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

  • Author Footnotes
    1 Permanent Address: Christiansgade 85, 5000 Odense C, Denmark.
    Maria Thorning
    Correspondence
    Corresponding author at: Department of Neurology, J.B. Winsløws Vej 4, 5000 Odense C, Denmark.
    Footnotes
    1 Permanent Address: Christiansgade 85, 5000 Odense C, Denmark.
    Affiliations
    Department of Neurology, Odense University Hospital, J.B. Winsloews Vej 4, 5000 Odense C, Denmark

    Orthopaedic Research Unit, Department of Clinical Research, University of Southern Denmark, J.B. Winsloews Vej 19,3, 5000 Odense C, Denmark

    Department of Neurobiology Research, Department of Molecular Medicine, University of Southern Denmark, J.B. Winsloews Vej 21, st., 5000 Odense C, Denmark

    BRIDGE - Brain Research – Inter Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, J.B. Winsloews Vej 19.3, 5000 Odense C, Denmark
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  • Helle Hvilsted Nielsen
    Affiliations
    Department of Neurology, Odense University Hospital, J.B. Winsloews Vej 4, 5000 Odense C, Denmark

    Department of Neurobiology Research, Department of Molecular Medicine, University of Southern Denmark, J.B. Winsloews Vej 21, st., 5000 Odense C, Denmark

    BRIDGE - Brain Research – Inter Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, J.B. Winsloews Vej 19.3, 5000 Odense C, Denmark
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  • Lars Henrik Frich
    Affiliations
    Department of Neurobiology Research, Department of Molecular Medicine, University of Southern Denmark, J.B. Winsloews Vej 21, st., 5000 Odense C, Denmark

    Department of Orthopaedics, Hospital Soenderjylland, Kresten Philipsens Vej 15, 6200 Aabenraa, Denmark

    Department of Regional Health Research, University of Southern Denmark, J.B Winsloews Vej 19.3, 5000 Odense C, Denmark
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  • Henrik Boye Jensen
    Affiliations
    Department of Brain and Nerve Diseases, Sygehus Lillebaelt, Sygehusvej 24, 6000 Kolding, Denmark

    Department of Regional Health Research, University of Southern Denmark, J.B Winsloews Vej 19.3, 5000 Odense C, Denmark
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  • Kate Lykke Lambertsen
    Affiliations
    Department of Neurology, Odense University Hospital, J.B. Winsloews Vej 4, 5000 Odense C, Denmark

    Department of Neurobiology Research, Department of Molecular Medicine, University of Southern Denmark, J.B. Winsloews Vej 21, st., 5000 Odense C, Denmark

    BRIDGE - Brain Research – Inter Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, J.B. Winsloews Vej 19.3, 5000 Odense C, Denmark
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  • Anders Holsgaard-Larsen
    Affiliations
    Orthopaedic Research Unit, Department of Clinical Research, University of Southern Denmark, J.B. Winsloews Vej 19,3, 5000 Odense C, Denmark

    Department of Orthopaedics and Traumatology, Odense University Hospital, J.B. Winsloews Vej 4, 5000 Odense C, Denmark
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  • Author Footnotes
    1 Permanent Address: Christiansgade 85, 5000 Odense C, Denmark.
Open AccessPublished:November 16, 2022DOI:https://doi.org/10.1016/j.clinbiomech.2022.105826

      Highlights

      • Two weeks of Fampridine treatment did not improve kinematic gait quality.
      • Gait function/performance improved following two weeks of Fampridine treatment.
      • No Fampridine induced improvements were detected in spatiotemporal parameters.
      • Changes in kinematic gait quality and gait function/performance did not correlate.

      Abstract

      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.gov NCT03847545

      Keywords

      1. Introduction

      Multiple sclerosis (MS) is a chronic inflammatory, demyelinating disease of the central nervous system and the most frequent neurological disease affecting young adults (
      • Filippi M.
      • Bar-Or A.
      • Piehl F.
      • et al.
      Multiple sclerosis.
      ). MS causes a variety of clinical manifestations including muscle weakness, spasticity, paresis, and sensory deficits (
      • Pau M.
      • Coghe G.
      • Atzeni C.
      • et al.
      Novel characterization of gait impairments in people with multiple sclerosis by means of the gait profile score.
      ), resulting in functional limitations such as reduced walking speed, endurance, and poor balance. Gait limitations is a main cause of disability in patients with MS (
      • Larocca N.G.
      Impact of walking impairment in multiple sclerosis: perspectives of patients and care partners.
      ), and up to 76% of patients require a walking aid or wheelchair at some stage (
      • Kister I.
      • Chamot E.
      • Salter A.R.
      • et al.
      Disability in multiple sclerosis: a reference for patients and clinicians.
      ).
      Fampridine is presently the only medical drug used to alleviate gait function in MS (
      • Ahdab R.
      • Shatila M.M.
      • Shatila A.R.
      • et al.
      Cortical excitability measures may predict clinical response to fampridine in patients with multiple sclerosis and gait impairment.
      ). It enhances signal conduction in demyelinated axons by blocking voltage-dependent potassium channels (
      • Hayes K.C.
      Fampridine-SR for multiple sclerosis and spinal cord injury.
      ). Clinical studies demonstrate improved walking speed (
      • Filli L.
      • Sutter T.
      • Easthope C.S.
      • et al.
      Profiling walking dysfunction in multiple sclerosis: characterisation, classification and progression over time.
      ;
      • Goodman A.D.
      • Brown T.R.
      • Edwards K.R.
      • et al.
      A phase 3 trial of extended release oral dalfampridine in multiple sclerosis.
      ;
      • Jensen H.
      • Ravnborg M.
      • Mamoei S.
      • et al.
      Changes in cognition, arm function and lower body function after slow-release Fampridine treatment.
      ;
      • Zörner B.
      • Filli L.
      • Reuter K.
      • et al.
      Prolonged-release fampridine in multiple sclerosis: improved ambulation effected by changes in walking pattern.
      ), walking endurance (
      • Filli L.
      • Sutter T.
      • Easthope C.S.
      • et al.
      Profiling walking dysfunction in multiple sclerosis: characterisation, classification and progression over time.
      ;
      • Zörner B.
      • Filli L.
      • Reuter K.
      • et al.
      Prolonged-release fampridine in multiple sclerosis: improved ambulation effected by changes in walking pattern.
      ), coordination (
      • Jensen H.
      • Ravnborg M.
      • Mamoei S.
      • et al.
      Changes in cognition, arm function and lower body function after slow-release Fampridine treatment.
      ;
      • Jensen H.B.
      • Nielsen J.L.
      • Ravnborg M.
      • et al.
      Effect of slow release-Fampridine on muscle strength, rate of force development, functional capacity and cognitive function in an enriched population of MS patients. A randomized, double blind, placebo controlled study.
      ), balance (
      • Hupperts R.
      • Lycke J.
      • Short C.
      • et al.
      Prolonged-release fampridine and walking and balance in MS: randomised controlled MOBILE trial.
      ;
      • Jensen H.
      • Ravnborg M.
      • Mamoei S.
      • et al.
      Changes in cognition, arm function and lower body function after slow-release Fampridine treatment.
      ), self-perceived gait function (
      • Goodman A.D.
      • Brown T.R.
      • Krupp L.B.
      • et al.
      Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial.
      ;
      • Hupperts R.
      • Lycke J.
      • Short C.
      • et al.
      Prolonged-release fampridine and walking and balance in MS: randomised controlled MOBILE trial.
      ), and Functional Ambulation Profile (FAP) Score (
      • Allart E.
      • Benoit A.
      • Blanchard-Dauphin A.
      • et al.
      Sustained-released fampridine in multiple sclerosis: effects on gait parameters, arm function, fatigue, and quality of life.
      ;
      • Rodriguez-Leal F.A.
      • Haase R.
      • Thomas K.
      • et al.
      Fampridine response in MS patients with gait impairment in a real-world setting: need for new response criteria?.
      ) (a composite value of selected spatiotemporal parameters) (
      • Givon U.
      • Zeilig G.
      • Achiron A.
      Gait analysis in multiple sclerosis: characterization of temporal-spatial parameters using GAITRite functional ambulation system.
      ) in a subset of patients with MS. However, the effect of fampridine on neuromechanical changes of gait, including the overall ‘quality of gait’, in patients with MS has not been examined.
      Three-dimensional gait analysis (3DGA) is an established method for objective quantification of kinematic, kinetic, and spatiotemporal parameters (
      • Benedetti M.G.
      • Piperno R.
      • Simoncini L.
      • et al.
      Gait abnormalities in minimally impaired multiple sclerosis patients.
      ;
      • Martin C.L.
      • Phillips B.A.
      • Kilpatrick T.J.
      • et al.
      Gait and balance impairment in early multiple sclerosis in the absence of clinical disability.
      ) and is considered the gold standard for gait analysis (
      • Cameron M.H.
      • Wagner J.M.
      Gait abnormalities in multiple sclerosis: pathogenesis, evaluation, and advances in treatment.
      ). The Gait Profile Score (GPS) is a summary measure of 3DGA that evaluates the overall quality of gait by comparing nine kinematic variables, described as Gait Variable Scores (GVS), relative to normative data. A higher GPS/GVS implies a larger deviation from a hypothetical “normal” gait and a greater level of impairment (
      • Baker R.
      • McGinley J.L.
      • Schwartz M.H.
      • et al.
      The gait profile score and movement analysis profile.
      ). GPS and/or GVS have been applied in previous studies involving patients with MS (
      • Andreopoulou G.
      • Mahad D.J.
      • Mercer T.H.
      • et al.
      Test-retest reliability and minimal detectable change of ankle kinematics and spatiotemporal parameters in MS population.
      ;
      • Coghe G.
      • Pau M.
      • Corona F.
      • et al.
      Walking improvements with nabiximols in patients with multiple sclerosis.
      ;
      • Morel E.
      • Allali G.
      • Laidet M.
      • et al.
      Gait profile score in multiple sclerosis patients with low disability.
      ;
      • Pau M.
      • Coghe G.
      • Atzeni C.
      • et al.
      Novel characterization of gait impairments in people with multiple sclerosis by means of the gait profile score.
      ;
      • Pau M.
      • Corona F.
      • Coghe G.
      • et al.
      Quantitative assessment of the effects of 6 months of adapted physical activity on gait in people with multiple sclerosis: a randomized controlled trial.
      ) and are considered feasible, reliable (
      • Andreopoulou G.
      • Mahad D.J.
      • Mercer T.H.
      • et al.
      Test-retest reliability and minimal detectable change of ankle kinematics and spatiotemporal parameters in MS population.
      ;
      • Pau M.
      • Coghe G.
      • Atzeni C.
      • et al.
      Novel characterization of gait impairments in people with multiple sclerosis by means of the gait profile score.
      ), and responsive in this population (
      • Pau M.
      • Coghe G.
      • Atzeni C.
      • et al.
      Novel characterization of gait impairments in people with multiple sclerosis by means of the gait profile score.
      ).
      The literature on fampridine-induced 3DGA changes in patients with MS, only include two publications on the same study: One demonstrating changes on kinematic variables (
      • Zörner B.
      • Filli L.
      • Reuter K.
      • et al.
      Prolonged-release fampridine in multiple sclerosis: improved ambulation effected by changes in walking pattern.
      ) and one on kinetic variables (
      • Weller D.
      • Lörincz L.
      • Sutter T.
      • et al.
      Fampridine-induced changes in walking kinetics are associated with clinical improvements in patients with multiple sclerosis.
      ). The study however, was performed during treadmill walking and the analysis included only a few kinematic variables, thus not allowing an interpretation of overall kinematic quality of gait (
      • Zörner B.
      • Filli L.
      • Reuter K.
      • et al.
      Prolonged-release fampridine in multiple sclerosis: improved ambulation effected by changes in walking pattern.
      ). The use of GPS/GVS, in combination with performance-based tests and self-perceived gait function, may help evaluate neuromechanical changes of fampridine on overall quality of gait.
      The aims of this study were to test the hypothesis that both gait quality (using GPS based on nine different GVS readings) and gait function (using performance-based tests, spatiotemporal variables, and self-perceived gait function) would improve in patients with MS after two weeks of fampridine treatment. Further, we hypothesized that changes in GPS would be associated with changes in performance-based tests and self-perceived gait function.

      2. Methods

      2.1 Participants and setting

      The present cohort study (without a separate control group) is part of a larger explorative, prospective observational cohort study (the MUST study) conducted at Odense University Hospital, Denmark from December 2018 to October 2021, in which participants were offered fampridine in a start-up period before evaluating its potential clinical impact. Therefore, the current sample includes both fampridine responders and non-responders (Trial registration: ClinicalTrials.gov NCT03847545). Data for the current sub-study were collected between May 2019 and May 2021 and are reported here according to the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) statement (
      • Vandenbroucke J.P.
      • von Elm E.
      • Altman D.G.
      • et al.
      Strengthening the reporting of observational studies in epidemiology (STROBE): explanation and elaboration.
      ). The study was approved by the National Committee on Health Research Ethics (S-20170203) and the Danish Data Protection Agency (2012-58-0018) and was conducted in accordance with the Declaration of Helsinki. Prior to testing, participants received oral and written information about the study and provided written informed consent.
      Eligible participants were recruited from the outpatient MS Clinic at Odense University Hospital. Inclusion criteria were a diagnosis of MS according to the McDonald 2010 criteria (
      • Polman C.H.
      • Reingold S.C.
      • Banwell B.
      • et al.
      Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria.
      ), age > 18 years, and an Expanded Disability Status Score (EDSS) between 4 and 7. Finally, participants should comply with clinical guidelines for receiving fampridine based on clinical symptoms and neurological evaluations. Exclusion criteria were history of epilepsy, MS attacks or acute decrease of functional capacity within 60 days, change in immunomodulatory treatment within 60 days, cancer within five years, clinically significant systemic disease, concomitant treatment with cimetidine, carvedilol, propranolol or metformin, and previous operations in the back or lower extremities.
      The participants included in the MUST study were randomly allocated to the present sub-study involving 3DGA (computerised at a sequence of 1:1) resulting in an extra test day at the test-site for each visit. The randomization procedure was done to reduce the number of time-consuming procedures and adhere to the sample size calculation (Section 2.3). Assessments were performed at baseline (T0), prior to starting fampridine, and at follow-up (T1) after 14 (±1) days of 10 mg fampridine® (Biogen, Cambridge, MA, USA) twice daily. Both T0 and T1 consisted of two consecutive days, one including the performance-based tests and one including 3DGA. Walking aids were used as required and kept identical for the individual tests at T0 and T1. At T0 baseline characteristics was collected, including age, gender, height and weight (from which Body Mass Index (BMI) was calculated), disease duration, and EDSS.

      2.2 Outcome measures

      2.2.1 Gait quality using 3D gait analysis

      Kinematic data were acquired using a Vicon T40 motion analysis system (Vicon, Oxford, UK) consisting of eight cameras sampling at 100 Hz. Prior to testing, relevant anthropometric measures were collected for the individual participant, followed by montage of 24 reflective markers and estimation of joint angles based on the modified Plug-In Gait model (
      • Davis R.B.
      • Õunpuu S.
      • Tyburski D.
      • et al.
      A gait analysis data collection and reduction technique.
      ).
      Participants walked barefooted at their normal self-selected walking speed, but were asked to adjust this at the follow-up visit if the self-selected walking-speed exceeded ±5% difference between the two visits. Data from five full gait cycles (unilateral heel-strike to heel-strike) for the dominant side (allowing suitable rest time between trials) at each visit were used for analyses. One assessor with 5 years of experience with this method (first study author) was responsible for marker placement, collecting the gait data, and data processing.
      Both GPS and the nine individual GVS were used to evaluate gait quality and potential kinematic changes at joint level, respectively according to Baker et al. 2009 (
      • Baker R.
      • McGinley J.L.
      • Schwartz M.H.
      • et al.
      The gait profile score and movement analysis profile.
      ). GPS is the root mean square (RMS) difference between the data of relevant kinematic variables of an individual participant and the averaged data from a reference group comprised of people without gait limitations. GVS refers to the RMS difference of the kinematic variables at each joint level: pelvic tilt, obliquity and rotation; hip flexion-extension, adduction-abduction, and rotation; knee flexion-extension; ankle dorsiflexion; and foot progression (
      • Baker R.
      • McGinley J.L.
      • Schwartz M.H.
      • et al.
      The gait profile score and movement analysis profile.
      ). For normative data, we used an age-matched reference group collected in our own lab (n: 29; Gender: 14 men/15 woman, age (mean (SD)): 50.5 years (10.3); BMI: 25.1 (3.0)).
      We processed the raw data using used Vicon Nexus Software (version 2.9.2 or later) and Vicon Polygon Software (version 4.4.5 or later) and subsequently analysed GPS and GVS using a custom-made MatLab script.

      2.2.2 Gait function

      Gait function was evaluated using spatiotemporal parameters captured during the 3DGA, performance-based tests, and a patient-reported measure. The Timed 25-Foot Walk (T25FW) measures short-distance walking speed and was performed according to the Multiple Sclerosis Functional Composite (
      • Fischer J.S.
      • Jak A.
      • Kniker J.
      • et al.
      Multiple Sclerosis Functional Composite (MSFC): Administration and Scoring Manual.
      ). The Six Spot Step Test (SSST) evaluates ambulatory function and involves criss-cross walking across a rectangular course as quickly as possible while kicking five blocks out of circles marked on the floor (
      • Nieuwenhuis M.M.
      • Van Tongeren H.
      • Sørensen P.S.
      • et al.
      The six spot step test: a new measurement for walking ability in multiple sclerosis.
      ). In the 2-min Walk Test (2MWT) (
      • Gijbels D.
      • Eijnde B.O.
      • Feys P.
      Comparison of the 2- and 6-minute walk test in multiple sclerosis.
      ), participants walked laps on a 20-m lane for 2 min, and the total distance travelled was recorded. Self-perceived impact of MS on gait function was measured using the 12-item MS Walking Scale (MSWS-12), a questionnaire evaluating gait limitations due to MS during the past two weeks (
      • Hobart J.C.
      • Riazi A.
      • Lamping D.L.
      • et al.
      Measuring the impact of MS on walking ability: the 12-item MS walking scale (MSWS-12).
      ). All included measuring tools are considered reliable and valid for the current patient group (
      • Callesen J.
      • Richter C.
      • Kristensen C.
      • et al.
      Test-retest agreement and reliability of the six spot step test in persons with multiple sclerosis.
      ;
      • Gijbels D.
      • Eijnde B.O.
      • Feys P.
      Comparison of the 2- and 6-minute walk test in multiple sclerosis.
      ;
      • Motl R.W.
      • Cohen J.A.
      • Benedict R.
      • et al.
      Validity of the timed 25-foot walk as an ambulatory performance outcome measure for multiple sclerosis.
      ;
      • Pilutti L.A.
      • Dlugonski D.
      • Sandroff B.M.
      • et al.
      Further validation of multiple sclerosis walking scale-12 scores based on spatiotemporal gait parameters.
      ;
      • Scalzitti D.A.
      • Harwood K.J.
      • Maring J.R.
      • et al.
      Validation of the 2-minute talk test with the 6-minute walk test and other functional measures in persons with multiple sclerosis.
      ).

      2.3 Statistical analysis

      Statistical analyses were performed using Stata/BE 17.0 (StataCorp LLC, College Station, TX, USA).
      Sample size calculation for the present analysis was performed a priori using previously reported GPS values on a comparable MS population (GPS mean ± SD) 9.1° ± 1.3° (
      • Andreopoulou G.
      • Mahad D.J.
      • Mercer T.H.
      • et al.
      Test-retest reliability and minimal detectable change of ankle kinematics and spatiotemporal parameters in MS population.
      ) and a minimal clinically important difference of 1.6° GPS, originally defined in a sample of children (
      • Baker R.
      • McGinley J.L.
      • Schwartz M.
      • et al.
      The minimal clinically important difference for the gait profile score.
      ). As no SD was reported for the original paper, we generalised the between-individual SD to the standard deviation of the change scores as SD = 1.3°. Based on a paired design, alpha = 0.05, 80% statistical power, assumption of Gaussian distribution of change scores, and attainment of minimal clinically important difference, a minimum of 9 participants were needed to reject the null hypothesis of no change from T0 to T1.
      Gaussian distribution for included data was investigated using normal probability plots and the Shapiro-Wilk test. To investigate changes between T0 and T1, we used Student's paired t-test with 95% confidence intervals (parametric) and Wilcoxon signed rank test with median values and bootstrap confidence intervals (95% BCa) (non-parametric).
      To compare characteristics of the included participants with MS to, those of the patients who were randomized to perform 3DGA but declined, we used Student's unpaired t-test (parametric) and Wilcoxon rank sum test (non-parametric).
      Due to the small sample size, we had no hypothesis for the specific form of association between GPS change scores and change scores of the performance-based measures and self-perceived gait function. Therefore, both Pearson's product-moment correlation coefficient r and Spearman's rank-order correlation coefficient ρ (rho) are reported. For kinematic and spatiotemporal data, the results for the dominant side are reported.

      3. Results

      Of the 71 patients with MS invited to participate in the larger cohort study (MUST), 16 declined. During the screening process, further 8 patients did not meet inclusion criteria. Of the remaining 47 participants, 26 were randomly allocated to 3DGA and 14 of these accepted the extra visit associated with the 3DGA; these 14 participants were included in the current sub-study (Fig. 1). No differences in characteristics were detected between the 14 included participants and the 12 patients who were randomized to 3DGA but declined (Table 1). All included participants completed both visits. The average age was 54 years, the majority were women, were overweight, and had an EDSS score between 4 and 6. The proportion using a walking aid during testing varied from 21% to 43% (Table 1).
      Fig. 1
      Fig. 1Flowchart.
      Illustration of the inclusion and the progress of all participants for the current sub-study on three-dimensional gait analysis (3DGA).
      Table 1Baseline characteristics of included participants and patients that declined to perform 3DGA.
      CharacteristicsPerformed 3DGA (n = 14)Declined 3DGA (n = 12)p-value
      Age, years53.6 (12.8)58.7 (12.9)0.18
      Females, n (%)9 (64)6 (50)1.00
      BMI, kg/m226.2 (3.9)NANA
      Disease duration, years21 (9.1)20.8 (10.1)0.95
      EDSS5.2 (0.8)5.6 (0.9)0.43
      Patients using walking aids during tests, n (%):
      3DGA4 (28.6)NANA
      T25FW3 (21.4)4 (33.3)0.53
      SSST3 (21.4)5 (41.7)0.27
      2MWT6 (42.9)6 (50.0)0.73
      Values are reported as mean (SD) or n (%).
      3DGA: Three-dimensional gait analysis; EDSS: Expanded Disability Status Score; T25FW: Timed 25-Foot Walk; SSST: Six Spot Step Test; 2MWT: 2-min Walk Test; NA; not applicable.
      We found no improvements in gait quality in terms of GPS or any kinematic changes at joint level by means of GVS (p > 0.05), following two weeks of fampridine treatment (Table 2a). However, we found significant improvement of gait function according to performance-based tests: T25FW, SSST, and 2MWT (p < 0.003) and self-perceived gait function: MSWS-12 (p < 0.001) (Table 2b). No significant changes were seen in the spatiotemporal parameters (p > 0.05) (Table 2b).
      Table 2aGait quality at baseline (T0) and 14-day follow-up (T1) for 14 patients with multiple sclerosis.
      Gait quality variablesT0T1Change [95% CI]% changep-value
      Overall GPS (degrees)8.50 (7.61/8.96)7.90 (7.39/9.35)−0.21 [−0.72; 0.29]−2.470.456
      GVS – dominant side (degrees)
      Pelvic tilt3.82 (2.71/7.10)5.24 (3.34/6.23)0.06[−1.35; 1.46]1.570.931
      Pelvic obliquity2.24 (1.85/2.76)2.05 (1.37/2.39)−0.22 [−0.49; 0.04]−9.820.094
      Pelvic rotation4.45 (3.70/5.76)5.38 (3.95/5.98)0.22 [−0.43; 0.86]4.940.482
      Hip flexion-extension9.18 (8.08/11.87)9.47 (7.69/12.74)0.31[−0.80; 1.42]3.380.561
      Hip abduction-adduction4.38 (3.41/4.95)4.15 (2.71/5.24)−0.22 [−0.80; 0.35]−5.020.410
      Hip rotation7.89 (6.32/11.82)7.11 (5.61/9.57)−1.03 [−3.16; 1.10]−13.050.316
      Knee flexion-extension13.25 (10.80/14.86)12.28 (8.38/15.03)−0.99 [−2.14; 0.17]−7.470.087
      Ankle dorsi flexion8.88 (7.08/10.23)8.68 (6.64/10.75)−0.30 [−1.09; 1.01]*−3.380.510
      Foot progression7.36 (5.12/8.50)6.96 (6.20/9.32)0.25 [−0.91; 1.41]3.400.648
      Table 2bGait function at baseline (T0) and 14-day follow-up (T1) for 14 patients with multiple sclerosis.
      Gait function variablesT0T1Change [95% CI]% changep-value
      Performance-based test and PROM
      T25FW (s)6.30 (5.35/7.05)5.58 (4.55/6.50)−0.82 [−1.16; –0.47]−11.51<0.001
      SSST (s)11.87 (3.87)10.22 (2.75)−1.65 [−2.65; −0.49]*−13.900.002
      2MWT (m)126.80 (25.71)149.84 (36.98)23.04 [14.03; 28.00]*18.170.001
      MSWS-12 (points)63.84 (13.44)41.37 (18.69)−22.47 [−29.17; −4.17]*−35.17<0.001
      Spatiotemporal parameters – dominant side
      Walking speed (m/s)0.94 (0.20)0.94 (0.19)0.00 [−0.01; 0.02]0.000.664
      Cadence (steps/min)105.17 (8.90)104.35 (9.48)−0.82 [–2.50; 0.86]–0.780.311
      Step length (m)0.54 (0.08)0.55 (0.08)0.01 [−0.00; 0.03]1.850.113
      Step width (m)0.17 (0.04)0.17 (0.04)0.00 [−0.01; 0.01]0.000.874
      Stride length (m)1.07 (0.16)1.08 (0.16)0.02 [−0.01; 0.04]0.930.160
      Values at T0 and T1 are mean (SD) or median (IQR). Change scores are mean [95% CI] if normally distributed or median [95% BCa] (followed by *) if non-normally distributed.
      GPS: Gait Profile Score; GVS: Gait Variable Scores; T25FW: Timed 25-Foot Walk; SSST: Six Spot Step Test; 2MWT: 2-min Walk Test; MSWS-12: 12-item MS Walking Scale; IQR: interquartile range; SD: standard deviation.
      No significant correlations were detected between change in GPS and changes in the performance-based tests or self-perceived gait function (p > 0.05), see Fig. 2.
      Fig. 2
      Fig. 2Scatterplots of associations.
      Scatterplots of associations between change in GPS and change in (A) T25FW, (B) SSST, (C) 2MWT and (D) MSWS-12 for 14 patients with multiple sclerosis.
      r: Pearson correlation coefficient; rho: Spearman's rank correlation coefficient; GPS: Gait Profile Score; T25FW: Timed 25-Foot Walk; SSST: Six Spot Step Test; 2MWT: 2-min Walk Test; MSWS-12: 12-Item MS Walking Scale.

      4. Discussion

      4.1 Main findings

      This is the first study examining potential fampridine-induced improvements in gait quality using a gait summary measure in patients with MS. The study represents a pragmatic clinical approach where participants were offered fampridine in a start-up period before evaluating its potential clinical impact. Therefore, the current study represents a sample including both fampridine responders and non-responders. Contrary to our hypothesis, we found no significant group mean improvements in gait quality and joint specific kinematic scores following fampridine treatment. However, improvements in the performance-based tests and self-perceived gait function confirmed our hypothesis of improved gait function. We found no significant associations between gait quality (GPS) and measures of gait function, consequently rejecting our hypothesis. Fampridine-induced changes thus appear to be restricted to performance-based gait variables and self-perceived gait function. As the underlying neuromechanical joint specific kinematic deviations (GVS) and overall quality of gait (GPS) showed no difference, the walking strategy remains unaltered i.e. MS-related gait limitations remain unchanged despite better function after two weeks of fampridine treatment.

      4.2 Quality of gait

      Compared to a median GPS of 4.8° in our age-matched reference group (data not shown), the participants with MS in the present study showed impaired gait quality at baseline, with a median GPS of 9.39° (IQR: 8.30°/9.82°), which is comparable with a GPS of 9.1° reported in a previous study on patients with MS (
      • Andreopoulou G.
      • Mahad D.J.
      • Mercer T.H.
      • et al.
      Test-retest reliability and minimal detectable change of ankle kinematics and spatiotemporal parameters in MS population.
      ). Thus, the observed lack of fampridine-induced change in gait quality cannot be ascribed to a flooring effect.
      A previous study demonstrated a minor fampridine-induced improvement in kinematic knee ROM of 2° during treadmill walking (
      • Zörner B.
      • Filli L.
      • Reuter K.
      • et al.
      Prolonged-release fampridine in multiple sclerosis: improved ambulation effected by changes in walking pattern.
      ). Together with current results of no improvements in GVS and GPS, this finding indicates that the kinematic strategy of patients with MS remains unaltered after a period of fampridine treatment. In contrast, a significant improvement of 10% (corresponding to 1.34° in the GPS) was found in patients with MS following one month of medical treatment for spasticity (nabiximols) (
      • Coghe G.
      • Pau M.
      • Corona F.
      • et al.
      Walking improvements with nabiximols in patients with multiple sclerosis.
      ); the median GPS (12.25°) was considerably poorer than that in the current study (9.39°), so direct comparisons especially of the difference in treatment outcome should be made with caution. Furthermore, no anchor-based MS-specific minimal clinically important change is defined for the GPS, and whether the observed change was clinically relevant, can be questioned. Fampridine-induced changes have been observed in some walking kinetics during treadmill walking, albeit on single patient and not group level, and not versus placebo (
      • Weller D.
      • Lörincz L.
      • Sutter T.
      • et al.
      Fampridine-induced changes in walking kinetics are associated with clinical improvements in patients with multiple sclerosis.
      ). Interestingly, the sub-group of patients displaying kinetic changes, also exhibited improvements in clinical walking tests. Thus, indicating that improvements in gait kinetics potentially influences gait performance, measured by clinical walking tests (
      • Weller D.
      • Lörincz L.
      • Sutter T.
      • et al.
      Fampridine-induced changes in walking kinetics are associated with clinical improvements in patients with multiple sclerosis.
      ).
      Compared to controls, patients with MS have demonstrated reduced velocity, cadence, and step length as well as increased base of support (
      • Givon U.
      • Zeilig G.
      • Achiron A.
      Gait analysis in multiple sclerosis: characterization of temporal-spatial parameters using GAITRite functional ambulation system.
      ). To the best of our knowledge, only two studies (
      • Allart E.
      • Benoit A.
      • Blanchard-Dauphin A.
      • et al.
      Sustained-released fampridine in multiple sclerosis: effects on gait parameters, arm function, fatigue, and quality of life.
      ;
      • Rodriguez-Leal F.A.
      • Haase R.
      • Thomas K.
      • et al.
      Fampridine response in MS patients with gait impairment in a real-world setting: need for new response criteria?.
      ) have examined changes in spatiotemporal parameters in patients with MS following fampridine treatment. Both studies (
      • Allart E.
      • Benoit A.
      • Blanchard-Dauphin A.
      • et al.
      Sustained-released fampridine in multiple sclerosis: effects on gait parameters, arm function, fatigue, and quality of life.
      ;
      • Rodriguez-Leal F.A.
      • Haase R.
      • Thomas K.
      • et al.
      Fampridine response in MS patients with gait impairment in a real-world setting: need for new response criteria?.
      ) evaluated the Functional Ambulation Profile (FAP) score, which is composite value of gait based on selected spatiotemporal parameters (
      • Givon U.
      • Zeilig G.
      • Achiron A.
      Gait analysis in multiple sclerosis: characterization of temporal-spatial parameters using GAITRite functional ambulation system.
      ). A significant positive change in FAP score was detected in both studies although one based the conclusion on group-level analysis (
      • Rodriguez-Leal F.A.
      • Haase R.
      • Thomas K.
      • et al.
      Fampridine response in MS patients with gait impairment in a real-world setting: need for new response criteria?.
      ) and the other used a categorical responder criterion threshold of 15% (
      • Allart E.
      • Benoit A.
      • Blanchard-Dauphin A.
      • et al.
      Sustained-released fampridine in multiple sclerosis: effects on gait parameters, arm function, fatigue, and quality of life.
      ). The latter additionally evaluated the spatiotemporal parameters separately, finding significant improvements in walking speed, cadence, and step-length (
      • Allart E.
      • Benoit A.
      • Blanchard-Dauphin A.
      • et al.
      Sustained-released fampridine in multiple sclerosis: effects on gait parameters, arm function, fatigue, and quality of life.
      ). Compared to our study, participants in both studies were more impaired at baseline according to clinical performance tests. Furthermore, unlike our study, the two previous studies did not match walking speed between sessions (
      • Allart E.
      • Benoit A.
      • Blanchard-Dauphin A.
      • et al.
      Sustained-released fampridine in multiple sclerosis: effects on gait parameters, arm function, fatigue, and quality of life.
      ;
      • Rodriguez-Leal F.A.
      • Haase R.
      • Thomas K.
      • et al.
      Fampridine response in MS patients with gait impairment in a real-world setting: need for new response criteria?.
      ), potentially introducing a biasing factor on gait variables (including spatiotemporal parameters and joint kinematics).

      4.3 Gait performance

      In contrast to measures of gait quality, significant improvements were seen on performance-based measures after fampridine treatment with the MSWS-12 showing the largest percentage improvement (−22.5 points/−35.2%). This positive change is substantial compared to most previous studies (
      • Brambilla L.
      • Rossi Sebastiano D.
      • Aquino D.
      • et al.
      Early effect of dalfampridine in patients with MS: a multi-instrumental approach to better investigate responsiveness.
      ;
      • Lo A.C.
      • Ruiz J.A.
      • Koenig C.M.
      • et al.
      Effects of dalfampridine on multi-dimensional aspects of gait and dexterity in multiple sclerosis among timed walk responders and non-responders.
      ;
      • Rodriguez-Leal F.A.
      • Haase R.
      • Thomas K.
      • et al.
      Fampridine response in MS patients with gait impairment in a real-world setting: need for new response criteria?.
      ) and represents an improvement larger than the defined minimal clinically important change from the patient's and therapist's perspectives (10.4 points and 11.4 points, respectively) (
      • Baert I.
      • Freeman J.
      • Smedal T.
      • et al.
      Responsiveness and clinically meaningful improvement, according to disability level, of five walking measures after rehabilitation in multiple sclerosis: a European multicenter study.
      ).
      The 2MWT also showed a large improvement (18.2%). Despite its strong discriminatory ability, the 2MWT has rarely been used to examine the effect of fampridine at group level, but a change of 14.8% was reported in a study on the response to fampridine (
      • Rodriguez-Leal F.A.
      • Haase R.
      • Thomas K.
      • et al.
      Fampridine response in MS patients with gait impairment in a real-world setting: need for new response criteria?.
      ). Although the previous study differed slightly in baseline EDSS characteristics and the participants covered a shorter distance in the 2MWT (
      • Rodriguez-Leal F.A.
      • Haase R.
      • Thomas K.
      • et al.
      Fampridine response in MS patients with gait impairment in a real-world setting: need for new response criteria?.
      ), both that study and our study obtained the minimally clinical important change value of 9.6 m (patient perspective) and 6.8 m (therapist perspective) (
      • Baert I.
      • Freeman J.
      • Smedal T.
      • et al.
      Responsiveness and clinically meaningful improvement, according to disability level, of five walking measures after rehabilitation in multiple sclerosis: a European multicenter study.
      ).
      The current improvements of −11.5% in T25FW and − 13.9% in SSST are in line with previously reported results in patients with MS (
      • Jensen H.
      • Ravnborg M.
      • Mamoei S.
      • et al.
      Changes in cognition, arm function and lower body function after slow-release Fampridine treatment.
      ;
      • Lo A.C.
      • Ruiz J.A.
      • Koenig C.M.
      • et al.
      Effects of dalfampridine on multi-dimensional aspects of gait and dexterity in multiple sclerosis among timed walk responders and non-responders.
      ). Notably, the group mean change does not reach the defined clinical relevancy of 20% for the T25FW (
      • Hobart J.
      • Blight A.R.
      • Goodman A.
      • et al.
      Timed 25-foot walk: direct evidence that improving 20% or greater is clinically meaningful in MS.
      ), which is often considered the response criterion for continued treatment with fampridine (
      • Hobart J.
      • Blight A.R.
      • Goodman A.
      • et al.
      Timed 25-foot walk: direct evidence that improving 20% or greater is clinically meaningful in MS.
      ;
      • Jensen H.
      • Ravnborg M.
      • Mamoei S.
      • et al.
      Changes in cognition, arm function and lower body function after slow-release Fampridine treatment.
      ). Similarly, SSST does not reach the threshold of >19% change for it to be considered a real change exceeding the measurement variability (
      • Callesen J.
      • Richter C.
      • Kristensen C.
      • et al.
      Test-retest agreement and reliability of the six spot step test in persons with multiple sclerosis.
      ). These thresholds however, may have been defined in patients with MS who display a higher level of gait limitations since their basis test results (mean T25FW: 8 to 45 s (
      • Hobart J.
      • Blight A.R.
      • Goodman A.
      • et al.
      Timed 25-foot walk: direct evidence that improving 20% or greater is clinically meaningful in MS.
      ); SSST: 5.6 to 61.1 s (
      • Callesen J.
      • Richter C.
      • Kristensen C.
      • et al.
      Test-retest agreement and reliability of the six spot step test in persons with multiple sclerosis.
      ) are substantially inferior to those demonstrated in our sample (mean T25FW: 6.3 s; mean SSST: 11.9 s). The case-mix of responders and non-responders in the current study may also explain the failure to achieve the thresholds for the T25FW and SSST.
      We found no association between improvement in gait quality and improvement in gait function. In view of the large and significant improvements seen in the functional tests and self-perceived gait function, the lack of change in gait quality is not due to a lack of response to fampridine. Instead, the positive fampridine effect on gait function is perhaps a result of improved signal conduction that results in a faster muscular response, rather than a direct effect on the movement pattern and thus kinematic gait quality evaluated by GPS and GVS. Improved gait quality would theoretically include a change in the MS patient's neuromechanical movement strategy, which most likely requires more than the short-term alteration of signal conduction in demyelinated axons that fampridine offers. The current lack of change in gait quality could thus be a consequence of both the short intervention and the isolated biochemical impact of fampridine. Future studies with longer intervention periods, possibly supplemented with targeted gait rehabilitation, are warranted to evaluate the potential influence of fampridine treatment on gait quality in patients with MS.

      4.4 Strengths and limitations

      Our study provides useful new clinical data on fampridine's effect on kinematic gait quality to add to its known impact on gait function in patients with MS. A further strength is that our GPS calculations were based on data from an able-bodied, age-matched reference group that were collected in our own laboratory. In addition, despite Baker et al. 2009 previously documented a weak correlation between GPS and walking speed (rho = −0.28) (
      • Baker R.
      • McGinley J.L.
      • Schwartz M.H.
      • et al.
      The gait profile score and movement analysis profile.
      ), we chose to match walking speed between sessions to fully eliminate its potential influence on kinematic variables (
      • Filli L.
      • Sutter T.
      • Easthope C.S.
      • et al.
      Profiling walking dysfunction in multiple sclerosis: characterisation, classification and progression over time.
      ).
      The present study has some methodological limitations. First, the pragmatic clinical approach entailed the inclusion of a sample including both fampridine responders and non-responders. This ruled out a randomized controlled trial approach, and thus also a causal investigation. The non-controlled and un-blinded design raises the possibilities of placebo effect, performance bias, and recall bias, all of which could influence the results. However, fampridine has previously been tested against placebo, and the extensive body of literature supporting a positive fampridine effect on gait function during a two-week trial (
      • Allart E.
      • Benoit A.
      • Blanchard-Dauphin A.
      • et al.
      Sustained-released fampridine in multiple sclerosis: effects on gait parameters, arm function, fatigue, and quality of life.
      ;
      • Goodman A.D.
      • Brown T.R.
      • Krupp L.B.
      • et al.
      Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial.
      ;
      • Goodman A.D.
      • Brown T.R.
      • Edwards K.R.
      • et al.
      A phase 3 trial of extended release oral dalfampridine in multiple sclerosis.
      ;
      • Lo A.C.
      • Ruiz J.A.
      • Koenig C.M.
      • et al.
      Effects of dalfampridine on multi-dimensional aspects of gait and dexterity in multiple sclerosis among timed walk responders and non-responders.
      ;
      • Zörner B.
      • Filli L.
      • Reuter K.
      • et al.
      Prolonged-release fampridine in multiple sclerosis: improved ambulation effected by changes in walking pattern.
      ) supports the current results.
      Although the sample size was defined a priori, this was based on a minimally clinically important GPS difference derived from children, as a MS-specific anchor-based difference was not available. In addition, the small sample size potentially reduces generalizability to the larger MS population. However, even though only 14, out of the 26 participants who were randomly allocated to 3DGA, accepted to perform this examination, a sub-group analysis of those randomized but not willing to undergo 3DGA yielded no difference in patient characteristics, suggesting high external validity.

      5. Conclusions

      In this prospective cohort study, improved gait function was observed in patients with MS following fampridine treatment according to performance-based tests and self-perceived gait function. However, no improvement in the kinematic quality of gait was seen. This may indicate that the impact of a two-week fampridine treatment is limited to improved signal conduction that leads to better gait performance.

      Author contribution

      Conception or design of the work: All.
      Coordinating the study: MT, AHL, HHN.
      Data collection: MT.
      Data-analysis: MT, AHL.
      Interpretation of data: MT, AHL, HHN, KLL.
      Writing – drafting the work: MT, AHL, HHN, KLL.
      Writing – Revision and editing of the work: All.
      Final approval of the version to be published: All.

      Declaration of Competing Interest

      The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:
      Helle Hvilsted Nielsen reports a relationship with Biogen that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Helle Hvilsted Nielsen reports a relationship with Roche that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Helle Hvilsted Nielsen reports a relationship with Sanofi Genzyme that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Helle Hvilsted Nielsen reports a relationship with Merck & Co Inc. that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Helle Hvilsted Nielsen reports a relationship with Novartis that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Helle Hvilsted Nielsen reports a relationship with Teva Pharmaceutical Industries Ltd. that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Henrik Boye Jensen reports a relationship with Biogen that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Henrik Boye Jensen reports a relationship with Roche that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Henrik Boye Jensen reports a relationship with Sanofi Genzyme that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Henrik Boye Jensen reports a relationship with Merck & Co Inc. that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Henrik Boye Jensen reports a relationship with Novartis that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Henrik Boye Jensen reports a relationship with Teva Pharmaceutical Industries Ltd. that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement.

      Acknowledgements

      This work was funded by The University of Southern Denmark , The Region of Southern Denmark [grant number: 17/33583 , 18/51851 ], Lounkaer Foundation, Augustinus' Foundation [grant number: 18-0217 ], The Danish Multiple Sclerosis Society [grant number: A35607 ], Lily Benthine Lund's Foundation [grant number: 5652 ], The Society of Multiple Sclerosis Patients on Funen, The of Chief Physician Committee Research Foundation [grant number: 70-A3228 ], The Promotion of Medical Science Foundation [grant number: 18-L-0369 ]. The study sponsors have no involvement in in the study or influence on the reporting of the results.
      We thank Dennis Brandborg Nielsen for software engineering assistance. Cecilie Dollerup Skov, Line Weis Andersen, and Gro Gynther Borges for the assistance with data collection. We thank Simon Bang Mohr Kristensen and Claire Gudex, BRIDGE, for statistical assistance and for proof-reading respectively. Furthermore, we wish to thank OPEN – Open Patient data Explorative Network.
      Finally, the authors would like to express their gratitude for the participants who volunteered to participate in the present study.

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