Validation of the Czech Version of the Dysphagia in Multiple Sclerosis Questionnaire (DYMUS).

Dysphagia is a common symptom of neurological disease, including multiple sclerosis (MS). The DYsphagia in MUltiple Sclerosis (DYMUS) questionnaire was developed as a screening tool for swallowing problems. The purpose of the present study was to validate the Czech version of the DYMUS questionnaire. We validated the questionnaire on a sample of 435 patients with MS and 135 healthy controls (HC) chosen by accidental sampling from larger, long-term studies conducted by the Prague MS Center. For the purposes of this study, we used both electronic (primary method of distribution) and paper-based (backup) versions of the questionnaire. The internal consistency of the whole scale was satisfactory (Cronbach's α =0.833). The DYMUS mean score in HC was 0.215 (standard deviation [SD] = 0.776). Normative data suggested a cut-off value for dysphagia between 1 and 2 points. Principal component analysis (PCA) showed a two-factor structure of the adapted scale. However, the structure did not completely correspond to the originally proposed dimensions of dysphagia for solids and liquids; our data supported dropout of item Q10. Criterion validity was proved by the difference in dysphagia between HC and patients MS (U = 25,546, p < 0.001) and by a positive correlation with the EDSS (Kendall's tau-b = 0.169, p < 0.001) and other patient-reported outcomes. The Czech version of the DYMUS questionnaire is a valid and reliable tool for evaluating swallowing impairment in Czech-speaking patients with MS. Moreover, the questionnaire can be administered electronically, with a paper-based backup.

Brainstem lesions are associated with diffuse spinal cord involvement in early multiple sclerosis.

BACKGROUND: Early infratentorial and focal spinal cord lesions on magnetic resonance imaging (MRI) are associated with a higher risk of long-term disability in patients with multiple sclerosis (MS). The role of diffuse spinal cord lesions remains less understood. The purpose of this study was to evaluate focal and especially diffuse spinal cord lesions in patients with early relapsing-remitting MS and their association with intracranial lesion topography, global and regional brain volume, and spinal cord volume. METHODS: We investigated 58 MS patients with short disease duration (< 5 years) from a large academic MS center and 58 healthy controls matched for age and sex. Brain, spinal cord, and intracranial lesion volumes were compared among patients with- and without diffuse spinal cord lesions and controls. Binary logistic regression models were used to analyse the association between the volume and topology of intracranial lesions and the presence of focal and diffuse spinal cord lesions. RESULTS: We found spinal cord involvement in 75% of the patients (43/58), including diffuse changes in 41.4% (24/58). Patients with diffuse spinal cord changes exhibited higher volumes of brainstem lesion volume (p = 0.008). The presence of at least one brainstem lesion was associated with a higher probability of the presence of diffuse spinal cord lesions (odds ratio 47.1; 95% confidence interval 6.9-321.6 p < 0.001) as opposed to focal spinal cord lesions (odds ratio 0.22; p = 0.320). Patients with diffuse spinal cord lesions had a lower thalamus volume compared to patients without diffuse spinal cord lesions (p = 0.007) or healthy controls (p = 0.002). CONCLUSIONS: Diffuse spinal cord lesions are associated with the presence of brainstem lesions and with a lower volume of the thalamus. This association was not found in patients with focal spinal cord lesions. If confirmed, thalamic atrophy in patients with diffuse lesions could increase our knowledge on the worse prognosis in patients with infratentorial and SC lesions.

Long-term outcomes in patients presenting with optic neuritis: Analyses of the MSBase registry.

BACKGROUND: Short-term outcomes of optic neuritis (ON) have been well characterized. Limited data exists on longer-term visual outcomes in patients who present with ON. The large MSBase registry allows for characterization of long-term visual outcomes after ON. METHODS: Via the MSBase Registry, data on patients from 41 centers was collected during routine clinical and research visits. Physical and visual disability were measured using the expanded disability status scale (EDSS) and the visual function score (VFS). Inclusion criteria for this analysis included age ≥ 18 years, clinically isolated syndrome (CIS), ON-onset, baseline visit within 6 months of onset, and at least one follow-up visit. Survival analysis was used to evaluate the association of disease-modifying treatment with time to conversion to clinically definite MS or sustained EDSS/VFS progression. RESULTS: Data from 60,933 patients were obtained from the MSBase registry in July 2019. Of these, 1317 patients met inclusion criteria; 935 were treated at some point in disease course, while 382 were never treated. At baseline, mean age was 32.3 ± 8.8 years, 74% were female, median EDSS was 2 (IQR 1-2), and median VFS was 1 (IQR 0-2). Median follow-up time was 5.2 years (IQR 2.4-9.3). Treatment was associated with reduced risk and delayed conversion to clinically definite MS (HR = 0.70, p < 0.001), sustained EDSS progression (HR = 0.46, p < 0.0001) and sustained VFS (HR = 0.41, p < 0.001) progression. CONCLUSIONS: In the MSBase cohort, treatment after ON was associated with better visual and neurological outcomes compared to no treatment. These results support early treatment for patients presenting with ON as the first manifestation of MS.

Why patients with multiple sclerosis perceive improvement of gait during treatment with natalizumab?

Gait impairment is one of the common manifestations of multiple sclerosis (MS) and contributes to a loss of quality of life. Natalizumab, an anti-α4 integrin monoclonal antibody, has been shown to have an effect in treatment of MS, reducing relapses and inflammatory lesions. Aim of our study was to assess how patients perceive gait impairment over the first year of treatment with natalizumab and what is the objective correlate of this change. This is an open-label prospective observational study. Subjective gait evaluation was measured by Multiple Sclerosis Walking Scale-12 (MSWS-12). Objective gait assessment included Timed 25-Foot Walk Test (T25FW) and spatiotemporal parameters of gait measured by a GAITRite instrument during a self-selected speed of walking (normal walk) and a fast speed of walking (fast walk). We analysed data of 50 patients with a relapsing-remitting form of MS, median EDSS 3.5 (range 1.5-5). MSWS-12 score significantly decreased between the baseline and month 12 of treatment (p < 0.001). Walking velocity and step length were significantly improved in Normal walk tests (p < 0.001). During the Fast walk tests, a step length and a double support time of the gait cycle were significantly improved (p = 0.001). Change in MSWS-12 score confirmed the clinically significant improvement of gait in patients with MS treated with natalizumab for 1 year. The analysis of spatiotemporal gait parameters has shown a significant improvement in self-selected gait velocity and step length.

Do eyes with and without optic neuritis in multiple sclerosis age equally?

PURPOSE: Anterior visual pathway reflects axonal loss caused by both optic neuritis (ON) and neurodegeneration in multiple sclerosis (MS). Although the axonal injury post-ON is thought to be complete by 6 months of onset, most studies using optical coherence tomography (OCT) to evaluate retinal changes as a marker of neurodegeneration exclude eyes with a history of ON or consider them separately. The objective of this study was to assess whether the eyes post-ON (>6 months) show in later years different rate of chronic retinal changes than the fellow eyes not affected by ON. PATIENTS AND METHODS: Fifty-six patients with MS with a history of ON in one eye (ON eyes) and no ON in the fellow (FL) eye, who were followed by OCT for >2 years, were selected from a cohort of patients with MS. Paired eye analysis was performed. RESULTS: Mean interval post-ON at baseline was 5.65 (SD 5.05) years. Mean length of follow-up by OCT was 4.57 years. There was no statistical difference in absolute or relative thinning of retinal nerve fiber layer in peripapillary area between the ON and FL eyes. CONCLUSION: This study has shown that we do not need to exclude eyes with a history of ON from longitudinal studies of neurodegeneration in MS, provided that we use data outside of the frame of acute changes post-ON. Long-term changes of peripapillary retinal nerve fiber layer in ON and FL eyes are equal.

Combining clinical and magnetic resonance imaging markers enhances prediction of 12-year employment status in multiple sclerosis patients.

BACKGROUND: Multiple sclerosis (MS) is frequently diagnosed in the most productive years of adulthood and is often associated with worsening employment status. However, reliable predictors of employment status change are lacking. OBJECTIVE: To identify early clinical and brain magnetic resonance imaging (MRI) markers of employment status worsening in MS patients at 12-year follow-up. METHODS: A total of 145 patients with early relapsing-remitting MS from the original Avonex-Steroids-Azathioprine (ASA) study were included in this prospective, longitudinal, observational cohort study. Cox models were conducted to identify MRI and clinical predictors (at baseline and during the first 12 months) of worsening employment status (patients either (1) working full-time or part-time with no limitations due to MS and retaining this status during the course of the study, or (2) patients working full-time or part-time with no limitations due to MS and switching to being unemployed or working part-time due to MS). RESULTS: In univariate analysis, brain parenchymal fraction, T1 and T2 lesion volume were the best MRI predictors of worsening employment status over the 12-year follow-up period. MS duration at baseline (hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.03-1.18; p = 0.040) was the only significant clinical predictor. Having one extra milliliter of T1 lesion volume was associated with a 53% greater risk of worsening employment status (HR = 1.53, 95% CI 1.16-2.02; p = 0.018). A brain parenchymal fraction decrease of 1% increased the risk of worsening employment status by 22% (HR = 0.78, 95% CI 0.65-0.95; p = 0.034). CONCLUSION: Brain atrophy and lesion load were significant predictors of worsening employment status in MS patients. Using a combination of clinical and MRI markers may improve the early prediction of an employment status change over long-term follow-up.

Quantification of Gait Abnormalities in Healthy-Looking Multiple Sclerosis Patients (with Expanded Disability Status Scale 0-1.5).

BACKGROUND: Gait impairment is a common symptom in multiple sclerosis (MS) patients, but there is a lack of evidence about gait performance in the group of MS patients with no apparent disability. The aim of our study was to evaluate gait characteristics in MS patients with no apparent impairment of walking and with an Expanded Disability Status Scale (EDSS 0-1.5), and to determine whether any abnormalities are detectable by common clinical tests. METHODS: This was an observational study of 64 MS patients with an EDSS 0-1.5 and 47 age- and sex-matched healthy controls. We measured their performance in the timed 25-foot walk test (T25FWT) and the 2-minute walk test (2MWT). The spatiotemporal parameters of gait were measured using a GAITRite instrument. RESULTS: MS patients with no apparent disability (EDSS 0-1.5) performed worse in T25FWT and 2MWT than normal controls. During the self-selected walking speed test on GAITRite, MS patients had a prolonged double support phase, and during the fast walking speed test, they had lower cadence and decreased step length.

The regulator's perspective: How should new therapies and follow-on products for MS be clinically evaluated in the future?

BACKGROUND: Although there is still no cure for multiple sclerosis (MS), the introduction of several innovative drugs with modes of action different from that of the existing drug arsenal and the progress in monitoring disease progression by imaging and using biomarkers are currently causing a knowledge surge. This provides opportunities for improving patient disease management. New therapies are also under development and pose challenges to the regulatory bodies regarding the optimal design of clinical trials with more patient-focused clinical endpoints. Moreover, with the upcoming patent expiry of some of the key first-line MS treatments in Europe, regulatory bodies will also face the challenge of recommending marketing authorisation for generic and abridged versions based on appropriate requirements for demonstrating equality/similarity to the innovator's product. OBJECTIVE: The goal of this article is to improve the understanding of the relevant guidance documents of the European Medicines Agency (EMA) on clinical investigation of medicinal products and to highlight the issues that the agency will need to clarify regarding follow-on products of first-line MS treatments. CONCLUSION: Today, it is clear that close collaboration between patients, healthcare professionals, regulatory bodies and industry is crucial for developing new safe and effective drugs, which satisfy the needs of MS patients.

Spatial and temporal characteristics of gait as outcome measures in multiple sclerosis (EDSS 0 to 6.5).

BACKGROUND: Gait impairment represents one of the most common and disabling symptom of multiple sclerosis. Quantification of the gait is an important aspect of clinical trials. In order to identify which temporal or spatial parameters of gait could be used as outcome measures in interventional studies of patients with different levels of disability, we evaluated characteristics of these parameters in MS patients across the whole spectrum of mobility from EDSS 0 to 6.5. METHODS: This is a cross-sectional study of spatial and temporal parameters of gait at self selected speed and at fast speed of walking in 284 patients with multiple sclerosis (108 men, mean age 38 years ± SD 10.8 years, range 18-64) divided into seven levels of disability (EDSS 0 to 1.5, EDSS 2.0 to 2.5, EDSS 3.0 to 3.5, EDSS 4.0 to 4.5, EDSS 5.0 to 5.5, EDSS 6.0, EDSS 6.5). RESULTS: The velocity of gait decreases with increasing EDSS levels. Hovewer, the spatio-temporal parameters of gait that are involved in this process differ across the EDSS levels. The step length is decreased at higher EDSS levels up to the EDSS 6.0, but was not different between EDSS 6.0 and 6.5. The step time is significantly longer at EDSS 6.0 and 6.5, while the step length remains the same at those levels. The increase in percentage of double support time becomes statistically significant at EDSS 3.0-3.5 and continues to increase until EDSS 6.5. Variability of step time, step length or step width did not show significant difference between studied EDSS levels. CONCLUSIONS: There is no single spatio-temporal parameter of gait (other than velocity of gait) that would show significant differences among all levels of EDSS. The step length reflects shortening of steps at lower EDSS levels (2.0 to 6.0), and percentage of double support time better reflects changes at higher EDSS levels 3.0 - 6.5. Gait variability is not associated with disability in MS and therefore would not be a suitable outcome measure. These observations have to be considered when designing gait experiments with temporal and spatial parameters of gait as outcomes.