| | Reliability of clinical outcome measures in Charcot-Marie-Tooth diseaseReceived 12 July 2007; accepted 6 September 2007. Abstract We assessed inter- and intra-rater reliability of outcome measures in Charcot-Marie-Tooth disease (CMT) patients. In 40 CMT patients, we assessed reliability of Overall Neuropathy Limitations Scale (ONLS), 10-m timed walk (T10MW), 9-hole-peg test (9-HPT), maximal voluntary isometric contraction (MVIC) of arm (elbow flexion, hand-grip, and three-point pinch) and leg (knee extension, foot dorsiflexion/plantar flexion). Reliability was substantial for ONLS, excellent for T10MW and 9-HPT. For MVIC, inter and intra-rater reliability was excellent for hand contractions; for leg contractions, intra-rater agreement was moderate to substantial, whereas inter-rater agreement was poor. An ad hoc device was produced to immobilize the foot and MVIC reliability was re-assessed in 26 CMT patients, resulting in excellent inter-rater and intra-rater reliability for foot dorsiflexion, and clear inter-rater improvement for foot plantar flexion. All outcome measures appear adequate for CMT assessment. Use of an immobilization device improves foot MVIC reliability, preventing biased findings in patients with greater strength. 1. Introduction  Charcot-Marie-Tooth disease (CMT) is the most common inherited neuromuscular disorder, with prevalence estimated at 17-41/100,000 [1]. It is genetically highly heterogeneous, but a duplication in 17p12, which includes the gene coding for the peripheral myelin protein 22 (PMP22), is by far the most common genetic abnormality, and is responsible for the type 1A demyelinating form of the disease (CMT1A) [2]. Passage et al. reported that chronic treatment with ascorbic acid (AA, vitamin C) is effective in mice overexpressing PMP22 [3], one of the models of the human disease [4].We therefore designed a phase III multicentre randomized placebo-controlled trial (CMT-TRIAAL) to evaluate the long-term efficacy of AA in CMT1A (EudraCT No: 2006-000032-27), adopting the Charcot-Marie-Tooth Neuropathy Score (CMTNS) [5] as primary outcome measure, as recommended by the 136th ENMC workshop on CMT1A [6], [7]. Other outcome measures in the trial were the Overall Neuropathy Limitations Scale (ONLS) [8], the 10-m timed walk (T10MW) [9], quantitative measures of isometric strength of upper and lower limbs (all recommended by the 136th European Neuro-Muscular Centre – ENMC – workshop) [7] and the 9-hole peg test (9-HPT) [10], [11]. The CMT-TRIAAL is ongoing. The aim of the present study was to assess the reliability of all secondary clinical outcome measures being used in the trial, given that the reliability of the primary outcome measure (CMTNS, a composite scale assessing symptoms, signs and electrophysiology) has already been established [5]. 2. Patients and methods 2.1. The study was performed in two phases 2.1.1. Phase I The inter- and intra-rater reliability of the following scales/tests was assessed in 40 CMT patients: (a) ONLS; (b) T10MW; (c) 9-HPT; (d) maximal voluntary isometric contraction (MVIC) of arm (elbow flexion, hand-grip, and three-point pinch) and leg (knee extension, foot dorsiflexion, and plantar flexion) [12], [13]. Twenty-three patients had CMT1A associated with the 17p12 duplication and 17 had other types of CMT (Table 1). Each patient was tested independently by ML, a female neurologist, and ES, a male physician, with at least 30 min rest between each assessment, with re-testing one week later by ML. For the inter-rater assessment, the two neurologists tested in random order. 2.1.2. Phase II Reliability data from Phase I were analysed and found to be unsatisfactory for proximal arm and leg, and distal leg MVIC. To improve the reliability of the all-important distal measurements, an apparatus was devised to immobilize the foot during isometric contraction (Fig. 1A), and inter- and intra-rater reliability for these tests were re-determined in 26 CMT patients (Table 1). Twenty-two patients participated to both study phases. Each patient was tested independently by ML and ES in random order with at least 30min rest between assessments, with re-testing a week later by ML (all cases) and ES (14 cases), in the same random order. 2.2. Description of tests and measures The ONLS consists of an arm and a leg function scale [8]; a total score in the range 0 (no activity limitation) to 12 (most severe limitation) is obtained. The T10MW is a timed mobility and leg function test [9]. Two practice runs are performed before the test. The 9-HPT is an established timed test of upper limb function [10], [11]. Practice runs, one for each hand, are performed before starting. MVIC was assessed with a hand-held dynamometer (Citec CT 3001, CIT Technics BV, Groningen, The Netherlands) evaluating three arm movements (elbow flexion, hand-grip, and three-point pinch) and three leg movements (knee extension, foot dorsiflexion, and foot plantar flexion) [12], [13]. The fixation device is a compact and simple-to-use apparatus for immobilizing the foot, and eliminating the examiner’s influence on strength measurements (Fig. 1). It was devised by the technical workshop of the Bioengineering Department, Polytechnic of Milan, Italy. Briefly, the dynamometer is securely fixed in the vertical frame of the device which is attached to a stable horizontal base; the frame can be raised, lowered and rotated on its axis, to ensure that the dynamometer is placed in the appropriate position for testing. With the patient supine, the dynamometer is placed just proximal to the dorsal surface of the metatarso-phalangeal joint (foot dorsiflexion), or to the plantar surface of the metatarso-phalangeal joint (foot plantar flexion). 3. Results 3.1. Phase I For the ONLS reliability was substantial (arm score inter-rater WK 0.65, 95% CI 0.44–0.86; arm score intra-rater WK 0.75, 95% CI 0.54–0.96; leg score inter-rater WK 0.63, 95% CI 0.41–0.85; leg score intra-rater WK 0.68, 95% CI 0.47–0.90). For arm score, the two raters disagreed in 12/40 patients, with two-step differences in two instances; intra-rater disagreement occurred in 9 patients, with a two-step difference in one instance. For leg score, the two raters disagreed on 10 patients with a two-step difference in one instance; intra-rater disagreement occurred in 9 patients, but never exceeded one step. Reliability was excellent for the T10MW (inter-rater ICC 0.97, 95% CI 0.88–0.99; intra-rater ICC 0.96, 95% CI 0.87–0.99) and for the 9-HPT (inter and intra-rater ICC 0.95, 95% CI 0.89–0.97). With regard to MVIC (see Table 2a, Table 2b), inter- and intra-rater reliability was excellent for hand grip (inter-rater ICC 0.96, intra-rater ICC 0.98), and the three-point pinch (inter-rater ICC 0.95, intra-rater ICC 0.94). Figures for elbow flexion ranged from fair (inter-rater ICC 0.27) to moderate (intra-rater ICC 0.69). Intra-rater agreement was moderate for foot plantar flexion and knee extension (ICC ranging from 0.60 to 0.77) and substantial for foot dorsiflexion (ICC 0.87), while inter-rater agreement was poor for all lower limb contractions. | | |  | Movement | Examiner | |
|---|
| ES | ML | ML, re-test | |
|---|
| Hand-grip | 108.7 (45.4); 29–220 | 108.0 (43.2); 32–211 | 105.6 (42.7); 32–225 | | | Three-point pinch | 67.1 (29.9); 21–133 | 68.4 (28.9); 20–129 | 68.3 (30.6); 22–144 | | | Elbow flexion | 175.3 (67.4); 55–344 | 106.5 (38.9); 27–194 | 99.8 (28.9); 29–160 | | | Foot dorsiflexion | 64.8 (53.8); 0–204 | 26.1 (16.8); 4–67 | 23.9 (16.8); 5–71 | | | Foot plantar flexion | 111.6 (49.4); 0–195 | 31.2 (9.6); 7–46 | 27.8 (9.8); 5–46 | | | Knee extension, seated | 174.6 (56.2); 62–281 | 93.8 (36.4); 28–196 | 88.6 (28.0); 27–133 | | | Knee extension, prone | 149.8 (49.9); 43–259 | 91.8 (32.2); 33–169 | 87.1 (27.2); 33–153 | | | | |
| | | | Movement | Inter-rater | Intra-rater, examiner ML | |
|---|
| ICC (95% CI) | MSD, SE (95% CI) | ICC (95% CI) | MSD, SE (95% CI) | |
|---|
| Hand-grip | 0.96 (0.94 to 0.98) | −0.75, 1.84 (−4.5 to 3.0) | 0.98 (0.96 to 0.99) | 2.35, 1.36 (−0.4 to 5.1) | | | Three-point pinch | 0.95 (0.90 to 0.97) | 1.32, 1.49 (−1.7 to 4.3) | 0.94 (0.89 to 0.96) | 0.15, 1.70 (−3.3 to 3.6) | | | Elbow flexion | 0.27 (0.05 to 0.42) | −68.80, 5.98 (−80.9 to −56.7) | 0.69 (0.42 to 0.85) | 6.7, 4.2 (−1.8 to 15.1) | | | Foot dorsiflexion | 0.15 (−0.02 to 0.30) | −38.65, 6.76 (−52.3 to −25.0) | 0.87 (0.81 to 0.91) | 2.22, 1.32 (−0.4 to 4.9) | | | Foot plantar flexion | −0.44 (−0.61 to −0.24) | −80.37, 6.93 (−94.4 to −66.3) | 0.65 (0.36 to 0.81) | 3.37, 1.20 (0.9 to 5.8) | | | Knee extension, prone | 0.17 (−0.07 to 0.37) | −58.00, 5.09 (−68.3 to −47.7) | 0.77 (0.53 to 0.90) | 4.65, 3.14 (−1.7 to 11.0) | | | Knee extension, seated | −0.19 (−0.39 to 0.01) | −80.70, 6.50 (−93.8 to −67.5) | 0.60 (0.19 to 0.87) | 5.27, 4.55 (−3.9 to 14.5) | | | | |
3.2. Phase II Use of the foot-immobilizing device produced (see Table 3a, Table 3b) substantial inter-rater agreement (ICC 0.87) for dorsiflexion with excellent intra-rater findings (ML, ICC 0.95; ES, ICC 0.94); for foot plantar flexion, inter-rater agreement improved from poor to moderate (ICC=0.59 with wide confidence intervals), and intra-rater agreement remained moderate (ICCs in range 0.65–0.69). | | | | Movement | Inter-rater | Intra-rater, examiner ML | Intra-rater, examiner ESa | |
|---|
| ICC (95% CI) | MSD, SE (95% CI) | ICC (95% CI) | MSD, SE (95% CI) | ICC (95% CI) | MSD, SE (95% CI) | |
|---|
| Foot dorsiflexion | 0.87 (0.66–0.97) | 2.31, 4.68 (−7.3–11.9) | 0.95 (0.87–0.98) | 0.88, 3.15 (−5.6–7.4) | 0.94 (0.83–0.97) | 3.77, 4.39 (−5.8–13.3) | | | Foot plantar flexion | 0.59 (0.24–0.78) | 8.96, 7.45 (−6.4–24.3) | 0.69 (0.42–0.83) | −4.16, 5.83 (−16.2–7.9) | 0.65 (0.35–0.78) | 1.54, 9.28 (−18.7–21.7) | | | | |
| a Assessed in 14 patients. |
Bland-Altman plots revealed that inter-observer differences increased markedly with increase in patient strength for foot dorsiflexion (Fig. 2a) and plantar flexion (Fig. 3a). Using the immobilizing device, we found no tendency for the examiners to systematically over- or underestimate MVIC (Figs. 2c and 3c), except that one set of measurements was distant from the equivalence line (outlier, Fig. 2c). For intra-rater agreement, mean force measurements were confined to a narrow range (foot dorsiflexion: 5–70 Newton, Fig. 2b; plantar flexion: 5–50 Newton, Fig. 3b; see also Table 2a), while using the immobilizing device the range was much wider (foot dorsiflexion: 0–110 Newton, Fig. 2d; plantar flexion: 5–150 Newton, Fig. 3d; see also Table 3a). These findings suggest that less reliable measurements were obtained in individuals with greater strength (particularly when tested by the female examiner) – a limitation overcome by use of the foot immobilizing device. 4. Discussion Valid, reliable, practical, and change-sensitive measures are vital for assessing intervention efficacy in CMT, which is a chronic slowly progressive disease also characterized by variable disease expression. Thus far, only a few studies have assessed the reliability of outcome measures in CMT patients. Measures evaluated were the CMTNS [5], hand function tests [18], and strength with various dynamometers [18], [19], [20]. Data on inter-rater agreement – fundamental in multicentre and long-term studies – are even scarcer [5], [19], [20]. Activity limitations scales such as the Overall Neuropathy Disability Score (ONDS) and timed tests like the T10MW and the 9-HPT have been widely employed for acute and chronic acquired dysimmune neuropathies [9], [21], [22], but to our knowledge only the 9-HPT has been used in CMT, specifically in a recently published study assessing test–retest reliability of upper limb function in 20 CMT patients [18]. We evaluated intra- and inter-rater agreement in activity limitation and impairment measures in a consistent CMT series. We found excellent reliability for the T10MW and 9-HPT, providing for the first time data on inter-rater agreement and lower limb function (T10MW); our findings on intra-rater reliability for upper limb function (9-HPT) are in agreement with those reported previously [18]. The ONLS, which has been recently validated in patients with diverse neuropathies mainly of dysimmune origin [8], also showed substantial reliability in our CMT patients. With regard to MVIC, intra-rater reliability was, as expected, higher than inter-rater reliability in all muscle groups tested, with greatest differences for lower limb measurements. The reliability of the distal arm (hand-grip and three-point pinch) measurements was excellent. For these measurements, the influence of the examiner is limited and the contractions are simple enough to produce consistent findings in different patients and examiners. Similar intra-rater findings were reported in a smaller series [18]. A dynamometer specific for intrinsic hand muscle testing also showed excellent reproducibility [20]. By contrast, proximal movements were not reliably assessed, but in a peripheral nerve disease with exclusive or predominant distal impairment, this outcome is of secondary importance. As a result of this finding proximal arm and leg MVICs are not being assessed in the CMT-TRIAAL [6]. Lack of agreement (particularly inter-rater agreement) for distal lower limb contractions is much more important, and has previously been reported in patients with spinal muscular atrophy [12], and neuropathic weakness [19], and also in normal subjects [23], [24]. Two factors have been suggested as contributing to the poor reliability of foot dorsiflexion testing: (a) the shortness of the lever used for testing foot dorsiflexion, and (b) the difficulty of positioning the dynamometer correctly, particularly when ankle contractures are present [12], [23]. The foot-immobilizing device we designed considerably improved inter-rater agreement – from fair to excellent for foot dorsiflexion, and from poor to moderate for foot plantar flexion. The improvement was also evident from the reduced mean score differences, and from the plots (Fig. 2, Fig. 3). Since distal leg contraction is of primary importance in CMT, and the device is easy to use and store, it has been adopted for use in the CMT-TRIAAL. To conclude, hand-held dynamometer testing can be reliably used to measure distal strength in patients with CMT, and hence can be used as an outcome measure in randomized controlled trials. However inter- and intra-rater findings for foot contractions, complemented by the Bland-Altman plots, suggest that these are less reliable in individuals with greater strength particularly when they are tested by an examiner weak, or perceived as weak. We therefore recommend that patients be tested by a trained examiner using a foot immobilizing device. All the other measures we assessed showed substantial to excellent inter- and intra-rater reliability and appear adequate for the assessment of CMT in randomized controlled trials. Further data, particularly from longitudinal studies, are needed to assess the sensitivity to change of these measures. Acknowledgements We are indebted to Manuela Galli (Bioengineering Department, Polytechnic of Milan) and Luca Scampini for designing the foot fixation device used for foot strength assessment in Phase II. We thank Don Ward for help with the English, and the people with CMT who participated in the study. The financial support of Telethon, Italy (Grants GUP04002 and GUP05007) is gratefully acknowledged. Appendix A. MVIC evaluation protocol The examiner held the dynamometer and the subject was required to press against the dynamometer applicator. Each effort was assessed three times on the patient’s preferred side only, with about 10s rest between each attempt; the highest score was considered. To examine the pinch and hand-grip the patient sat upright, with the shoulder adducted, elbow flexed at 90°, forearm pronated and wrist extended. The examiner stood in front of the patient and held the dynamometer. For the pinch test, the patient placed the distal phalanx of the thumb on the lower part of the applicator and the distal phalanges of the first and second fingers on the upper part of the applicator, and then performed the pinch. For the hand-grip test the patient squeezed the handgrip. Elbow flexors were examined in the position reported by van der Ploeg et al. [25]. To test knee extension the patient sat on an examination couch with feet suspended over the couch but not touching the floor, and gripped the edge of the couch with both hands. The examiner sat in front of the patient and positioned the applicator of the dynamometer on the skin at the level of the anterior surface of the distal tibia, and the patient was instructed to extend the knee. We also tested knee extension with the patient lying prone, the knee flexed at 90°, with the examiner standing beside the patient and placing the dynamometer in the same position as the seated test. To examine foot dorsiflexion and plantar flexion, the patient was supine on the couch, and examiner close to the patient’s feet. The applicator was placed just proximal to the dorsal surface of the metatarso-phalangeal joint (foot dorsiflexion), or to the plantar surface of the metatarso-phalangeal joint (foot plantar flexion). Appendix B. * The CMT-TRIAAL Study Group B.1. Investigators IRCCS Foundation, “C. Besta” Neurological Institute, Milan: D. Pareyson, E. Salsano, C.Marelli, V. Scaioli, C. Ciano, M. Rimoldi, G. Lauria, E. Rizzetto, F. Camozzi; Department of Neurology, Ophthalmology and Genetics, University of Genoa: A. Schenone, M. Grandis, E. Narciso, L. Nobbio, L. Benedetti; Department of Neurological and Visual Sciences, Section of Clinical Neurology, University of Verona: N. Rizzuto, G.M. Fabrizi, T. Cavallaro, L. Bertolasi, A. Casano; Department of Neurological Sciences, Federico II University of Naples: L. Santoro, F. Manganelli, C. Pisciotta; Department of Neurology, “Salvatore Maugeri” Foundation, IRCCS, Telese Terme: M. Nolano; Department of Neurosciences, Psychiatry and Anesthesiology, University of Messina: G.Vita, A. Mazzeo, R. Di Leo, P. Girlanda, G. Majorana, M. Aguennouz, A. Ciranni, N. Lanzano; Department of Medical Sciences, Neurologic Unit, “Magna Graecia” University of Catanzaro: A. Quattrone, P. Valentino, R. Nisticò, D. Pirritano, A. Clodomiro, M. Canino; Department of Neurosciences, Sacro Cuore Catholic University, and Don Gnocchi Foundation, Rome: L. Padua, C. Pazzaglia; UILDM - Rome: T. Mignogna; Department of Neuroscience, University of Parma: F. Gemignani, F. Brindani, F. Vitetta; Department of Pharmacological Sciences, School of Pharmacy, University of Milan: F. Visioli, P. Bogani; (all in Italy). Trial Steering Committee: 1R.A.C. Hughes (Chair), D. Pareyson (chief investigator), A. Solari (co-chief investigator, study coordinator), A. Schenone, F Visioli. Independent Data & Safety Monitoring Committee: 2G.L. Mancardi (Chair), A. Solari, G. Cavaletti, 3S. Galimberti. Trial Coordination and Management: A. Solari, D. Radice, D. Calabrese, G. Ferrari. Pharmacology Committee: F. Visioli, M. Rimoldi. Neurophysiology Committee: V. Scaioli, L. Santoro, L. Padua. Neurobiology Committee: 4M.W. Sereda, A. Schenone, L. Santoro, G. 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a Neuroepidemiology Unit, IRCCS Foundation, “C. Besta” Neurological Institute, Via Celoria 11, 20133 Milan, Italy b Division of Biochemistry and Genetics, IRCCS Foundation, “C. Besta” Neurological Institute, Milan, Italy c Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy  Corresponding author. Tel.: +39 02 2394 2391; fax: +39 02 7060 6233.
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