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Responsiveness of the Motor Function Measure in Neuromuscular Diseases

  • Carole Vuillerot
    Correspondence
    Reprint requests to Carole Vuillerot, MD, PhD, L'Escale, Service central de rééducation, Hôpital Femme Mère Enfant, F-69677, Bron Cedex, France
    Affiliations
    Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, L'Escale, Service de Médecine Physique et de Réadaptation Pédiatrique, Bron, France

    Université de Lyon, Lyon, France

    Université Lyon I, Villeurbanne, France

    CNRS UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique Santé, Pierre-Bénite, France
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  • Christine Payan
    Affiliations
    Hôpital Pitié-Salpêtrière, Institute of Myology, Assistance Publique-Hôpitaux de Paris, Paris, France
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  • Françoise Girardot
    Affiliations
    Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, L'Escale, Service de Médecine Physique et de Réadaptation Pédiatrique, Bron, France
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  • Jacques Fermanian
    Affiliations
    Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France
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  • Jean Iwaz
    Affiliations
    Hospices Civils de Lyon, Service de Biostatistique, Lyon, France

    Université de Lyon, Lyon, France

    Université Lyon I, Villeurbanne, France

    CNRS UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique Santé, Pierre-Bénite, France
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  • Carole Bérard
    Affiliations
    Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, L'Escale, Service de Médecine Physique et de Réadaptation Pédiatrique, Bron, France
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  • René Ecochard
    Affiliations
    Hospices Civils de Lyon, Service de Biostatistique, Lyon, France

    Université de Lyon, Lyon, France

    Université Lyon I, Villeurbanne, France

    CNRS UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique Santé, Pierre-Bénite, France
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  • MFM Study Group

      Abstract

      Vuillerot C, Payan C, Girardot F, Fermanian J, Iwaz J, Bérard C, Ecochard R, the MFM Study Group. Responsiveness of the Motor Function Measure in neuromuscular diseases.

      Objectives

      To study the responsiveness (sensitivity to change) of the Motor Function Measure (MFM) in detecting change in neuromuscular disease patients with the intent of using this measure in future clinical trials.

      Design

      Prospective cohort observational study.

      Setting

      Inpatient and outpatient facilities for follow-up and treatment of neuromuscular diseases.

      Participants

      Patients (N=152) with various neuromuscular diseases aged 6 to 60 years.

      Interventions

      Not applicable.

      Main Outcome Measure(s)

      We used the MFM total score and its 3 subscores on 2 measurements grossly 1 year apart. The physicians and the patients (or proxy) were asked to provide their perceived change in functional status since the first MFM. These changes were expressed in 3 outcomes: deterioration, stability, or improvement.

      Results

      The overall 12-month-standardized mean change of the total score mean ± SD annual total score change was −2.4±5.5 points (P<.001), with patients with Duchenne muscular dystrophy (DMD) presenting the most significant change (−5.8±6.3, P<.001). The change in patients reporting deterioration (34%) was significantly larger than that of those reporting stability (47%) or improvement (10%) (−4.4±6.4 vs −2.0±5.6 and +0.9±4.4 points, respectively, P<.01). The 12-month-standardized total score changes were significantly greater in physician-rated deteriorated (49%) versus stable patients (51%), with mean differences in scores being −5.3±7.6 and −1.2±5.3, respectively (P<.001).

      Conclusions

      The MFM showed a good responsiveness, especially in patients with DMD and agreements with patients' and physicians' perceived change. Confirming this responsiveness requires larger age groups of patients with DMD and other neuromuscular diseases as well as disease-specific interexamination delays.

      Key Words

      List of Abbreviations:

      DMD (Duchenne muscular dystrophy), MFM (Motor Function Measure), NMD (neuromuscular disease), SRM (standardized response mean)
      MOST NEUROMUSCULAR DISEASES (NMDs) cause progressive muscle weakness that leads to impaired motor functions.
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      Profiles of neuromuscular diseases: design of the protocol.
      This deterioration is the main concern of the patient and the physician and should be the focus of patient follow-up and therapeutic intervention. Thus, many physicians and therapists consider that assessing muscle function is a key step in measuring changes and evaluating the outcomes of therapeutic interventions.
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      Measurement in Duchenne muscular dystrophy: considerations in the development of a neuromuscular assessment tool.
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      However, the measurement of muscle weakness is often difficult, and the muscles to test vary according to the disease.
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      Clinical evaluator reliability for quantitative and manual muscle testing measures of strength in children.
      Several functional tests have been developed to assess motor function in patients with NMDs. Some of them were validated in terms of reliability,
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      • Payan C.
      • Hodgkinson I.
      • Fermanian J.
      A motor function measure for neuromuscular diseases: construction and validation study.
      • Mazzone E.S.
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      • Vasco G.
      • et al.
      Reliability of the North Star Ambulatory Assessment in a multicentric setting.
      • Mazzone E.
      • Martinelli D.
      • Berardinelli A.
      • et al.
      North Star Ambulatory Assessment, 6-minute walk test and timed items in ambulant boys with Duchenne muscular dystrophy.
      • Mercuri E.
      • Messina S.
      • Battini R.
      • et al.
      Reliability of the Hammersmith functional motor scale for spinal muscular atrophy in a multicentric study.
      but the psychometric properties of most of them are still to be properly established
      • Scott E.
      • Mawson S.J.
      Measurement in Duchenne muscular dystrophy: considerations in the development of a neuromuscular assessment tool.
      • Fermanian J.
      [Validation of assessment scales in physical medicine and rehabilitation: how are psychometric properties determined?].
      American Educational Research Association, American Psychological Association, & National Council of Measurement in Education
      Standards for educational and psychological testing.
      • Berard C.
      • Fermanian J.
      • Payan C.
      Outcome measure for SMA II and III patients.
      whereas the current development of clinical trials in NMDs imposes a strict monitoring of changes in neuromuscular statuses and responses to treatment using valid, reliable, responsive, and feasible measures with established psychometric properties.
      • Scott E.
      • Mawson S.J.
      Measurement in Duchenne muscular dystrophy: considerations in the development of a neuromuscular assessment tool.
      Thus, 1 crucial attribute of motor function tests is responsiveness
      • Oeffinger D.
      • Bagley A.
      • Rogers S.
      • et al.
      Outcome tools used for ambulatory children with cerebral palsy: responsiveness and minimum clinically important differences.
      ; that is, the ability to detect change or stability in absence of change.
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      • Guyatt G.
      A methodological framework for assessing health indices.
      Indeed, responsiveness is essential to assess the efficacy of a treatment and monitor longitudinal changes over time.
      • Guyatt G.H.
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      • Charlson M.
      • Levine M.N.
      • Mitchell A.
      Responsiveness and validity in health status measurement: a clarification.
      • Sloan J.
      • Symonds T.
      • Vargas-Chanes D.
      • Fridley B.
      Practical guidelines for assessing the clinical significance of health-related quality of life changes within clinical trials.
      There are many approaches to assess responsiveness,
      • Middel B.
      • van Sonderen E.
      Statistical significant change versus relevant or important change in (quasi) experimental design: some conceptual and methodological problems in estimating magnitude of intervention-related change in health services research.
      but at present there is no consensus on the best method to use.
      Furthermore, most current tests do not allow quantitative measurements of functional change. For example, the functional rating scales of Brooke et al
      • Brooke M.H.
      • Griggs R.C.
      • Mendell J.R.
      • Fenichel G.M.
      • Shumate J.B.
      Clinical trial in Duchenne dystrophy, 1: the design of the protocol.
      or Vignos et al
      • Vignos Jr, P.J.
      • Spencer Jr, G.E.
      • Archibald K.C.
      Management of progressive muscular dystrophy of childhood.
      provide a grade or stage to rapidly describe a patient's status rather than a quantitative measure of motor function limitation. Such scales lack accuracy and responsiveness because big changes are needed to move from one stage to another. In fact, the Brooke scale
      • Brooke M.H.
      • Griggs R.C.
      • Mendell J.R.
      • Fenichel G.M.
      • Shumate J.B.
      Clinical trial in Duchenne dystrophy, 1: the design of the protocol.
      was considered acceptable for grading arm function in Duchenne muscular dystrophy (DMD) but unable to discriminate between different levels of severity in slowly progressive muscular dystrophies.
      • Lue Y.J.
      • Lin R.F.
      • Chen S.S.
      • Lu Y.M.
      Measurement of the functional status of patients with different types of muscular dystrophy.
      The limits of such scales were mostly linked to their low discriminant powers or to large floor effects.
      • Lue Y.J.
      • Lin R.F.
      • Chen S.S.
      • Lu Y.M.
      Measurement of the functional status of patients with different types of muscular dystrophy.
      More recent scales were developed to measure the motor function in specific NMDs: the Hammersmith Functional Motor Scale for Spinal Muscular Atrophy
      • Main M.
      • Kairon H.
      • Mercuri E.
      • Muntoni F.
      The Hammersmith functional motor scale for children with spinal muscular atrophy: a scale to test ability and monitor progress in children with limited ambulation.
      or the Expanded Hammersmith Functional Motor Scale
      • O'Hagen J.M.
      • Glanzman A.M.
      • McDermott M.P.
      • et al.
      An expanded version of the Hammersmith Functional Motor Scale for SMA II and III patients.
      in spinal muscular atrophy and the Hammersmith Motor Ability Scale
      • Scott O.M.
      • Hyde S.A.
      • Goddard C.
      • Dubowitz V.
      Quantitation of muscle function in children: a prospective study in Duchenne muscular dystrophy.
      or the North Star Ambulatory Assessment
      • Mazzone E.S.
      • Messina S.
      • Vasco G.
      • et al.
      Reliability of the North Star Ambulatory Assessment in a multicentric setting.
      • Mazzone E.
      • Martinelli D.
      • Berardinelli A.
      • et al.
      North Star Ambulatory Assessment, 6-minute walk test and timed items in ambulant boys with Duchenne muscular dystrophy.
      in DMD.
      Other “composite” scales combine different types of measures (motor function, daily activity, etc). To our knowledge, only the Egan Klassification scale
      • Steffensen B.F.
      • Lyager S.
      • Werge B.
      • Rahbek J.
      • Mattsson E.
      Physical capacity in non-ambulatory people with Duchenne muscular dystrophy or spinal muscular atrophy: a longitudinal study.
      and ACTIVLIM, the self-administered questionnaire,
      • Vandervelde L.
      • Van den Bergh P.Y.
      • Goemans N.
      • Thonnard J.L.
      Activity limitations in patients with neuromuscular disorders: a responsiveness study of the ACTIVLIM questionnaire.
      • Vandervelde L.
      • Van den Bergh P.Y.
      • Goemans N.
      • Thonnard J.L.
      ACTIVLIM: a Rasch-built measure of activity limitations in children and adults with neuromuscular disorders.
      have been the object of responsiveness studies in the context of NMDs. However, a study over 5 years has shown highly significant changes in the Egan Klassification sum (−4 points, P<.001) in 19 patients with DMD but not in 13 patients with spinal muscular atrophy (−1 point, P=.09).
      • Steffensen B.F.
      • Lyager S.
      • Werge B.
      • Rahbek J.
      • Mattsson E.
      Physical capacity in non-ambulatory people with Duchenne muscular dystrophy or spinal muscular atrophy: a longitudinal study.
      Nevertheless, ACTIVLIM has shown good responsiveness indices that support its potential future use in clinical trials to monitor patients with NMDs, especially patient ability to perform daily activities.
      • Vandervelde L.
      • Van den Bergh P.Y.
      • Goemans N.
      • Thonnard J.L.
      Activity limitations in patients with neuromuscular disorders: a responsiveness study of the ACTIVLIM questionnaire.
      • Vandervelde L.
      • Van den Bergh P.Y.
      • Goemans N.
      • Thonnard J.L.
      ACTIVLIM: a Rasch-built measure of activity limitations in children and adults with neuromuscular disorders.
      The Motor Function Measure (MFM) is a relatively recent tool designed for most of the NMDs and applicable to all degrees of disease severity in ambulant and nonambulant patients aged 6 to 60 years.
      • Berard C.
      • Payan C.
      • Hodgkinson I.
      • Fermanian J.
      A motor function measure for neuromuscular diseases: construction and validation study.
      This measure has shown excellent psychometric characteristics including construct validity, concurrent validity, and reproducibility.
      • Berard C.
      • Payan C.
      • Hodgkinson I.
      • Fermanian J.
      A motor function measure for neuromuscular diseases: construction and validation study.
      The purpose of the present study was to investigate the responsiveness of the MFM scores (3 subscores and a total score) and relate these changes to patient- and physician-perceived functional change since the last visit.

      Methods

      Participants

      Participant recruitment was carried out between May 2002 and July 2004 in 18 centers: 7 French centers for functional rehabilitation after hospitalization and 11 hospital departments of physical medicine and rehabilitation (10 French and 1 Swiss). All children and adult patients with NMD aged 6 to 60 years visiting these facilities were consecutively solicited. Informed consent was necessary for eligibility. Different consent protocols and forms were used for adult and pediatric patients. Adult patients gave signed informed consents. Pediatric patients gave their assent, and their parents or other legally authorized individuals gave signed consents to carry out the research.
      Further conditions were (1) having 1 of the main NMDs for which the MFM was validated: DMD, Becker muscular dystrophy, facioscapulohumeral dystrophy, limb-girdle muscular dystrophy, myotonic dystrophy, spinal muscular atrophy, congenital myopathy and congenital muscular dystrophy, or hereditary neuropathy; (2) having a diagnosis by genetic analysis or, if unavailable, an evocative muscle biopsy; and (3) receiving rehabilitation but not pharmacologic treatments. Patients with recent musculoskeletal surgery (within 3mo) or severe cognitive or behavioral problems were excluded (patients with mild to moderate cognitive or behavioral impairments are able to understand and perform the MFM tasks).
      For the present study, among 306 contacted patients, 3 were excluded for refusal to participate or lack of genetic analyses. Thus, 303 patients accepted the first MFM at baseline examination (MFM1). Later, 9 centers had difficulties in again calling the same patients at the convenient dates for the second MFM (MFM2). Thus, 155 patients could be reached, and only 3 refused to participate. Thus, 152 patients participated in MFM2.
      The study was approved by the Ethics Committee of Lyon A (France) and the Ethics Committee of Lausanne University (Switzerland). All adult patients and parents of affected children gave their written informed consent prior to inclusion.

      Procedure

      Finally, only 152 patients passed the MFM twice, at baseline (MFM1 measurement) and roughly 1 year later (MFM2 measurement). In most cases, MFM1 and MFM2 were administered to each patient by the same physiotherapist. At the second visit, physicians and patients (or parents of children) were asked to provide their perceived change in functional status since MFM1. Herein, these perceived changes are expressed in 3 outcomes: deterioration, stability, or improvement.

      Measures

      The MFM consists of 32 items (tasks) divided into 3 domains that provide a detailed profile of the physical impairment: D1, standing and transfers; D2, axial and proximal motor capacity; and D3, distal motor capacity. It takes on average 36 minutes to complete the whole MFM. The scoring of each item uses a 4-point Likert scale based on the subject's maximal abilities without assistance: 0 = cannot initiate the exercise or cannot maintain the starting position; 1 = partially complete the exercise; 2 = complete the exercise with compensations, slowness, or obvious clumsiness; and 3 = complete the exercise with a standard pattern. The method of scoring each item is detailed in the user's manual available in English, French, Spanish, Portuguese, German, Dutch, and Turkish (downloadable from www.mfm-nmd.org). The 32 scores to the 32 tasks are summed to yield a total score that is then expressed as a percentage of the maximum possible score (no physical impairment) × 100: the lower is the total score and the more severe is the impairment. Each of the 3 subscores (D1, D2, and D3) is also expressed as a percentage of the maximum possible score within each dimension.
      During the visits, the therapist assessed the functional capacities of the patients with the Brooke upper extremity functional rating scale
      • Brooke M.H.
      • Griggs R.C.
      • Mendell J.R.
      • Fenichel G.M.
      • Shumate J.B.
      Clinical trial in Duchenne dystrophy, 1: the design of the protocol.
      and the Vignos functional rating scale.
      • Vignos Jr, P.J.
      • Spencer Jr, G.E.
      • Archibald K.C.
      Management of progressive muscular dystrophy of childhood.

      Data Analysis

      In each patient, absolute change was the difference between MFM1 and MFM2 total score or subscores. Additionally, a mean score change (with SD) was calculated over all patients for the total score and each subscore (D1, D2, and D3). The median, maximum, and minimum changes were also calculated. Because of an important variation in follow-up (9–24mo), individual scores were transformed into annual (12-month-standardized) score changes by linear interpolation and reported as mean and SD.
      The responsiveness of the MFM was assessed using the standardized response mean (SRM) defined as the mean of all score changes (the mean of all individual differences MFM2 score minus MFM1 score) divided by the SD of those changes (the SD of all differences). According to the MFM structure and to the SRM formula, the higher the SRM, the greater is the change in patient status. In addition, according to Cohen's rule of thumb, 0.2 to 0.3 values could be regarded as small, around 0.5 values as medium, and over 0.8 values as large.
      • Cohen J.
      Statistical power analysis for the behavioral sciences.
      The 12-month-standardized mean score changes were tested versus 0 (0 being the mean score change in case the MFM2 score equals the MFM1 score) using the nonparametric Wilcoxon 2-tailed test.
      One comparison of absolute changes in MFM scores between groups rated as improved, unchanged, or worsened by the patients themselves and another comparison between groups rated by the physicians were performed using nonparametric tests (Mann-Whitney U or Kruskal-Wallis).
      Data were analyzed with BMDP software.a The statistical significance was set at P<.05.

      Results

      Patient Characteristics and Follow-Up

      Evaluations of the 152 patients took place between October 2003 and July 2004: 87 children (67 boys and 20 girls; mean age ± SD, range: 11.4±3.14y, 6–17y) and 65 adults (42 men and 23 women; 38±12.33y, 18–61y). The main patient characteristics at inclusion are displayed in table 1. DMD was the largest NMD group (n=41). At inclusion, 42% of the patients were nonambulant, especially in DMD and spinal muscular atrophy groups, and 21% were ventilated.
      Table 1Main Patient Characteristics at Inclusion According to the Type of NMD
      DiseaseNumberMean Age (y)Age Range (y)Boys/MenAmbulantWheelchair BoundVignos ScoreBrooke Score
      DMD41136–304110317.4 (9)
      Mean (median) score.
      3.3 (3)
      Mean (median) score.
      Becker muscular dystrophy17309–62171433.8 (3)1.9 (1)
      Facioscapulohumeral dystrophy17378–59101433.2 (2)2.8 (3)
      Other progressive muscular dystrophies
      Mainly, limb-girdle muscular dystrophy.
      18286–57111085.7 (4)3.1 (3)
      Congenital myopathy and congenital muscular dystrophy15166–396875.4 (5)2.9 (3)
      Myotonic dystrophy103511–505912.7 (2)1.9 (1)
      Spinal muscular atrophy17186–59116116.7 (9)2.6 (3)
      Hereditary neuropathy17215–5781701.41 (1)1 (1)
      Whole sample152235–6210988645.1 (4)2.6 (2)
      NOTE. N=152.
      low asterisk Mean (median) score.
      Mainly, limb-girdle muscular dystrophy.
      Regarding follow-up, 14 patients were followed for less than 12 months, 112 patients for 13 to 18 months, and 26 patients for more than 18 months. The mean ± SD follow-up duration was 474.2±85.14 days. The minimum, median, and maximum follow-up durations were 266, 465, and 688 days, respectively.
      The mean ± SD interval (range) separating MFM1 from MFM2 was 16±3 months (9–24mo).

      MFM Score Changes

      The mean ± SD MFM total score over the 152 patients was 61.7±26.7 at MFM1 and 58.5±28.2 at MFM2. The motor function of the whole sample, expressed as 12-month-standardized mean score change, decreased significantly for the D1 subscore (−2.2%±8.4%, P<.01), the D2 subscore (−3.0%±8.0%, P<.001), and the total score (−2.4%±5.5%, P<.001). The SRM of the total score was medium (.43). Concurrently, the SRMs relative to Vignos
      • Vignos Jr, P.J.
      • Spencer Jr, G.E.
      • Archibald K.C.
      Management of progressive muscular dystrophy of childhood.
      and Brooke
      • Brooke M.H.
      • Griggs R.C.
      • Mendell J.R.
      • Fenichel G.M.
      • Shumate J.B.
      Clinical trial in Duchenne dystrophy, 1: the design of the protocol.
      scores were medium and small (.42 and .24, respectively). Here, it should be noted that there was no correlation between MFM baseline values and the follow-up duration (Spearman's correlation coefficient ρ=.06) and no correlation between the follow-up duration and the mean 12-month-standardized score change (ρ=.14).
      Table 2 shows the 12-month-standardized mean score change and the SRM calculated for each subscore and each NMD. In DMD, all subscores (D1, D2, and D3) and the total score showed significant changes.
      Table 212-Month-Standardized Mean Score Change in Each MFM Subscore Per NMD Group
      DiseasenMFM D1 Subscore (Standing and Transfers)MFM D2 Subscore (Axial and Proximal Motor Capacity)MFM D3 Subscore (Distal Motor Capacity)MFM Total Score
      Mean Score Change ± SDSRMMean Score Change ± SDSRMMean Score Change ± SDSRMMean Score Change ± SDSRM
      DMD41−5.0±10.7
      Significant (P<.05) nonparametric Wilcoxon 2-tailed test—SRM.
      0.47−7.5±11.0
      Significant (P<.05) nonparametric Wilcoxon 2-tailed test—SRM.
      0.68−4.2±13.8)
      Significant (P<.05) nonparametric Wilcoxon 2-tailed test—SRM.
      0.30−5.8±6.3
      Significant (P<.05) nonparametric Wilcoxon 2-tailed test—SRM.
      0.91
      Becker muscular dystrophy17−1.6±8.40.19−3.0±5.9
      Significant (P<.05) nonparametric Wilcoxon 2-tailed test—SRM.
      0.51−0.9±6.60.14−2.0±6.10.33
      Facioscapulohumeral dystrophy17−1.7±4.60.37−1.3±4.90.27−1.2±7.00.17−1.5±3.40.43
      Other progressive muscular dystrophies
      Mainly, limb-girdle muscular dystrophy.
      18−3.3±12.80.26−3.2±7.00.461.0±5.4−0.19−2.3±7.20.32
      Congenital myopathy and congenital muscular dystrophy150.2±5.9−0.04−0.03±7.00.00−1.1±6.10.17−0.1±3.30.04
      Myotonic dystrophy10−0.4±4.60.08−1.7±8.20.21−1.0±5.10.19−1.0±4.50.22
      Spinal muscular atrophy170.3±3.5−0.070.7±3.9−0.19−1.7±6.80.250.01±2.90.00
      Hereditary neuropathy17−1.4±2.10.26−0.36±1.10.360.7±2.90.24−0.8±2.60.31
      Whole sample152−2.2±8.4
      Significant (P<.05) nonparametric Wilcoxon 2-tailed test—SRM.
      0.27−3.0±8.0
      Significant (P<.05) nonparametric Wilcoxon 2-tailed test—SRM.
      0.38−1.5±8.8
      Significant (P<.05) nonparametric Wilcoxon 2-tailed test—SRM.
      0.17−2.4±5.5
      Significant (P<.05) nonparametric Wilcoxon 2-tailed test—SRM.
      0.43
      low asterisk Significant (P<.05) nonparametric Wilcoxon 2-tailed test—SRM.
      Mainly, limb-girdle muscular dystrophy.
      In DMD, the SRM of the total score was the largest (.91) whereas that of D1 and D2 was medium (.47 and .68, respectively). Concurrently, the SRMs relative to Vignos
      • Vignos Jr, P.J.
      • Spencer Jr, G.E.
      • Archibald K.C.
      Management of progressive muscular dystrophy of childhood.
      and Brooke
      • Brooke M.H.
      • Griggs R.C.
      • Mendell J.R.
      • Fenichel G.M.
      • Shumate J.B.
      Clinical trial in Duchenne dystrophy, 1: the design of the protocol.
      scores were medium (.59 and .48, respectively).
      In smaller NMD groups (<20 patients in each one), the only significant decrease was seen in Becker muscular dystrophy for D2: −3.0%±5.9% (P=.05).
      Median, maximum, and minimum 12-month-standardized score changes are shown in Supplemental table 1, which is available online only at http://www.archives-pmr.org/.

      Patient- and Physician-Perceived Change

      Among patient answers, 28 answers to the question about the change in functional status between MFM1 and MFM2 were unusable (12 inadequate responses and 16 missing, of which 13 were addressed to children). Among the 124 responders, 46 reported deterioration, 64 reported stability, and 14 reported improvement. Figure 1 shows the 12-month-standardized mean changes according to the subscores and the total score of the MFM. Regarding the total score, the 12-month-standardized mean change between MFM1 and MFM2 was −4.4%±6.4% in patients who reported deterioration, −2.0%±5.6% in those who reported stability, and 0.9%±4.4% in those who reported improvement (P<.01). The changes were significant in patients reporting deterioration or stability (P<.001 and P<.01 respectively).
      Figure thumbnail gr1
      Fig 1Patient-reported 12-month-standardized mean score changes (deterioration, stability, or improvement) in each dimension subscore (D1, D2, D3) and total score between MFM test 1 and MFM test 2 one year later. The error bars correspond to the standard errors.
      The physicians' answers as to the changes in the functional states of their patients were as follows: deterioration 74, stability 77, and only 1 improvement. Figure 2 shows the 12-month-standardized mean changes according to the MFM subscores and the total score. Regarding the total score, the change between MFM1 and MFM2 was higher among the physician-reported deteriorations (−5.3%±7.6%) than among physician-reported stability (−1.2%±5.3%, P<.001). These changes were significant (P<.001 and P<.05, respectively).
      Figure thumbnail gr2
      Fig 2Physician-reported 12-month-standardized mean score changes (deterioration or stability) in each dimension subscore (D1, D2, D3) and total score between MFM test 1 and MFM test 2 one year later. The error bars correspond to the standard errors.
      In the 28 patients with unusable responses to the question about the perceived change, the MFM rather revealed deteriorations (12-month-standardized mean score change −5.6±8.8), but according to the physicians' answers, 10 were stable and 18 deteriorating.
      Finally, the agreement between patient-rated and physician-rated perceived change was 65%; that is, 81 of 124 (0, 45, and 36 agreements on improvement, stability, and deterioration, respectively).

      Discussion

      The present investigation showed, overall, that the motor function, as measured by the MFM total score, decreased significantly along time, confirming the relentless progressive clinical course of all studied NMDs. The most interesting results concerned patients with DMD. Indeed, patients with DMD showed the largest and most statistically significant mean change in total score among all other patients experiencing functional deficiency whatever the diagnosis (−5.8%± 6.3% vs −4.4%±6.4%). This was expected because patients with DMD form the most important subgroup due to the high incidence of the disease in the population but this does not mean that the MFM is DMD-specific; it rather reflects DMD's faster dynamics versus other NMDs. Additionally, compared with untreated controls, patients with DMD treated with steroids showed significantly less decreases in the MFM total score and the D2 subscore.
      • Vuillerot C.
      • Girardot F.
      • Payan C.
      • et al.
      Monitoring changes and predicting loss of ambulation in Duchenne muscular dystrophy with the Motor Function Measure.
      Thus, one may assume that the MFM may be reliably used in clinical trials to monitor patients with DMD receiving various treatments. In contrast, the 12-month-standardized mean score changes seen in other diseases were not found significant, especially regarding the total score. This can be explained by larger SDs around the total scores, smaller number of patients, and slower rates of progression than DMD (congenital muscular dystrophy, facioscapulohumeral dystrophy, spinal muscular atrophy, or Becker muscular dystrophy). In the latter diseases, further studies and larger patient samples are needed to confirm the ability of the MFM to detect changes over longer periods (>2y).
      The results showed that the 12-month-standardized mean changes of the MFM total score were lower in the patients (or physicians) who reported stability than in those who reported deterioration. Although it is already well known that self-perceived changes over time of any outcome may reach statistical significance without being clinically meaningful,
      • Oeffinger D.
      • Bagley A.
      • Rogers S.
      • et al.
      Outcome tools used for ambulatory children with cerebral palsy: responsiveness and minimum clinically important differences.
      significant MFM changes were considered clinically meaningful by the patients or the physicians reporting deterioration. From our results, it can be expected that a change of at least 5 points on the total MFM score will be perceived by patient or physician. In the case of stability, the results showed that the total MFM score was more responsive than the reporting by the patients or the physicians. Insufficient data were available concerning improvement.
      Overall, the MFM could be a useful complementary instrument to use in addition to other tools such as those that explore muscle strength, autonomy in daily life activities, or quality of life.
      • Guinvarch S.
      • Bérard C.
      • Calmels P.
      Affections neuromusculaires.
      • Abresch R.T.
      • Seyden N.K.
      • Wineinger M.A.
      Quality of life: issues for persons with neuromuscular diseases.
      • Vuillerot C.
      • Hodgkinson I.
      • Bissery A.
      • et al.
      Self-perception of quality of life by adolescents with neuromuscular diseases.
      The present study did not include any objective measure of muscle strength such as the Manual Muscle Testing or the Quantitative Muscle Testing because the muscles to be tested vary according to the NMD. Indeed, the Manual Muscle Testing has a poor interrater reproducibility
      • Escolar D.M.
      • Henricson E.K.
      • Mayhew J.
      • et al.
      Clinical evaluator reliability for quantitative and manual muscle testing measures of strength in children.
      and in young children with spinal muscle atrophy, the Quantitative Muscle Testing may remain stable despite deteriorating motor functions.
      • Iannaccone S.T.
      • Russman B.S.
      • Browne R.H.
      • Buncher C.R.
      • White M.
      • Samaha F.J.
      DCN/Spinal Muscular Atrophy Group
      Prospective analysis of strength in spinal muscular atrophy.
      Additionally, together with the MFM, these tests would have been too lengthy and strenuous. In our opinion, a motor function scale such as the MFM would be more indicated and feasible than muscle strength measurement to monitor changes in NMD in multicenter settings, especially in young children with muscle weakness. An abbreviated version (20 items) is also being developed for the younger patients (2–6y).
      Ideally, a comparison of the MFM results with those of other validated outcome measures would have enhanced our conclusions, but this was not possible because most other validated outcome measures are disease-specific, thus not applicable to the wide range of diseases we dealt with. Nevertheless, comparisons are ongoing in DMD, myotonic dystrophy, calpainopathy, and Pompe disease.
      Finally, some NMDs cause rapid changes that lead to loss of the walking ability. Some tests are specific for walking children, such as the 6-minute walk test,
      • McDonald C.M.
      • Henricson E.K.
      • Han J.J.
      • et al.
      The 6-minute walk test as a new outcome measure in Duchenne muscular dystrophy.
      • Montes J.
      • McDermott M.P.
      • Martens W.B.
      • et al.
      Muscle Study Group and the Pediatric Neuromuscular Clinical Research Network
      Six-Minute Walk Test demonstrates motor fatigue in spinal muscular atrophy.
      the Hammersmith Motor Ability Scale,
      • Scott O.M.
      • Hyde S.A.
      • Goddard C.
      • Dubowitz V.
      Quantitation of muscle function in children: a prospective study in Duchenne muscular dystrophy.
      or the North Star Ambulatory Assessment.
      • Mazzone E.S.
      • Messina S.
      • Vasco G.
      • et al.
      Reliability of the North Star Ambulatory Assessment in a multicentric setting.
      • Mazzone E.
      • Martinelli D.
      • Berardinelli A.
      • et al.
      North Star Ambulatory Assessment, 6-minute walk test and timed items in ambulant boys with Duchenne muscular dystrophy.
      They are increasingly used in clinical trials but are obviously of limited value when the trial patients are at risk of losing ambulation during the study. Other tests specific for patients who have lost ambulation such as the Egan Klassification scale
      • Steffensen B.F.
      • Lyager S.
      • Werge B.
      • Rahbek J.
      • Mattsson E.
      Physical capacity in non-ambulatory people with Duchenne muscular dystrophy or spinal muscular atrophy: a longitudinal study.
      or the Hammersmith functional motor scale
      • Mercuri E.
      • Messina S.
      • Battini R.
      • et al.
      Reliability of the Hammersmith functional motor scale for spinal muscular atrophy in a multicentric study.
      • Main M.
      • Kairon H.
      • Mercuri E.
      • Muntoni F.
      The Hammersmith functional motor scale for children with spinal muscular atrophy: a scale to test ability and monitor progress in children with limited ambulation.
      cannot be used at all stages of a number of diseases. The MFM is applicable to both ambulant and nonambulant patients. This favors its use as a single tool in a large panel of diseases.

      Study Limitations

      The first limitation of the present study is a sampling bias. In this preliminary investigation, we wanted to focus on the NMDs that start during childhood. This had 3 expected but important consequences. First, an overrepresentation of DMD, the most prevalent among these NMDs. The misbalance in NMD group sizes (DMD group was more than twice as large as the others) does not allow a comparison between diseases.
      Second, the inclusion of children and adults over a wide age range (despite the predominance of children). This increased the representativeness but causes interpretation problems. Certainly, all NMDs do not progress at the same rates at all age levels. So, the present conclusions cannot be fully extrapolated to older patients who form the majority in slowly to moderately progressive NMD groups. We believe that this was unavoidable at the start of our program. We are fully aware that studies dedicated to specific ages, diseases, body constitutions, and shapes are needed and require much greater sample sizes.
      Third, patients with rapidly progressive diseases, such as amyotrophic lateral sclerosis, were not included. Thus, the interexamination interval of 1 year was too short to detect change in the slowly progressive NMDs considered (facioscapulohumeral dystrophy, myotonic dystrophy, hereditary neuropathy, etc). In clinical studies of slowly progressive diseases, this interval should probably be extended to 2 years or more. Separate investigations by disease would have allowed easier and clearer comparisons between diseases and measures but, in our collaborative context, conducting the investigations by separate disease would have drastically reduced the sample sizes and age spans. In fact, we are currently designing disease-specific studies with conveniently chosen interexamination intervals. Future studies per specific disease should also include muscle testing. Also, a study on the relationship between muscle weakness (Manual Muscle Testing, Quantitative Muscle Testing, Biodex tests) and MFM scores in a few specific NMDs is underway and will soon yield its results.
      Two other linked limitations are the wide variability in time intervals between MFM1 and MFM2 and the transformation of the score difference into 12-month-standardized mean changes. First, a 1-year delay was originally decided because it is, in our practice, the delay between 2 regular follow-up visits. This delay was not complied with in many cases (112 MFM2 carried out 12–18mo after MFM1). The most simple and statistically robust solution was to consider the hypothesis of a linear change in patient motor function over 1 year or 2. This hypothesis is certainly questionable, and the interpolation solution was not optimal but was the most reasonable and able to stand in the case of slowly progressive NMDs.
      Another questionable decision is the exclusion of patients with “severe” cognitive or behavioral impairments. In fact, previous works on the MFM have shown that patients with mild to moderate (but not severe) cognitive or behavioral impairments are able to understand simple instructions and willing to perform the MFM tasks. The results of MFM in such conditions remain fairly reliable and interpretable. The decision to exclude severely affected patients was made by each physician who was, in almost all cases, the physician in charge of the potential participant. Nevertheless, we remain in search of a simple and rapid test to render this exclusion more objective.
      One may also criticize the use of questions about self-perceived and physician-perceived changes. The MFM is able, alone, to give an objective answer to the question: “How did the functional status of the patient evolve between MFM1 and MFM2?” and it did. However, we also wanted a subjective self-assessment using a single question and not a whole questionnaire, which would have lengthened the visit and generated complex validation concerns. This question may be considered as an anchor-based approach that complements the statistical approach: the latter is meant to reveal minimally clinically meaningful differences versus the statistically significant differences that are not always clinically meaningful.
      • Revicki D.A.
      • Cella D.
      • Hays R.D.
      • Sloan J.A.
      • Lenderking W.R.
      • Aaronson N.K.
      Responsiveness and minimal important differences for patient reported outcomes.
      • de Vet H.C.
      • Terwee C.B.
      • Ostelo R.W.
      • Beckerman H.
      • Knol D.L.
      • Bouter L.M.
      Minimal changes in health status questionnaires: distinction between minimally detectable change and minimally important change.

      Conclusions

      The MFM showed a good overall responsiveness in monitoring the clinical course of various NMDs, especially over the short term in the fast progressing DMD. The majority of the results were in line with patient-reported and physician-reported progressions of the NMDs. Compared with other instruments, the MFM can be used in less constrained conditions over wider ranges of diseases and time spans. Although it cannot replace some very specific instruments, it offers a reliable and responsive complementary assessment of the overall functional status.
      • a
        Statistical Solutions, Stonehill Corporate Ctr, Ste 104, 999 Broadway, Saugus, MA 01906.

      Acknowledgments

      We thank the members of the MFM Collaborative Study Group who carried out the MFM tests. The group is composed of the following French and Swiss medical doctors and physical therapists who participated in the MFM validation and sensitivity to change: M. Fournier-Méhouas, MD, V. Tanant, SRP (Hôpital de l'Archet, Nice), F. Beltramo, MD, C. Marchal, MD, C. Capello, MD (Hôpital Brabois, Nancy), D. Fort, MD, M. Desingue, SRP (Centre de Rééducation Enfants, Flavigny-sur-Moselle), C. Bérard, MD, I. Hodgkinson, MD, PhD, F. Girardot, SRP, F. Locqueneux, SRP (l'Escale, Centre Hospitalier Lyon-Sud, Lyon), J. Lachanat, MD, D. Denis, SRP (Fondation Richard, Lyon), J. Nielsen, MD, C. Glardon, SRP, S. Igolen-Augros, SRP (Hôpital Orthopédique de Lausanne, Suisse), A. Fares, MD, G. Le Claire, MD, J.L. Le Guiet, SRP, D. Lefeuvre-Brule, SRP (Centre de Kerpape, Ploemeur), J.Y. Mahé, MD, C. Nogues, SRP (Centre de Pen Bron, La Turballe), L. Feasson, MD, A. Jouve, SRP (Hôpital Bellevue, Saint-Etienne), M. Schmuck, MD (Service de Soins à Domicile, Roanne), P. Kieny, MD, G. Morel, SRP (Résidence La Forêt, Saint-Georges-sur-Loire), J.A. Urtizberea, MD, PhD, C. Themar Noel, MD, F. Cottrel, SRP, V. Doppler, SRP, J. Paulus, SRP (Institut de Myologie, Hôpital Pitié-Salpêtrière, Paris), F. Vandenborre, MD, C. Pastorelli, SRP (Hôpital Raymond Poincaré, Garches), I. Desguerre, MD, PhD (Hôpital Saint Vincent de Paul, Paris), E. Boulvert, SRP (Centre de rééducation Petit Tremblay, Corbeil-Essonnes), B. Pialoux, MD, P. Gallien, SRP, F. Letanoux, SRP (Centre Hospitalier Régional Pontchaillou, Rennes), P. Dudognon, MD, J.Y. Salle, MD, F. Parpeix, SRP, P. Morizio, SRP (Centre Hospitalier Universitaire Dupuytren, Limoges), V. Bourg, MD, B. Moulis-Wyndels, SRP (Centre Paul Dottin, Ramonville Saint-Agne), M. Marpeau, MD, F. Barthel, MD, D. Trabaud, D. Rouif, M. Vercaemer (Centre St Jean de Dieu, Paris), G. Viet, MD, B. Degroote, SRP (Hôpital Swinghedaw, Lille), and A. Carpentier, MD, I. Bourdeauducq, SRP (Centre Marc Sautelet, Villeneuve d'Ascq).

      Supplementary data

      Supplemental Table 112-month Standardized Median, Maximum, and Minimum Changes in MFM Subscores and Total Score
      DiseaseD1 SubscoreD2 SubscoreD3 SubscoreTotal MFM Score
      Duchenne muscular disease
       Median0−5.18−3.34−6.46
       Maximum13.9711.8725.516.81
       Minimum−34.06−47.58−66.35−19.35
      Becker's muscular dystrophy
       Median0−1.890−1.21
       Maximum21.892.9610.1612.23
       Minimum−19.15−20.75−18.81−18.48
      Facioscapulohumeral muscular dystrophy
       Median0000
       Maximum9.845.389.583.20
       Minimum−12.23−15.21−25.20−8.15
      Other progressive muscular dystrophies
       Median0−1.800−1.23
       Maximum19.0711.119.906.97
       Minimum−41.71−19.37−15.37−24.21
      Congenital myopathy/Congenital muscular dystrophy
       Median000−0.67
       Maximum13.1812.134.907.06
       Minimum−9.75−11.22−20.80−5.05
      Myotonic dystrophy type 1
       Median−0.870−1.42−0.38
       Maximum6.937.504.644.22
       Minimum−7.92−23.06−9.88−11.53
      Spinal muscular atrophy
       Median00−30
       Maximum87.966.904.46
       Minimum−8.42−6.04−19.67−6.02
      Charcot-Marie-Tooth disease
       Median−1.9600−0.67
       Maximum8.0212.134.984.07
       Minimum−11.44−8.51−6.28−4.65

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