as well. A two-way mixed repeated measures ANCOVA, controlling for sex and age, was performed to evaluate the effect of vision, MS diagnosis, and the interaction of both in static posturography parameters. The difference between both closed and open eyes conditions was calculated for each parameter and further analyzed according to MS-relevant clinical variables. The magnitude of the vision effect differed between pwMS and HC as a significant interaction between the vision and the MS diagnosis in the delineated area (p < 0.001) and average speed of sway (p = 0.001) was seen. These parameters had a greater increase in pwMS than in HC after closing eyes. For the average sway, a significant main effect of vision was present (p = 0.047). Additionally, the differences obtained between open and closed eyes conditions assessed with the delineated area and average speed of sway were moderately correlated to the assessed clinical tests EDSS (r = 0.405 and r = 0.329, respectively) and the MSFC (r = -0.385 and r = -0.259, respectively). In our study, pwMS were more dependent of visual feedback than HC to maintain postural control. This easy and short evaluation by static posturography could support the development of targeted preventive measures and interventions in pwMS.

Correction to: Real-World Evidence on the Patterns of Increased Societal Economic Relapse Costs in Patients with Multiple Sclerosis.

In the original version of this article, the title of the article has been published incorrectly.

Real-World Evidence on the Societal Economic Relapse Costs in Patients with Multiple Sclerosis.

BACKGROUND: Relapses are the hallmark of multiple sclerosis (MS). Analyses have shown that the cost of MS increases during periods of relapse. However, results are inconsistent between studies, possibly due to different study designs and the different implications of relapses with respect to patient characteristics. OBJECTIVES: The aims were to estimate and describe direct and indirect relapse costs and to determine differences in costs with respect to patient characteristics. Furthermore, we describe the pharmacoeconomic impact during the relapse follow-up. METHODS: Data were extracted from two German, multicenter, observational studies applying a validated resource costs instrument. Relapse costs were calculated as the difference in quarterly costs between propensity score (PS)-matched patients with and without relapses (1:1 ratio). For relapse active patients, we additionally calculated the difference between quarterly costs prior to and during relapse and determined costs in the post-relapse quarter. RESULTS: Of 1882 patients, 607 (32%) presented at least one relapse. After PS-matching, 597 relapse active and relapse inactive patients were retained. Relapse costs (in 2019 values) ranged between €791 (age 50 + years) and €1910 (disease duration < 5 years). In mildly disabled and recently diagnosed patients, indirect relapse costs (range €1073-€1207) constantly outweighed direct costs (range €591-€703). The increase from prior quarter to relapse quarter was strongest for inpatient stays (+ 366%, €432; p < 0.001), day admissions (+ 228%, €57; p < 0.001), and absenteeism (127%, €463; p < 0.001). In the post-relapse quarter, direct costs and costs of absenteeism remained elevated for patients with relapse-associated worsening. CONCLUSION: A recent diagnosis and mild disability lead to high relapse costs. The results suggest the necessity to incorporate patient characteristics when assessing relapse costs.

The Multiple Sclerosis Health Resource Utilization Survey (MS-HRS): Development and Validation Study.

BACKGROUND: Survey-based studies are frequently used to describe the economic impact of multiple sclerosis (MS). However, there is no validated health resource survey available, preventing comparison of study results and meaningful conclusions regarding the efficiency of long-term treatments. OBJECTIVE: The aim of this study was to develop and validate a tablet- and paper-based MS health resource utilization survey. METHODS: We developed and validated the Multiple Sclerosis Health Resource Utilization Survey (MS-HRS), consisting of 24 cost items for paper and tablet users. Data for validation came from two large German observational studies. Survey practicability was assessed according to the response rate. Reliability was described using test-retest reliability as well as Guttman lambda. Construct validity was assessed as convergent and discriminant validity via correlations with associated patient-reported outcomes and known-group analyses. RESULTS: In total, 2207 out of 2388 (response rate: 92.4%) patients completed the survey and were included to determine psychometric properties. The test-retest reliability had an intraclass correlation coefficient of 0.828 over a course of 3 months. Convergent validity analyses showed that total costs correlated positively with increased disability (r=0.411, P<.001). For discriminant validity, correlations of total costs with the Treatment Satisfaction Questionnaire for Medication ranged from -0.006 (convenience) to -0.216 (effectiveness). The mean annual cost was €28,203 (SD €14,808) (US $39,203; SD US $20,583) with disease-modifying therapies. CONCLUSIONS: The MS-HRS is a multilingual, reliable, valid, electronically available, and easy-to-administer questionnaire providing a holistic cross-sectional and longitudinal assessment of resource utilization in patients with MS.