iMAX: A new tool for assessment of motor axon excitability. A multicenter prospective study.

OBJECTIVE: This study was undertaken to establish by a multicentric approach the reliability of a new technique evaluating motor axon excitability. METHODS: The minimal threshold, the lowest stimulus intensity allowing a maximal response by 1 mA increments (iUP) and then by 0.1 mA adjustments (iMAX) were prospectively derived from three nerves (median, ulnar, fibular) in four university centers (Liège, Marseille, Fraiture, Nice). iMAX procedure was applied in 28 healthy volunteers (twice) and 32 patients with Charcot-Marie-Tooth (CMT1a), chronic inflammatory demyelinating polyneuropathy (CIDP), Guillain-Barré syndrome (SGB) or axonal neuropathy. RESULTS: Healthy volunteers results were not significantly different between centers. Correlation coefficients between test and retest were moderate (> 0.5). Upper limits of normal were established using the 95th percentile. Comparison of volunteers and patient groups indicated significant increases in iMAX parameters especially for the CMT1a and CIDP groups. In CMT1a, iMAX abnormalities were homogeneous at the three stimulation sites, which was not the case for CIDP. CONCLUSIONS: The iMAX procedure is reliable and allows the monitoring of motor axon excitability disorders. SIGNIFICANCE: The iMAX technique should prove useful to monitor motor axonal excitability in routine clinical practice as it is a fast, non-invasive procedure, easily applicable without specific software or devices.

Quantitative assessment of muscle echogenicity in Charcot-Marie-Tooth disease type 1A by automatic thresholding methods.

OBJECTIVE: To investigate the utility of automatic thresholding methods for quantitative muscle echogenicity assessment as a marker of disease severity in Charcot-Marie-Tooth disease type 1A (CMT1A). METHODS: Muscle ultrasound was performed in 15 CMT1A patients and 7 healthy controls. Muscle echogenicity of six limb muscles in each subject was assessed by 16 automatic thresholding methods and conventional grey-scale analysis. Echogenicity of each method in CMT1A patients was compared with that in controls. A correlation between the echogenicity and CMT neuropathy score (CMTNS) was also analysed in CMT1A patients. RESULTS: Significant differences in mean echogenicity of the 6 muscles between CMT1A patients and controls were found both in grey-scale analysis (p < 0.01) and 11 of the 16 automatic thresholding methods (p < 0.05 in each method). In CMT1A patients, mean echogenicity of the 6 muscles was positively correlated with CMTNS in 8 of the 16 automatic thresholding methods, but not in grey-scale analysis. CONCLUSION: Automatic thresholding methods can be used to detect the difference in muscle echogenicity between CMT1A patients and controls. Echogenicity parameters correlate with the disease severity. SIGNIFICANCE: Quantitative muscle echogenicity assessment by automatic thresholding methods shows potential as a surrogate marker of disease progression in CMT1A.

CMT subtypes and disease burden in patients enrolled in the Inherited Neuropathies Consortium natural history study: a cross-sectional analysis.

BACKGROUND: The international Inherited Neuropathy Consortium (INC) was created with the goal of obtaining much needed natural history data for patients with Charcot-Marie-Tooth (CMT) disease. We analysed clinical and genetic data from patients in the INC to determine the distribution of CMT subtypes and the clinical impairment associated with them. METHODS: We analysed data from 1652 patients evaluated at 13 INC centres. The distribution of CMT subtypes and pathogenic genetic mutations were determined. The disease burden of all the mutations was assessed by the CMT Neuropathy Score (CMTNS) and CMT Examination Score (CMTES). RESULTS: 997 of the 1652 patients (60.4%) received a genetic diagnosis. The most common CMT subtypes were CMT1A/PMP22 duplication, CMT1X/GJB1 mutation, CMT2A/MFN2 mutation, CMT1B/MPZ mutation, and hereditary neuropathy with liability to pressure palsy/PMP22 deletion. These five subtypes of CMT accounted for 89.2% of all genetically confirmed mutations. Mean CMTNS for some but not all subtypes were similar to those previously reported. CONCLUSIONS: Our findings confirm that large numbers of patients with a representative variety of CMT subtypes have been enrolled and that the frequency of achieving a molecular diagnosis and distribution of the CMT subtypes reflects those previously reported. Measures of severity are similar, though not identical, to results from smaller series. This study confirms that it is possible to assess patients in a uniform way between international centres, which is critical for the planned natural history study and future clinical trials. These data will provide a representative baseline for longitudinal studies of CMT. CLINICAL TRIAL REGISTRATION: ID number NCT01193075.

Postural stabilization and balance assessment in Charcot-Marie-Tooth 1A subjects.

The aim of the present study was to assess postural stabilization skill in adult subjects affected by Charcot-Marie-Tooth disease (CMT) type 1A. For this purpose ground reaction force (GRF) was measured by means of a piezoelectric force platform during the sit-to-stand (STS) movement, until a steady state erect posture was achieved. Specific indexes to quantify Centre of Mass acceleration, both during postural stabilization and during quiet standing, were computed using a mathematical model. Forty-seven CMT1A subjects were recruited for the study, and the control group was formed by forty-one age- and sex-matched healthy subjects. The results show that CMT1A subjects are less stable than controls during the quiet stance. Greater difficulty (high values of Yinf, the final instability rate) to maintain erect posture appears to be mainly associated with plantar-flexor muscle weakness, rather than to damage of the proprioceptive system. The worst performances shown by CMT1A subjects in the stabilization phase (high values of I, the global index of postural stabilization performance) seem to be associated with reduced muscle strength and the loss of large sensory nerve fibres. Distal muscle weakness appears to affect both postural stabilization and quiet erect posture. The presented protocol and the analysis of postural stabilization parameters provide useful information on CMT1A balance disorders.

An anterior ankle-foot orthosis improves walking economy in Charcot-Marie-Tooth type 1A patients.

BACKGROUND: Ankle-foot orthoses are commonly prescribed in Charcot-Marie-Tooth type 1A disease to improve quality of walking and reduce the risk of falling due to the foot drop. OBJECTIVES: This study aimed at assessing the effect of an anterior ankle-foot orthosis on walking economy in a group of Charcot-Marie-Tooth type 1A patients. STUDY DESIGN: Within-group comparisons. METHODS: 7 Charcot-Marie-Tooth type 1A patients (four women and three men; 37 ± 11 years; age range = 22-53 years) were asked to walk on a circuit at their self-selected speeds ('slow', 'comfortable' and 'fast') in two walking conditions: (1) with shoes only and (2) with Taloelast(®) anterior elastic ankle-foot orthoses. Speed of walking and metabolic cost of walking energy cost per unit of distance were assessed at the three self-selected speeds of walking for both walking conditions. RESULTS: Speed of walking at the three self-selected speeds did not differ between shoes only and anterior elastic ankle-foot orthoses, whereas walking energy cost per unit of distance at comfortable speed was lower in patients using anterior elastic ankle-foot orthoses with respect to shoes only (2.39 ± 0.22 vs 2.70 ± 0.19 J kg(-1) m(-1); P < 0.05). CONCLUSIONS: In Charcot-Marie-Tooth type 1A patients, the use of anterior elastic ankle-foot orthoses improved walking economy by reducing the energy cost of walking per unit of distance, thus reflecting a lower level of metabolic effort and improved mechanical efficiency in comparison with shoes only. CLINICAL RELEVANCE: From a practical perspective, Charcot-Marie-Tooth type 1A patients with anterior elastic ankle-foot orthoses can walk for a longer duration with a lower level of physical effort. Improvements in walking economy due to ankle-foot orthoses are likely a consequence of the reduction in steppage gait.

Outcome measures for Charcot-Marie-Tooth disease: clinical and neurofunctional assessment in children.

Charcot-Marie-Tooth (CMT) disease is the most common inherited neuromuscular disorder, presenting with symptoms often occurring since childhood, and showing a progressive course. At present, there are no valid and reliable measures for evaluation of impairment and disability in the pediatric population. The aim of this study was to determine the usefulness of outcome measures, commonly used in adult patients, in CMT children. We report the results of a comprehensive evaluation of 21 children affected with CMT type 1A, including clinical examinations, measure of hand and foot muscle strength with a hand-held dynamometer, and the following scales: CMT Neuropathy Score or its clinical component CMT Examination Score, Overall Neuropathy Limitations Scale (ONLS), Walk-12 questionnaire, and nine-hole peg test (9-HPT). Hand grip, three-point pinch, and foot dorsiflexion strength were significantly lower than age/sex equivalent in almost all cases. 9-HPT was significantly abnormal in 62% of patients and CMT Examination Score was <10 points in all cases. ONLS showed presence of minor disability in the upper limbs in 57% and mild abnormalities of gait in 71% of patients. Overall, these scales demonstrated limited potential to measure disability and severity of the disease confirming that it is necessary to identify specific scales for children with CMT.

Assessment of appropriate ankle-foot orthoses models for patients with Charcot-Marie-Tooth disease.

OBJECTIVE: : The purpose of this study was to demonstrate to what extent ankle-foot orthoses improve posture and gait control in patients with Charcot-Marie-Tooth disease and to identify the most appropriate characteristics of ankle-foot orthoses for patients regarding their clinical characteristics. DESIGN: : Twenty-six Charcot-Marie-Tooth patients were recruited. Clinical data (such as levels of sensory and muscular deficits) and posture and gait capacities were collected in three randomized experimental conditions (wearing ordinary shoes or with plastic and elastic orthoses). Several subgroups of patients, constituted using predictive value analysis, were associated using the probabilities of enhancing posture and gait control while wearing the various models of orthoses. RESULTS: : Compared with ordinary shoes alone, adding plastic ankle-foot orthoses partially improved both gait and posture control, whereas wearing elastic orthoses only partially affected the more dynamic gait control. Furthermore, the choice between the two models can be clarified by taking into account distal lower limb muscle capacity. CONCLUSIONS: : Ankle-foot orthosis prescription appears relevant for improving balance and gait performance in Charcot-Marie-Tooth patients, particularly when the model adequately compensates for specific muscle deficits. This study also provides objective arguments for making adequate bracing.

Charcot-Marie-Tooth 1A patients with low level of impairment have a higher energy cost of walking than healthy individuals.

The study aimed at quantifying the walking energy cost of a group of Charcot-Marie-Tooth 1A patients (CMT1A), with low severity of walking impairment, in comparison with healthy individuals. Oxygen uptake was measured in 8 patients (age-range 20-48 years; Barthel >90; Tinetti >20) and 8 healthy individuals, matched for age and gender, when walking on a circuit for 5-min at their self-selected speeds ("slow", "comfortable" and "fast"). Both comfortable and fast speeds were lower in patients than in the control group (0.92±0.16 vs 1.16±0.22 and 1.27±0.27 vs 1.61±0.22 m s⁻¹, respectively; P<0.05), whereas walking energy cost per unit of distance was higher in patients than in the control group (P<0.05) at both "comfortable" (2.27±0.35 vs 1.92±0.21 J kg⁻¹m⁻¹) and "fast" speed (3.05±0.35 vs 2.37±0.42 J kg⁻¹m⁻¹). CMT1A patients, therefore, choose to walk slower but with higher metabolic cost compared to healthy individuals, despite no clinically evident walking impairment, which is likely due to altered walking patterns.

Manual dexterity in hereditary motor and sensory neuropathy type 1a: severity of limitations and feasibility and reliability of two assessment instruments.

OBJECTIVE: To assess the prevalence and significance of impaired manual dexterity in hereditary motor and sensory neuropathy type 1a (HMSN 1a), with the Sollerman hand function and the Functional Dexterity test, and compare the reliability and agreement of the tests. DESIGN: Descriptive cross-sectional study. SUBJECTS: Forty-nine subjects with HMSN 1a. RESULTS: Forty-six (94%) subjects had an abnormal Sollerman sum score (< 80) for the dominant hand. The most difficult subtests required finger grips such as pulp, tripod and lateral pinches. Dexterity scores of both hands were categorized as "moderately functional". Test-retest reliability was excellent for the Sollerman test, with intraclass correlation coefficients between 0.98 and 0.99 (95% confidence interval (CI) 0.97-0.99), and good for Functional Dexterity test scores with correlation coefficients between 0.83 and 0.95 (95% CI. 71-0.97). The 95% limits of agreement between Sollerman tests showed that differences greater than 3 points can be interpreted as a change in dexterity. The Functional Dexterity test limits were wide. CONCLUSION: Impaired manual dexterity is common among subjects with HMSN 1a, stressing that the evaluation of dexterity is an essential element of the functional assessment. Both tests are able to detect impaired manual performance in HMSN 1a. For monitoring of disease progression and the effects of treatment programmes the Sollerman test is most suitable.

Assessment of axonal loss in Charcot-Marie-Tooth neuropathies.

Sensory loss and weakness in Charcot-Marie-Tooth (CMT) neuropathy is due to axonal loss. However, the pattern and degree of axonal loss cannot be accurately determined from routine electrodiagnostic or strength testing due to collateral reinnervation. We sought to quantify axonal loss in two upper extremity muscles in CMT1A and CMT2 subjects using the electrophysiologic endpoint measure of motor unit number estimation (MUNE). Hypothenar and biceps-brachialis muscle groups were studied in 9 CMT1A, 9 CMT2, and 10 control subjects. The spike-triggered averaging (STA) technique was used to collect surface motor unit potentials for MUNE calculations, and a needle electrode was used to collect corresponding intramuscular data. Maximal voluntary hypothenar and handgrip strength was measured quantitatively, while biceps-brachialis strength was measured qualitatively. Compared to normal subjects, CMT1A and CMT2 subjects had significantly lower MUNE values in hypothenar muscles. Biceps-brachialis MUNE values were reduced in CMT2 but not in CMT1A subjects. In support of proximal axonal loss in CMT2 subjects, surface motor unit and intramuscular potential amplitudes were higher in biceps-brachialis muscles compared to controls. Correlations between quantitative strength and MUNE were significant for hypothenar but not for grip muscle groups. Axonal loss is demonstrated in distal muscles in CMT1A and CMT2 supporting a length-dependent axonopathy. Despite clinical findings of normal or near-normal strength and small reductions in compound muscle action potential (CMAP) amplitude, MUNE values were significantly lower in CMT2 subjects in proximal muscles, consistent with more diffuse denervation. These data indicate that subclinical axonal loss is present that cannot be appreciated using clinical examination or routine electrodiagnostic techniques.

[Electrophysiological assessment of median sensory nerve function in HMSN type I by intraneural neurography].

Microneurography (MNG) performed in the forearm segment of the median nerve enabled us to assess compound nerve action potentials reflecting the density of large myelinated sensory fibers around the microelectrode. We examined sensory nerve function of the median nerve in seven patients with hereditary motor and sensory neuropathy type I (HMSN-I) with conventional surface-electrode technique and MNG. In six of seven patients sensory nerve action potentials were not elicited with the surface-electrode method. In contrast, compound nerve action potentials (CNAPs) were evoked in all seven patients with MNG. Although the normal waveform of CNAP is characterized by a large triphasic wave with subsequent small multiphasic waves, the triphasic wave was diminished and prolonged small multiphasic waves were prominent in the patients. Maximal nerve conduction velocity and amplitude of the wave were decreased to 69% and 9% of age-matched control values, respectively. These changes detected in patients with HMSN-I could be interpreted as a result of large myelinated fiber loss and segmental demyelination of sensory nerves. We showed that sensory fiber dysfunction in HMSN-I could be quantitatively evaluated with MNG, even though the sensory action potential was not elicited with the surface-electrode method.

Penetrance of the hereditary motor and sensory neuropathy Ia mutation: assessment by nerve conduction studies.

The clinical expression of hereditary motor and sensory neuropathy type I (HMSN I) is age-dependent. Autosomal dominant HMSN I is heterogeneous at a molecular level with genes localized on chromosomes 1, 17, and possibly other chromosomes. In order to define accurately the penetrance of a single HMSN I gene mutation, we performed nerve conduction studies in HMSN I families whose genetic defect was linked to chromosome 17 (HMSN Ia). All HMSN Ia subjects tested had slow nerve conduction velocities with a mean median velocity 20 +/- 6 m/sec, which did not change with age. The range of conduction velocities from affected individuals did not overlap those from their clinically normal relatives, indicating complete penetrance of the gene from early childhood. The results indicate that motor nerve conduction studies in children can add additional information for linkage studies and genetic counseling.