Bart Bartels

The Six-Minute Walk Test in Chronic Pediatric Conditions: A Systematic Review of Measurement Properties

Background The Six-Minute Walk Test (6MWT) is increasingly being used as a functional outcome measure for chronic pediatric conditions. Knowledge about its measurement properties is needed to determine whether it is an appropriate test to use. Purpose The purpose of this study was to systematically review all published clinimetric studies on the 6MWT in chronic pediatric conditions. Data Sources The databases MEDLINE, EMBASE, CINAHL, PEDro, and SPORTDiscus were searched up to February 2012. Study Selection Studies designed to evaluate measurement properties of the 6MWT in a chronic pediatric condition were included in the systematic review. Data Extraction The methodological quality of the included studies and the measurement properties of the 6MWT were examined. Data Synthesis A best evidence synthesis was performed on 15 studies, including 9 different chronic pediatric conditions. Limited evidence to strong evidence was found for reliability in various chronic conditions. Strong evidence was found for positive criterion validity of the 6MWT with peak oxygen uptake in some populations, but negative criterion validity was found in other populations. Construct validity remained unclear in most patient groups because of methodological flaws. Little evidence was available for responsiveness and measurement error. Studies showed large variability in test procedures despite existing guidelines for the performance of the 6MWT. Limitations Unavailability of a specific checklist to evaluate the methodological quality of clinimetric studies on performance measures was a limitation of the study. Conclusions Evidence for measurement properties of the 6MWT varies largely among chronic pediatric conditions. Further research is needed in all patient groups to explore the ability of the 6MWT to measure significant and clinically important changes. Until then, changes measured with the 6MWT should be interpreted with caution. Future studies or consensus regarding modified test procedures in the pediatric population is recommended.

Cardiopulmonary Exercise Testing in Children and Adolescents With Dystrophinopathies: A Pilot Study.

Purpose: To determine exercise response during cardiopulmonary exercise testing in children and adolescents with dystrophinopathies. Methods: Exercise response on the cardiopulmonary exercise test (CPET) was compared with a standard care test protocol. Results: Nine boys (aged 10.8 ± 4.7 years) with Becker muscular dystrophy (n = 6) and Duchenne muscular dystrophy (n = 3) were included. The feasibility of the CPET was similar to a standard care test protocol, and no serious adverse events occurred. In 67% of the subjects with normal or only mildly impaired functional capacity, the CPET could be used to detect moderate to severe cardiopulmonary exercise limitations. Conclusions: The CPET seems to be a promising outcome measure for cardiopulmonary exercise limitations in youth with mild functional limitations. Further research with larger samples is warranted to confirm current findings and investigate the additional value of the CPET to longitudinal follow-up of cardiomyopathy and the development of safe exercise programs for youth with dystrophinopathies.

Muscle strength and motor function throughout life in a cross-sectional cohort of 180 patients with spinal muscular atrophy types 1c–4

Natural history studies in spinal muscular atrophy (SMA) have primarily focused on infants and children. Natural history studies encompassing all age groups and SMA types are important for the interpretation of treatment effects of recently introduced survival motor neuron gene‐augmenting therapies.

A continuous repetitive task to detect fatigability in spinal muscular atrophy

BackgroundTo determine the value of a continuous repetitive task to detect and quantify fatigability as additional dimension of impaired motor function in patients with hereditary proximal spinal muscular atrophy (SMA).ResultsIn this repeated measure case-control study 52 patients with SMA types 2–4, 17 healthy and 29 disease controls performed five consecutive rounds of the Nine-Hole Peg test to determine the presence of fatigability. We analysed differences in test performance and associations with disease characteristics. Five patients with SMA type 2 (22%) and 1 disease control (3%) could not finish five rounds due to fatigue (p = 0.01). Patients with SMA type 2 performed the test significantly more slowly than all other groups (p < 0.005) and disease controls were slower than healthy controls (p < 0.05). Patients with SMA type 2 performed round five 27% slower than round one, while healthy controls performed round five 14% faster than round one (p = 0.005). There was no difference between SMA type 3a, type 3b/4 or disease controls and healthy controls (p > 0.4). Time needed to complete each round during the five-round task increased in 15 patients with SMA type 2 (65%), 4 with type 3a (36%), 4 with type 3b/4 (22%), 9 disease controls (31%) and 1 healthy control (6%). There was no effect of age at disease onset or disease duration in SMA type 2 (p = 0.39). Test-retest reliability was high.ConclusionFatigability of remaining arm function is a feature of SMA type 2 and can be determined with continuous repetitive tasks.

The POWER-tool: Recommendations for involving patient representatives in choosing relevant outcome measures during rare disease clinical trial design

In clinical trials, it is relevant to ask patients and/or their caregivers which aspects concerning their disease they consider important to measure when a new intervention is being investigated. Those aspects, useful as outcome measures in a trial, are of pivotal importance for the result of the trial and the subsequent decision-making. In rare diseases the choice of outcome measures may be even more important, due to the small numbers and heterogeneity of the patients that are included. We have developed a tool to involve patients in the determination of outcome measures and the choice of measurement instruments. This tool was developed together with a patient think tank, consisting of a group of rare disease patient representatives, and by interviewing end users. We have road-tested our tool in an ongoing trial, and evaluated it during a focus group meeting. The tool consists of three steps: 1) Preparation, 2) Consultation of patients, 3) Follow-up during which the consultation results are implemented in the trial design. The tool provides guidelines for researchers to include the patients opinion in the choice of outcome measures in the trial design stage. We describe the development of the POWER-tool (Patient participation in Outcome measure WEighing for Rare diseases), and first experiences of the tool in an ongoing trial.

Protocol for a phase II, monocentre, double-blind, placebo-controlled, cross-over trial to assess efficacy of pyridostigmine in patients with spinal muscular atrophy types 2–4 (SPACE trial)

Introduction Hereditary proximal spinal muscular atrophy (SMA) is caused by homozygous loss of function of the survival motor neuron 1 gene. The main characteristic of SMA is degeneration of alpha motor neurons in the anterior horn of the spinal cord, but recent studies in animal models and patients have shown additional anatomical abnormalities and dysfunction of the neuromuscular junction (NMJ). NMJ dysfunction could contribute to symptoms of weakness and fatigability in patients with SMA. We hypothesise that pyridostigmine, an acetylcholinesterase inhibitor that improves neuromuscular transmission, could improve NMJ function and thereby muscle strength and fatigability in patients with SMA. Methods and analysis We designed a monocentre, placebo-controlled, double-blind cross-over trial with pyridostigmine and placebo to investigate the effect and efficacy of pyridostigmine on muscle strength and fatigability in patients with genetically confirmed SMA. We aim to include 45 patients with SMA types 2–4, aged 12 years and older in the Netherlands. Participants receive 8 weeks of treatment with pyridostigmine and 8 weeks of treatment with placebo in a random order separated by a washout period of 1 week. Treatment allocation is double blinded. Treatment dose will gradually be increased from 2 mg/kg/day to the maximum dose of 6 mg/kg/day in four daily doses, in the first week of each treatment period. The primary outcome measures are a change in the Motor Function Measure and repeated nine-hole peg test before and after treatment. Secondary outcome measures are changes in recently developed endurance tests, that is, the endurance shuttle nine-hole peg test, the endurance shuttle box and block test and the endurance shuttle walk test, muscle strength, level of daily functioning, quality of and activity in life, perceived fatigue and fatigability, presence of decrement on repetitive nerve stimulation and adverse events. Ethics and dissemination The protocol is approved by the local medical ethical review committee at the University Medical Center Utrecht and by the national Central Committee on Research Involving Human Subjects. Findings will be shared with the academic and medical community, funding and patient organisations in order to contribute to optimisation of medical care and quality of life for patients with SMA. Trial registration number NCT02941328.

First international workshop on rehabilitation management and clinical outcome measures for spinal muscular atrophy

Twenty-one physical and occupational therapists from the USA and Europe (Italy, United Kingdom and Netherlands) met in Dallas, Texas USA on October 16 and 17, 2016. The purpose of this meeting was to review the current landscape of rehabilitation management and clinical outcome measures for spinal muscular atrophy (SMA). The workshop was organized into three sessions entitled: (1) Rehabilitation and Musculoskeletal Considerations; (2) SMA Clinical Outcome Measures; and (3) Rehabilitation Devices for Evaluation and Treatment. A closing session was included to summarize the meeting topics, next steps and proposed action items.

Skeletal muscle training for spinal muscular atrophy type 3

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease caused by a genetic mutation in the survival motor neuron 1 (SMN1) gene (5q11.2-q13.3) (Lefebvre 1995). With an incidence of one in 10,000 live births, it is the leading genetic cause of infant death (Lunn 2008; Mercuri 2012). SMA is characterized by degeneration of spinal cord α-motor neurons, which results in progressive proximal muscle weakness, fatigue, scoliosis, nutritional problems, respiratory complications, and severe functional limitations. SMA has a broad clinical spectrum but in general can be classified into four clinical types on the basis of age of onset and maximum motor function achieved (Mercuri 2012). SMA type 3 (Kugelberg-Welander disease) is the mildest subtype but shows large clinical heterogeneity, which can be further classified into type 3a (clinical symptoms before three years of age) and type 3b (clinical symptoms after three years of age) (Zerres 1997). Symptoms become evident after the age of 18 months. Children generally reach all major milestones, including independent walking, but their level of motor performance varies greatly. Some children are hardly able to stand up and take a few steps unaided, while others walk well, are able to climb stairs, and mainly experience problems in running and sports (Rudnik-Schoneborn 2001). Long-term follow-up studies (follow-up time of two to 20 years) in people with SMA type 2 and type 3 suggest a very slow deterioration of muscle strength and motor function that takes years to detect (Deymeer 2008; Kaufmann 2012; Werlauff 2012). Nevertheless, about 50% of people with SMA type 3 will lose independent ambulation during the second decade of life and only a small subgroup will remain ambulatory throughout life (Mercuri 2012; Russman 1996). In general people with SMA type 3b perform better on functional outcome measures, such as the six-minute walk test and the Hammersmith Functional Motor Scale Expanded, in comparison to people with SMA type 3a (Mazzone 2013; Montes 2010). There is no proven effective drug treatment for SMA type 3 (Wadman 2012), and current standards of care concentrate on SMA-associated complications, such as impaired mobility, scoliosis, fatigue, and respiratory infections. (aut. ref.)