Impact of newborn screening for very-long-chain acyl-CoA dehydrogenase deficiency on genetic, enzymatic, and clinical outcomes.

Most infants with very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD) identified by newborn screening (NBS) are asymptomatic at the time of diagnosis and remain asymptomatic. If this outcome is due to prompt diagnosis and initiation of therapy, or because of identification of individuals with biochemical abnormalities who will never develop symptoms, is unclear. Therefore, a 10-year longitudinal national cohort study of genetically confirmed VLCADD patients born before and after introduction of NBS was conducted. Main outcome measures were clinical outcome parameters, acyl-CoA dehydrogenase very long chain gene analysis, VLCAD activity, and overall capacity of long-chain fatty acid oxidation (LC-FAO flux) in lymphocytes and cultured skin fibroblasts. Median VLCAD activity in lymphocytes of 54 patients, 21 diagnosed pre-NBS and 33 by NBS was, respectively, 5.4% (95% confidence interval [CI]: 4.0-8.3) and 12.6% (95% CI: 10.7-17.7; P < 0.001) of the reference mean. The median LC-FAO flux was 33.2% (95% CI: 22.8-48.3) and 41% (95% CI: 40.8-68; P < 0.05) of the control mean, respectively. Clinical characteristics in 23 pre-NBS and 37 NBS patients revealed hypoglycemic events in 12 vs 2 patients, cardiomyopathy in 5 vs 4 patients and myopathy in 14 vs 3 patients. All patients with LC-FAO flux <10% developed symptoms. Of the patients with LC-FAO flux >10% 7 out of 12 diagnosed pre-NBS vs none by NBS experienced hypoglycemic events. NBS has a clear beneficial effect on the prevention of hypoglycemic events in patients with some residual enzyme activity, but does not prevent hypoglycemia nor cardiac complications in patients with very low residual enzyme activity. The effect of NBS on prevalence and prevention of myopathy-related complications remains unclear.

Assessment of fatigability in patients with spinal muscular atrophy: development and content validity of a set of endurance tests.

BACKGROUND: Fatigability has emerged as an important dimension of physical impairment in patients with Spinal Muscular Atrophy (SMA). At present reliable and valid outcome measures for both mildly and severely affected patients are lacking. Therefore the primary aim of this study is the development of clinical outcome measures for fatigability in patients with SMA across the range of severity. METHODS: We developed a set of endurance tests using five methodological steps as recommended by the 'COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN). In this iterative process, data from multiple sources were triangulated including a scoping review of scientific literature, input from a scientific and clinical multidisciplinary expert panel and three pilot studies including healthy persons (N = 9), paediatric patients with chronic disorders (N = 10) and patients with SMA (N = 15). RESULTS: Fatigability in SMA was operationalised as the decline in physical performance. The following test criteria were established; one method of testing for patients with SMA type 2-4, a set of outcome measures that mimic daily life activities, a submaximal test protocol of repetitive activities over a longer period; external regulation of pace. The scoping review did not generate suitable outcome measures. We therefore adapted the Endurance Shuttle Walk Test for ambulatory patients and developed the Endurance Shuttle Box and Block Test and the - Nine Hole Peg Test for fatigability testing of proximal and distal arm function. Content validity was established through input from experts and patients. Pilot testing showed that the set of endurance tests are comprehensible, feasible and meet all predefined test criteria. CONCLUSIONS: The development of this comprehensive set of endurance tests is a pivotal step to address fatigability in patients with SMA.

Exploring functional strength changes during nusinersen treatment in symptomatic children with SMA types 2 and 3.

The Hammersmith Functional Motor Scale-Expanded (HFMSE) is a validated outcome measure for monitoring changes in functional strength in patients with spinal muscular atrophy (SMA). The objective of this study was to explore changes in HFMSE item-scores in children with SMA types 2 and 3a treated with nusinersen over a period of six to twenty months. We stratified patients according to motor ability (sitting and walking), and calculated numbers and percentages for each specific improvement (positive score change) or decrease (negative score change) for the total group and each subgroup and calculated frequency distributions of specific score changes. Ninety-one percent of the children showed improvement in at least 1 item, twenty-eight percent showed a score decrease in 1 or more items. In the first six to twenty months of nusinersen treatment motor function change was characterized by the acquisition of the ability to perform specific tasks with compensation strategies (score changes from 0 to 1). Children with the ability to sit were most likely to improve in items that assess rolling, whilst children with the ability to walk most likely improved in items that assess half-kneeling. The ability most frequently lost was hip flexion in supine position.

Randomized double-blind placebo-controlled crossover trial with pyridostigmine in spinal muscular atrophy types 2-4.

Hereditary proximal spinal muscular atrophy causes weakness and increased fatigability of repetitive motor functions. The neuromuscular junction is anatomically and functionally abnormal in patients with spinal muscular atrophy. Pharmacological improvement of neuromuscular transmission may therefore represent a promising additional treatment strategy. We conducted a Phase II, monocentre, placebo-controlled, double-blind, cross-over trial with the acetylcholinesterase inhibitor pyridostigmine in treatment-naïve patients with spinal muscular atrophy types 2-4. We investigated the safety and efficacy of pyridostigmine on fatigability and motor function. Each participant received pyridostigmine and a placebo for 8 weeks, in random order. Primary outcomes were the repeated nine-hole peg test for fatigability and motor function measure. Secondary outcomes were patient-reported effects, endurance shuttle test combined scores and adverse events. We included 35 patients. For the repeated nine-hole peg test, the mean difference was 0.17 s/trial (95% confidence interval: -1.17-1.49; P = 0.8), favouring placebo, and for the motor function measure, 0.74% (95% confidence interval: 0.00-1.49; P = 0.05), favouring pyridostigmine. Around 74% of patients reported medium-to-large beneficial effects of pyridostigmine on fatigability, compared with 29.7% in the placebo arm. This was paralleled by a reduced dropout risk of 70% on the endurance shuttle test combined scores (hazard ratio: 0.30; 95% confidence interval: 0.15-0.58) under pyridostigmine. Adverse events, mostly mild and self-limiting, occurred more frequently under pyridostigmine. No serious adverse events related to the study medication were observed. Patients with spinal muscular atrophy tolerated pyridostigmine well. There were no significant differences in primary outcomes, but the self-reported reduction of fatigability and improved endurance shuttle test combined score performance suggest that pyridostigmine may be useful as an additional therapy to survival motor neuron-augmenting drugs. Trial registration number: EudraCT: 2011-004369-34, NCT02941328.

Population-based assessment of nusinersen efficacy in children with spinal muscular atrophy: a 3-year follow-up study.

Nusinersen (Spinraza®) improves survival of infants with hereditary proximal spinal muscular atrophy and motor function in children up to 12 years. Population-based assessments of treatment efficacy are limited and confined to select cohorts of patients. We performed a nationwide, population-based, single-centre cohort study in children with spinal muscular atrophy younger than 9.5 years at start of treatment in line with reimbursement criteria in the Netherlands. We assessed age-relevant motor function scores, the need for tube feeding, hours of ventilatory support and documented adverse events. We used linear mixed modelling to assess treatment effects. We compared motor function during treatment with natural history data and to individual trajectories of muscle strength and motor function before the start of treatment. We included 71 out of 72 Dutch children who were treated (median age 54 months; range 0-117) and followed them for a median of 38 months (range 5-52). We observed improvement of motor function in 72% and stabilization in another 18% of the symptomatic children, which differed from the natural disease course in a matched cohort of which we had previously collected natural history data. Longitudinal analysis showed that motor function improved up to a median of 24 months (range 12-30) of treatment after which it stabilized. Shorter disease duration at start of treatment resulted in better treatment efficacy (P < 0.01). Sixteen children (23%) achieved new motor milestones. Bulbar and respiratory function did not improve significantly during treatment. In 15 patients from whom treatment-naïve data were available, the pre-treatment trajectory of motor function decline changed to stabilization or improvement after the start of treatment. We documented 82 adverse events after 934 injections (9%) in 45 patients. None of the adverse events led to treatment discontinuation. Intrathecal nusinersen treatment is safe and improves or stabilizes motor function in 90% of young children with spinal muscular atrophy types 1c-3a. We did not observe improvement of respiratory and bulbar functions.

Muscle strength, aerobic capacity and physical activity in independent ambulating children with lumbosacral spina bifida.

PURPOSE: This cross-sectional study investigates deficits and associations in muscle strength, 6-minute walking distance (6MWD), aerobic capacity (VO(2peak)), and physical activity (PA) in independent ambulatory children with lumbosacral spina bifida. METHOD: Twenty-tree children participated (13 boys, 10 girls). Mean age (SD): 10.4 (+/-3.1) years. Muscle strength (manual muscle testing and hand-held dynamometry), 6MWD, VO(2peak) (maximal exercise test on a treadmill), and PA (quantity and energy expenditure [EE]), were measured and compared with aged-matched reference values. RESULTS: Strength of upper and lower extremity muscles, and VO(2peak) were significantly lower compared to reference values. Mean Z-scores ranged from -1.2 to -2.9 for muscle strength, and from -1.7 to -4.1 for VO2peak. EE ranged from 73 - 84% of predicted EE. 6MWD was significantly associated with muscle strength of hip abductors and foot dorsal flexors. VO(2peak) was significantly associated with strength of hip flexors, hip abductors, knee extensors, foot dorsal flexors, and calf muscles. CONCLUSIONS: These children have significantly reduced muscle strength, 6MWD, VO(2peak) and lower levels of PA, compared to reference values. VO(2peak) and 6MWD were significantly associated with muscle strength, especially with hip abductor and ankle muscles. Therefore, even in independent ambulating children training on endurance and muscle strength seems indicated.

Pelvic floor rehabilitation in children with functional LUTD: does it improve outcome?

INTRODUCTION: If children do not experience satisfactory relief of lower urinary tract dysfunction (LUTD) complaints after standard urotherapy is provided, other treatment options need to be explored. To date, little is known about the clinical value of pelvic floor rehabilitation in the treatment of functional voiding disorders. OBJECTIVE: Therefore, we compared pelvic floor rehabilitation by biofeedback with anal balloon expulsion (BABE) to intensive urotherapy in the treatment of children with inadequate pelvic floor control and functional LUTD. STUDY DESIGN: A retrospective chart study was conducted on children with functional incontinence and inadequate pelvic floor control. All children referred for both intensive inpatient urotherapy and pelvic floor rehabilitation between 2010 and 2018 were considered for inclusion. A total of 52 patients were eligible with 25 children in the group who received BABE before inpatient urotherapy, and 27 children in the group who received BABE subsequently to urotherapy. Main outcome measurement was treatment success according to International Children's Continence Society criteria measured after treatment rounds and follow-up. RESULTS: Baseline characteristics demonstrate no major differences between the BABE and control group. There was a significant difference in improvement between BABE and inpatient urotherapy after the first and second round of treatment (round 1: BABE vs urotherapy; 12% vs 70%, respectively, round 2: urotherapy vs BABE; 92% vs 34%, respectively, both P < .001). In both cases, the urotherapy group obtained greater results (Fig. 1). When the additional effect of BABE on urotherapy treatment is assessed, no significant difference is found (P = .355) in the children who received BABE; 30 (58%) showed improvement on pelvic floor control. DISCUSSION: Our findings imply that training pelvic floor control in combination with inpatient urotherapy does not influence treatment effectiveness on incontinence. Intensive urotherapy contains biofeedback by real-time uroflowmetry; children receive direct feedback on their voiding behaviour. Attention offered to the child and achieving cognitive maturity with corresponding behaviour is of paramount importance. It is known that combining several kinds of biofeedback does not enhance the outcome. However, our results do not provide a conclusive answer to the effectiveness of pelvic floor physical therapy in the treatment of children with LUTD because we specifically investigated BABE. CONCLUSION: In this study, we could not prove that pelvic floor rehabilitation by BABE has an additional effect on inpatient urotherapy on incontinence outcomes. Considering the invasive nature of BABE, the use of BABE to obtain continence should therefore be discouraged.

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.

The effects of orthoses, footwear, and walking aids on the walking ability of children and adolescents with spina bifida: A systematic review using International Classification of Functioning, Disability and Health for Children and Youth (ICF-CY) as a reference framework.

BACKGROUND: To date no review has been published that analyzes the efficacy of assistive devices on the walking ability of ambulant children and adolescents with spina bifida and, differentiates between the effects of treatment on gait parameters, walking capacity, and walking performance. OBJECTIVES: To review the literature for evidence of the efficacy of orthotic management, footwear, and walking aids on gait and walking outcomes in ambulant children and adolescents with spina bifida. STUDY DESIGN: Systematic literature review. METHODS: A systematic literature search was performed to identify studies that evaluated the effect of any type of lower limb orthoses, orthopedic footwear, or walking aids in ambulant children (≤18 years old) with spina bifida. Outcome measures and treatment results for gait parameters, walking capacity, and walking performance were identified using International Classification of Functioning, Disability and Health for Children and Youth (ICF-CY) as the reference framework. RESULTS: Six case-crossover studies met the criteria and were included in this systematic review. Four studies provided indications of the efficacy of the ankle-foot orthosis in improving a number of kinematic and kinetic properties of gait, stride characteristics, and the oxygen cost of walking. Two studies indicated that walking with forearm crutches may have a favorable effect on gait. The evidence level of these studies was low, and none of the studies assessed the efficacy of the intervention on walking capacity and walking performance. CONCLUSIONS: Some data support the efficacy of using ankle-foot orthosis and crutches for gait and walking outcomes at the body functions and structures level of the ICF-CY. Potential benefits at the activities and participation level have not been investigated. CLINICAL RELEVANCE: This is the first evidence-based systematic review of the efficacy of assistive devices for gait and walking outcomes for children with spina bifida. The ICF-CY is used as a reference framework to differentiate the effects of treatment on gait parameters, walking capacity, and walking performance.

Randomized controlled study of home-based treadmill training for ambulatory children with spina bifida.

BACKGROUND: Many ambulatory children with spina bifida (SB) decline in their walking despite stable or even improved motor function. OBJECTIVE: The authors evaluated the effects of a home-based treadmill training program on both ambulatory function and aerobic fitness. METHODS: This randomized clinical trial of 34 ambulatory children with SB allocated 18 to supervised treadmill training for 12 weeks at home and 14 to usual care. Patients in home training exercised twice a week at an intensity of 66% of HR(peak) (peak heart rate) and gradually progressed from 70% to 140% of their individual walking speed. Main outcome measures were obtained at baseline, after intervention, and 3 months postintervention. Ambulation was measured using the 6-minute walk test (6MWT), during which gross energy consumption (ECS(gross)) and energy cost were calculated. Maximal exercise capacity was measured using an incremental treadmill test. Both VO(2peak) and speed(peak) were recorded as outcome parameters. RESULTS: After training, significant changes were seen between the groups for 6MWT (P = .002; d = 1.08), speed(peak) (P = .001; d = 1.14), VO(2peak) (P = .034; d = 0.78), and ECS(gross) (P = .004; d = 1.01). Long-term effects were recorded for 6MWT (P = .003; η = 0.34), speed(peak) (P = .003; η = 0.35), and ECS(gross) (P = .014; η = 0.29) but not for VO(2peak). CONCLUSION: A home-based, progressive treadmill training program for ambulatory children with SB has a large long-term effect on ambulation, with a moderate short-term effect on VO(2peak).

Reproducibility of maximal and submaximal exercise testing in "normal ambulatory" and "community ambulatory" children and adolescents with spina bifida: which is best for the evaluation and application of exercise training?

BACKGROUND: With emerging interest in exercise and lifestyle interventions for children and adolescents with spina bifida, there is a need for appropriate measurements in exercise testing. OBJECTIVE: The purpose of this study was to assess both reliability and agreement of maximal and submaximal exercise measures in "normal ambulatory" and "community ambulatory" children and adolescents with spina bifida. DESIGN: This was a reproducibility study. METHODS: Twenty-three children and adolescents with spina bifida (10 normal ambulatory and 13 community ambulatory) participated in the study. Maximal exercise outcomes were measured using a graded treadmill test. Peak measures (peak oxygen uptake [V(O2)peak], peak heart rate [HRpeak], heart rate response [HRR], and oxygen pulse) were recorded. For submaximal measures, heart rate (HR) and oxygen uptake (V(O2)) at the ventilatory threshold and oxygen uptake efficiency slope (OUES) were derived from the maximal measures. Functional performance was measured as the 6-minute walking distance and the maximal speed during the treadmill test. After checking for normality and heteroscedasticity, paired t tests, intraclass correlation coefficients (ICCs), and the smallest detectable difference (SDD) or the coefficient of variation (CV) were calculated. RESULTS: Performance measures showed good reliability and agreement. For maximal measures, acceptable ICCs were found for all measures. For submaximal measures, only HR at the ventilatory threshold showed an ICC of less than .80. Agreement showed a CV of less than 10% for all measures, except for V(O2) at the ventilatory threshold, HRR, and OUES. LIMITATIONS: Limitations of the study include missing data due to equipment failure. Furthermore, the outcomes were limited to normal ambulatory and community ambulatory children and adolescents with spina bifida. CONCLUSIONS: Both maximal and submaximal measures of exercise testing can be used for discriminative purposes in ambulatory children and adolescents with spina bifida. For evaluative purposes, HR measures are superior to V(O2) measures, while taking into account the individual variation of 5% to 8%. The SDD was 0.5 km/h for peak speed and 36.3 m for 6-minute walking distance. Heart rate response, oxygen pulse, and OUES are not recommended in the evaluation of exercise testing in this population.

Effect of biofeedback training on paradoxical pelvic floor movement in children with dysfunctional voiding.

OBJECTIVES: Dynamic perineal ultrasonography to assess the function of the pelvic floor muscles in children with micturition complaints shows that many children with daytime incontinence or recurrent urinary tract infections use their pelvic floor paradoxically. They strain when asked to withhold urine, or they have no voluntary control of the pelvic floor muscles at all. The aim of this study was to record the pelvic floor function and evaluate the physical therapy regimens for children with dysfunctional voiding (DV) and paradoxical pelvic floor function. METHODS: A total of 65 patients with DV, many who also had constipation, were diagnosed with paradoxical movement of the pelvic floor. The patients were asked to contract their pelvic floor muscles during a perineal dynamic ultrasound investigation. Of the 52 patients treated by physical therapists, 32 had a single 1-hour biofeedback session with rectal examination and anal balloon expulsion. In the remaining 20 patients, this was followed by 2 weeks of biofeedback balloon expulsion training at home. Forty control patients were observed. RESULTS: In 13 of the 65 patients, the diagnosis could not be confirmed by the physical therapists. At 6 to 10 months after training, 50 of the 52 other patients had normal voluntary pelvic floor muscle control. Of the 40 control patients, 39 had normal pelvic floor control. CONCLUSIONS: The results of this study have demonstrated that pelvic floor dysfunction occurs frequently in children with DV and can be cured by dedicated physical therapy. The clinical importance of this phenomenon is not yet clear. Prospective studies will teach us more about the true incidence and therapeutic effect of pelvic floor dysfunction on DV.

Physical function and fitness in long-term survivors of childhood leukaemia.

OBJECTIVE: To evaluate the physical function and fitness in survivors of childhood leukaemia 5-6 years after cessation of chemotherapy. MATERIALS AND METHODS: Thirteen children (six boys and seven girls; mean age 15.5 years) who were treated for leukaemia were studied 5-6 years after cessation of therapy. Physical function and fitness were determined by anthropometry, motor performance, muscle strength, anaerobic and aerobic exercise capacity. RESULTS: On motor performance, seven of the 13 patients showed significant problems in the hand-eye co-ordination domain. Muscle strength only showed a significantly lower value in the mean strength of the knee extensors. The aerobic and the anaerobic capacity were both significantly reduced compared to reference values. CONCLUSION: Even 5-6 years after cessation of childhood leukaemia treatment, there are still clear late effects on motor performance and physical fitness. Chemotherapy-induced neuropathy and muscle atrophies are probably the prominent cause for these reduced test results. Physical training might be indicated for patients surviving leukaemia to improve fitness levels and muscle strength.