Performance Measures and Plasma Biomarker Levels in Patients with Multiple Sclerosis after 14 Days of Fampridine Treatment: An Explorative Study.

Peripheral cytokine levels may serve as biomarkers for treatment response and disease monitoring in patients with multiple sclerosis (pwMS). The objectives were to assess changes in plasma biomarkers in PwMS after 14 days of fampridine treatment and to explore correlations between changes in performance measures and plasma biomarkers. We included 27 PwMS, 14 women and 13 men, aged 52.0 ± 11.6 years, with a disease duration of 17 ± 8.5 years, and an Expanded Disability Status Scale of 6 [IQR 5.0/6.5]. Gait and hand function were assessed using performance tests completed prior to fampridine and after 14 days of treatment. Venous blood was obtained, and chemiluminescence analysis conducted to assess plasma cytokines and neurodegenerative markers. All performance measures demonstrated improvements. Biomarkers showed decreased tumor necrosis factor (TNF) receptor-2 levels. Associations were found between change scores in (i) Six Spot Step Test and Interleukin (IL)-2, IL-8, and IL-17 levels; (ii) timed 25-foot walk and interferon-γ, IL-2, IL-8, TNF-α, and neurofilament light levels, and (iii) 12-Item Multiple Sclerosis Walking Scale and IL-17 levels. The associations may reflect increased MS-related inflammatory activity rather than a fampridine-induced response or that a higher level of inflammation induces a better response to fampridine.

Criterion validity of muscle strain analyses of skeletal muscle function in patients with multiple sclerosis.

BACKGROUND: Despite the wide range of existing performance measures to evaluate functional status of patients with multiple sclerosis, the heterogeneous nature of the disease hinders clinical characterization and monitoring of disease severity. Speckle tracking ultrasonography is a non-invasive technique to assess isolated muscle function by evaluating the contractile properties of muscle tissue, i.e. muscle strain. The aim of this study was to investigate whether muscle strain measured by speckle tracking ultrasonography could be a useful quantitative measure of muscle function in patients with multiple sclerosis. The criterion validity of muscle strain was compared to that of validated performance measures of upper and lower extremity function. METHODS: This cross-sectional study used baseline data from an explorative observational cohort study (the MUST study). Participants recruited from a hospital outpatient MS clinic underwent speckle tracking ultrasonography of the biceps brachii, supraspinatus, and soleus muscles of the dominant side according to pre-defined submaximal isometric contractions. Participants also completed the Timed 25-Foot Walk Test, the Six Spot Step Test, the 2-minute walking test, the Nine-Hole Peg Test, the 12-item Multiple Sclerosis Walking Scale, and the Oxford Shoulder Score. Gaussian distribution was investigated by visual inspection of normal probability plots and the Shapiro-Wilk test. The Timed 25-Foot Walk Test and Nine-Hole Peg Test were selected as gold standards for function of the lower and upper extremities, respectively. Criterion validity was assessed using Spearman's rank-order correlation coefficient ρ (rho), comparing the muscle strain and performance measures against predefined gold standards. Differences in criterion validity were estimated using squared correlations on the Fischer's Z-scale, with non-parametric bootstrapping to obtain bias-corrected, accelerated bootstrap confidence intervals (95% BCa). RESULTS: Criterion validity showed good to excellent correlations between the gold standard for lower extremity function and the 2-minute walking test and Six Spot Step Test, and a fair correlation to the 12-item Multiple Sclerosis Walking Scale. No significant correlation was found between the gold standard for upper extremity function and the performance measure. There were no significant correlations between the gold standards and muscle strain. CONCLUSION: The absence of criterion validity for muscle strain alongside fair to strong criterion validity for the performance measures indicates that speckle tracking ultrasonography assessment of muscle strain is either invalid or evaluates other constructs of multiple sclerosis. Muscle strain assessed by speckle tracking ultrasonography cannot be recommended for the evaluation of treatment effects or disease progression in multiple sclerosis.

Gait quality and function after fampridine treatment in patients with multiple sclerosis - A prospective cohort study.

BACKGROUND: Fampridine has shown to improve walking speed, motor control, and balance in patients with multiple sclerosis. However, potential fampridine-induced changes in gait quality and underlying mechanisms, evaluated by three-dimensional gait analysis, are poorly examined. The aim was to examine if two weeks of fampridine treatment would improve gait quality (using Gait Profile Score and Gait Variable Scores from three-dimensional gait analysis) and gait function (using performance-based tests, spatiotemporal parameters, and self-perceived gait function). METHODS: 14 participants with multiple sclerosis were included (9 women and 5 men, age 53.6 ± 12.8 years, disease duration 21 ± 9.1 years) in this cohort study. Tests were completed prior to fampridine and after 14 (± 1) days of treatment. Three-dimensional gait analyses were completed, and kinematic measures were calculated for overall gait quality using Gait Profile Score, and for joint-specific variables, Gait Variable Scores. Gait function was assessed using spatiotemporal parameters, performance-based tests, and a patient-reported outcome measure. Student's paired t-test/Wilcoxon signed rank test were used to compare baseline and follow-up variables. Sample size calculation for Gait Profile Score required at least 9 participants. FINDINGS: No fampridine-induced improvements in gait quality were demonstrated. For gait function, improvements were found in performance-based tests (Timed 25-Foot Walk: -11.5%; Six Spot Step Test: -13.9%; 2-Minute Walk Test: 18.2%) and self-perceived gait function (12-itemMS Walking Scale: -35.2%). INTERPRETATION: Although two weeks of fampridine treatment in patients with multiple sclerosis improved gait function, there was no change in overall kinematic quality of gait. TRIAL REGISTRATION: This work was collected as a part of a registered clinical trial (MUST): ClinicalTrials.govNCT03847545.

Evaluation of functional outcome measures after fampridine treatment in patients with multiple sclerosis - An interventional follow-up study.

OBJECTIVE: The purpose of this interventional study on participants with multiple sclerosis (MS) with walking disability was to evaluate changes in functional hand and walking measurements after fampridine treatment, after stratifying by the Expanded Disability Status Scale (EDSS). We furthermore wanted to investigate different functional measurements to evaluate their ability to detect responders to fampridine with a clinically relevant improvement. METHODS: Patients were recruited from the MS Clinic at Odense University Hospital and were classified into two disability groups based on their EDSS score (moderate EDSS (EDSSMod) 4.5-5.5 [n = 19] and severe EDSS (EDSSSev) 6.0-7.0 [n = 14]). At baseline (visit 1) they completed the Timed 25-Foot Walk (T25FW), 2-Minute Walk Test (2MWT), Nine Hold Peg Test (9HPT), 12-item Multiple Sclerosis Walking Scale (MSWS-12), and the Six Spot Step Test (SSST). Participants were given 10 mg twice daily fampridine for 14 days before retested (visit 2). For each measurement, cut-off values were used to define responders with a clinically relevant improvement to treatment. The measurements were evaluated separately and in combination. RESULTS: Of the 33 participants, 25 (75.8%) were identified as having a clinically relevant improvement (CRI). For all patients combined (EDSSAll), all five measurements showed significant functional improvement after treatment. For the individual measurements, the highest participant response rates after 14 days of fampridine treatment were seen on the MSWS-12 (57.6%) and 2MWT (42.4%). The 2MWT also showed the largest performance improvement (18.5%) from visit 1 to visit 2. For patients with severe disability (EDSSSev), no significant improvement was seen after fampridine treatment on the T25FW, and most of the responders to T25FW had moderate disability (EDSSMod, 71.5%). Conversely for the SSST, most responders were EDSSSev (83.3%). No participants had a clinically relevant improvement on the 9HPT. The combination of T25FW, SSST, and MSWS-12 was less sensitive in distinguishing responders from non-responders, whereas the combination of 2MWT and MSWS-12 identified the same responders and could better distinguish fampridine responders from non-responders. CONCLUSION: EDSS level did not influence the effect of fampridine treatment on functional hand and walking measures and the responsiveness of the measurements differed only a little between moderate and severe EDSS levels. The combination of self-reported walking capacity (MSWS-12) and walking endurance (2MWT) was better than T25FW, SSST, and MSWS-12 at detecting clinically meaningful improvement after fampridine treatment, which could prove useful in the clinical monitoring of walking disabilities in MS during fampridine treatment.

Threshold values of ankle dorsiflexion and gross motor function in 60 children with cerebral palsy.

Background and purpose - Threshold values defining 3 categories of passive range of motion are used in the Cerebral Palsy follow-Up Program to guide clinical decisions. The aim of this study was to investigate the threshold values by testing the hypothesis that passive range of motion in ankle dorsiflexion is associated with gross motor function and that function differs between the groups of participants in each category. Patients and methods - We analyzed data from 60 ambulatory children (aged 5-9 years) with spastic cerebral palsy. Outcomes were passive range of motion in ankle dorsiflexion with flexed and extended knee and gross motor function (Gait Deviation Index, Gait Variable Score of the ankle, peak dorsiflexion during gait, 1-minute walk, Gross Motor Function Measure, the Pediatric Quality of Life Inventory Cerebral Palsy Module, and Pediatric Outcomes Data Collection Instrument). Results - Significant (p < 0.05) and moderate correlations were documented for range of motion versus Gait Variable Score of the ankle (r = -0.37 and r = -0.37) and range of motion versus peak dorsiflexion (r = 0.49 and r = 0.55). Differences between the groups formed by the categories were shown for Gait Variable Score of the ankle and peak dorsiflexion (p < 0.05). No other significant correlations or differences between the categories were observed. Interpretation - The results suggest that threshold values for ankle dorsiflexion used in the Cerebral Palsy follow-Up Program are of limited clinical value in assessing overall gross motor function, but may be used to identify deviations in ankle-specific gait function.

Immediate effect of valgus bracing on knee joint moments in meniscectomised patients: An exploratory study.

OBJECTIVES: Patients undergoing medial arthroscopic partial meniscectomy are at increased risk of developing and/or progressing knee osteoarthritis, with increased medial compartment load being a potential contributor. The aim of this study was to evaluate the immediate effect of a valgus unloader knee brace on knee joint moments in patients following medial arthroscopic partial meniscectomy. DESIGN: Within-participant design. METHODS: Twenty-two patients (age 35-55 years) who had undergone medial arthroscopic partial meniscectomy within the previous 8-15 months completed three-dimensional analysis of gait, forward lunge and one-leg rise during two conditions: with and without a valgus unloader knee brace. Outcome measures included the peak and impulse of the knee adduction moment and the peak knee flexion moment. RESULTS: The peak knee flexion moment increased during brace condition for forward lunge (mean difference [95% CI]) 0.54 [0.27-0.82] (Nm/(BW×HT)%), p<0.001 and one-leg rise (mean difference 0.45 [95% CI 0.08-0.82] (Nm/(BW×HT)%), p=0.022). No other significant differences were found between conditions in any of the included tasks. CONCLUSIONS: A significant effect of the knee brace was detected in terms of an increase in peak knee flexion moment during the more demanding tasks such as forward lunge and one-leg rise. This increase implies enhanced stability of the knee provided by the brace, which may induce increased knee function and knee-related confidence during strenuous tasks. Future research is required to explore the structural implications.