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Charcot-Marie-Tooth disease (CMT) is a common heritable peripheral neuropathy. There is no treatment for any form of CMT although clinical trials are increasingly occurring. Patients usually develop symptoms during the first two decades of life but there are no established outcome measures of disease severity or response to treatment. We identified a set of items that represent a range of impairment levels and conducted a series of validation studies to build a patient-centered multi-item rating scale of disability for children with CMT.
As part of the Inherited Neuropathies Consortium, patients aged 3–20 years with a variety of CMT types were recruited from the USA, UK, Italy and Australia. Initial development stages involved: definition of the construct, item pool generation, peer review and pilot testing. Based on data from 172 patients, a series of validation studies were conducted, including: item and factor analysis, reliability testing, Rasch modeling and sensitivity analysis.
Seven areas for measurement were identified (strength, dexterity, sensation, gait, balance, power, endurance), and a psychometrically robust 11-item scale constructed (Charcot-Marie-Tooth disease Pediatric Scale: CMTPedS). Rasch analysis supported the viability of the CMTPedS as a unidimensional measure of disability in children with CMT. It showed good overall model fit, no evidence of misfitting items, no person misfit and it was well targeted for children with CMT.
The CMTPedS is a well-tolerated outcome measure that can be completed in 25-minutes. It is a reliable, valid and sensitive global measure of disability for children with CMT from the age of 3 years.
Charcot-Marie-Tooth disease (CMT) is named for the three neurologists who described it in the late 1800s.1,2 CMT affects ~1 in 2500 people and is among the most common inherited neurological disorders.3 The majority of patients with CMT have autosomal dominant inheritance, although X-linked dominant and autosomal recessive forms also exist. Most patients have a ‘typical’ CMT phenotype characterized by distal weakness, sensory loss, foot deformities (pes cavus and hammer toes) and absent ankle reflexes. Many patients develop severe disability in infancy or early childhood (congenital hypomyelinating neuropathy and Dejerine-Sottas neuropathy), while others develop few if any symptoms of neuropathy until adulthood.
At present, mutations in more than 50 genes have been identified that cause CMT. These genes and their proteins constitute a human ‘microarray’ of molecules that are necessary for the normal function of myelinated axons in the peripheral nervous system. These mutations have illuminated important intracellular pathways leading to demyelination or axonal degeneration, including intracellular protein trafficking, axonal transport, regulation of transcription and mitochondrial fusion/fission. As a result, rational hypothesis driven treatment approaches are underway and some clinical trials for CMT1A, the most common form of CMT, have been completed.4–7 However, clinical trials depend on carefully chosen outcome measures used in appropriately selected patients to have the best chance of success.
Outcome measures need to be clinimetrically well validated and meet the demands of being well-tolerated, valid, reliable and sensitive.8 In adults with CMT, the CMT Neuropathy Score (CMTNS) has been implemented as the primary outcome measure in numerous drug trials.5,6 The CMTNS is a composite score based on patient history, neurological examination, activity limitations and clinical neurophysiology, and can detect an increase in impairment on a yearly basis.9 However, the CMTNS has limited sensitivity in children to differentiate levels of disease severity,10 and the influence of growth and development that normally occurs during childhood on the CMTNS is unknown.
Since most forms of CMT affect children there is a need for a clinical tool to measure impairment in children with CMT. For example, most patients with CMT1A11 and CMT1X,12,13 the two most common forms of CMT, develop symptoms within the first two decades of life. Many patients with CMT2A, the most common form of CMT2, are wheelchair bound by 21 years.14 Moreover, childhood may be the ideal time to institute treatments for CMT before chronic changes of demyelination or axonal degeneration have occurred that make repair more difficult.15 In this article we describe efforts by our Inherited Neuropathies Consortium to develop a multidimensional pediatric scale for children with CMT.
The first crucial step in designing such a scale was to ensure its ability to measure outcomes that are relevant to neuropathy and disability, using test items that are sufficiently sensitive and responsive to change. This allows precise assessment of baseline performance and disease severity, monitoring of outcomes longitudinally in studies of natural history, and the determination of responses to existing and novel interventions. Our scale needed to be unambiguously constructed to represent only one of the outcome levels according to the International Classification of Functioning, Disability and Health (ICF).16 Disability has been proposed as the preferential level for measuring therapeutic response in adults and children with CMT.8 The World Health Organization (WHO) defines disability as an umbrella term, covering impairments, activity limitations and participation restrictions.
Most disability scales used in the neuropathies have been validated using Classical Test Theory statistical techniques, such as inter-item correlations and factor analysis. Use of new psychometric methods such as the Rasch model, a modern technique that forms part of Item Response Theory, is regarded as a more clinically and scientifically meaningful scale development approach to measure disability.17 Rasch analysis is a probabilistic mathematical modeling technique used to assess properties of outcome measures including unidimensionality (extent to which items measure a single construct), item difficulty (relative difficulty of the items when compared to one another) and person separation (extent to which items distinguish between distinct levels of functioning). Rasch analysis has been widely used in the development and validation of outcome measures in neurology.18,19
In this study, we identified a set of items that represent a range of impairment levels in childhood CMT and conducted a series of validation studies, including Rasch analysis, to build a linearly weighted disability scale for children with CMT, known as the Charcot-Marie-Tooth disease Pediatric Scale (CMTPedS).
We conducted two phases of research: development and validation of the CMTPedS. Ethics approval from all institutions for all studies, and written informed assent/consent from all children and their families was obtained.
The development stages of CMTPedS involved:
An extensive review of the literature on measurement of disability in children with CMT identified the need for a patient-centered multiple item rating scale with broad application to reflect all aspects of disability in children with all types of CMT from the age of 3 years.
We searched MEDLINE (from January 1966), EMBASE (from January 1980), CINAHL (from January 1982), AMED (from January 1985), Cochrane Neuromuscular Disease Group Specialized Register and reference lists of articles. We contacted experts in the field to identify additional test items. A large pool of items was generated capturing: symptoms; foot and ankle involvement; hand dexterity; strength; sensation; balance; gait; motor function. The item pool included many tests all tapping the same underlying construct, and were selected based on disease-specificity, functional/patient-relevance, reliability/validity, responsiveness to change, availability of published norms, duration and ease of interpretation. Items were reduced based on being simple, safe to administer, well-tolerated, valid, reliable and sensitive.
Quality, suitability and coverage of potential items was peer-reviewed by 23 expert clinicians, scientists and patient representatives from Australia, Belgium, France, Germany, Italy, Netherlands, Spain, UK and USA at the 168th European NeuroMuscular Centre (ENMC) International Workshop.8 Based on experts’ opinion, items with insufficient face/content validity were removed to form the preliminary version of the CMTPedS containing 37 items.
Following training of clinicians from USA, UK, Italy and Australia through a face-to-face workshop, online manual and video resources, the CMTPedS was pilot-tested with four affected children to check for administration problems, item instructions, order and duration. The preliminary CMTPedS could be completed in 45–60 minutes and was well accepted by the children. Feedback informed the working version of the CMTPedS containing 28 items (Table 1).
During a 14-month test period, the working version of the CMTPedS was prospectively administered to 172 children aged 3–20 years through the Inherited Neuropathies Consortium. A series of internal and external validation studies were conducted with these data in SPSS v18.0 and RUMM2030, as detailed in Table 2, in accordance with established methods.20-26 A glossary of statistical terminology to clarify the methods and results for the general readership is provided in Supplementary Table 1.
Patient profile of the 172 cases was: 90 female (52%); mean age 10.8yrs (SD 4.2); mean height 1.44m (SD 0.22); mean weight 42.5kg (SD 18.9). Right limb was dominant in 90% of cases. The sample comprised a broad range of CMT types: 48% Type 1A; 9% Type 1B-E; 6% X-linked; 6% Type 2A-L; 5% Type 4A-J; 1% Dejerine-Sottas; <1% Type 5; 23% Unidentified gene.
Rating scales, based on modern psychometric validation, are increasingly used as primary outcome measures in natural history studies and clinical trials. The quality of the rating scale has the potential to influence the outcome of clinical trials and patient care.17 We performed a rigorous development and validation process to evaluate the CMTPedS. Based on the developmental phase of research, the CMTPedS is clinically meaningful, related to an explicit construct and easily interpretable. Based on the validation phase, the CMTPedS is a stable, reliable and psychometrically robust outcome measure for young children and adolescents with CMT to enable precise disease-relevant assessment. Based on the sensitivity analysis, the CMTPedS is highly sensitive to age and CMT type, generally not influenced by gender, and clearly reflects the severity of the disease.
There are no other measurement scales for children with CMT. The CMTNS, which has been validated in adults,49 has limited application in children because only four of nine items are regarded as sensitive.10 There are few scales in the neuropathy field,18,51 and none in the inherited neuropathies, validated with modern psychometric methods. Rasch has become the preferential method of validation. The Rasch model focuses on the probability of individuals scoring on an item correctly given their responses to other items in the scale (‘fit’). Within the framework of Rasch, the scale should work the same way, irrespective of the group being assessed (e.g. items should behave similarly independent of age, gender or diagnosis grouping).20 Rasch analysis supported the viability of the 11-item CMTPedS as a unidimensional measure of disability in children with CMT. It showed good overall model fit, no evidence of misfitting items, no person misfit, ability to differentiate groups of patients, no differential item functioning and it was well targeted for children with CMT.
There is international support for the CMTPedS to be implemented as the primary outcome measure in studies of children with CMT.8 The CMTPedS was designed to supplement a thorough neurological examination and capture functionally relevant limitations caused by CMT in the pediatric population. It is intended to have broad application in natural history studies and clinical trials of rehabilitative (e.g. orthoses, stretching, strengthening), pharmacological (e.g. curcumin, anti-progesterone) and surgical (e.g. foot and hand tendon transfer, arthodesis, hip dysplasia) interventions. At this stage, and by design, the CMTPedS is limited to children. However because it is based on activities that are relevant to daily life, there will be a demand to broaden the application of the CMTPedS to enable long term studies into adulthood to ensure consistent measurement across the lifespan of patient’s with CMT.
This study is primarily based on a cross-sectional analysis. In the future, 5-year follow-up data will be available through the Inherited Neuropathies Consortium to determine the longitudinal responsiveness and minimal clinically important difference of the CMTPedS. These data will demonstrate how large a change in CMTPedS points would be regarded by patients, parents and clinicians as indicating a meaningful improvement in day-to-day function following an experimental intervention. Different subtypes of CMT vary in severity and rate of progression. For instance, CMT1A, the most common form of CMT, is thought to progress quite slowly during childhood while patients with CMT2A are wheelchair bound by 21 years. Therefore, as suggested by our preliminary longitudinal data, it is likely that the rate of change of CMTPedS will vary, depending on the CMT subtype. To determine this experimentally will undoubtedly require larger numbers of children with different subtypes assessed longitudinally for 2-5 years, as we propose to do within our Consortium. Furthermore, even within subtype, patient to patient variability will influence the rate of change of the CMTPedS. For instance, the preliminary longitudinal data revealed five cases of CMT1A that showed an improvement on the CMTPedS while the other six cases of CMT1A did not. This accurately reflects the well-known heterogeneity of the disease, particular during childhood where rapid periods of growth and development can produce a variable clinical presentation and rate of progression.
Indeed, results from our 1-year placebo-controlled clinical trial of ascorbic acid for 81 children with CMT1A showed some cases of marked improvement in strength and motor function equally in both the treatment and control group.4 While the CMTPedS was not utilized in this trial as an outcome measure, the fundamental components of strength and motor function are common elements and illustrate the point of variability in patient response during childhood growth and development. The implications of this phenotypic variability on future clinical trial design requires larger samples to increase power and longer follow-up duration to account for natural growth fluctuations.
In conclusion, the final 11-item CMTPedS is a well-tolerated outcome measure that can be completed in 25 minutes. It generates a normally distributed score ranging from 0 to 44 points which is a reliable, valid and sensitive measure of disability for children with CMT from the age of 3 years.
We are grateful for the assistance of site co-investigators: Allan Glanzman, PT (Children's Hospital of Philadelphia, PA, USA), Polly Swingle, PT; Agnes Patzko, MD; Sindhu Ramchandren, MD (Wayne State University Detroit, MI, USA), Isabella Moroni, MD; Emanuela Pagliano, MD (IRCCS Foundation Carlo Besta Neurological Institute, Milan, Italy); Katy Eichinger, PT (University of Rochester, Rochester, NY, USA), Andy Hiscock, PT (UCL Institute of Child Health & Great Ormond Street Hospital, London, UK), Monique Ryan, MD; Eppie Yiu, MD (Royal Children's Hospital, Melbourne, Australia), Manoj Menezes, MD (Children's Hospital at Westmead, University of Sydney, Australia). Part of this work was undertaken at University College London Hospitals/University College London, which received a proportion of funding from the Department of Health's National Institute for Health Research Biomedical Research Centres funding scheme. We thank the authors who provided additional normative reference values: Gloria R. Gogola, MD (Shriners Hospitals for Children, Houston, Texas) and Raoul H. H. Engelbert, PhD, PT (Hogeschool van Amsterdam, The Netherlands). We also wish to thank the patients and their families for their participation in the study.
This research was supported by grants from the NHMRC (National Health and Medical Research Council of Australia, #1007569), NIH (National Institutes of Neurological Disorders and Stroke and Office of Rare Diseases, #U54NS065712), Charcot Marie Tooth Association (CMTA), Muscular Dystrophy Association (MDA) and CMT Association of Australia (CMTAA).