Botulinum neurotoxin type A responders among children with spastic cerebral palsy: Pattern-specific effects.

AIM: To identify short-term effects of botulinum neurotoxin type A (BoNT) injections on gait and clinical impairments, in children with spastic cerebral palsy (CP), based on baseline gait pattern-specific subgroups. METHOD: Short-term effects of BoNT injections in the medial hamstrings and gastrocnemius were defined in a retrospective convenience sample of 117 children with CP (median age: 6 years 4 months; GMFCS I/II/III: 70/31/16; unilateral/bilateral: 56/61) who had received gait analyses before and 2 months post-BoNT. First, baseline gait patterns were classified. Statistical and meaningful changes were calculated between pre- and post-BoNT lower limb sagittal plane kinematic waveforms, the gait profile score, and non-dimensional spatiotemporal parameters for the entire sample and for pattern-specific subgroups. These gait waveforms per CP subgroup at pre- and post-BoNT were also compared to typically developing gait and composite scores for spasticity, weakness, and selectivity were compared between the two conditions. RESULTS: Kinematic improvements post-BoNT were identified at the ankle and knee for the entire sample, and for subgroups with apparent equinus and jump gait. Limbs with baseline patterns of dropfoot and to a lesser extent true equinus showed clear improvements only at the ankle. In apparent equinus, jump gait, and dropfoot, spasticity improved post-BoNT, without leading to increased weakness or diminished selectivity. Compared to typical gait, knee and hip motion improved in the crouch gait subgroup post-BoNT. CONCLUSION: This comprehensive analysis highlighted the importance of investigating BoNT effects on gait and clinical impairments according to baseline gait patterns. These findings may help identify good treatment responders.

Increased muscle responses to balance perturbations in children with cerebral palsy can be explained by increased sensitivity to center of mass movement.

BACKGROUND: Balance impairments are common in children with cerebral palsy (CP). Muscle activity during perturbed standing is higher in children with CP than in typically developing (TD) children, but we know surprisingly little about how sensorimotor processes for balance control are altered in CP. Sensorimotor processing refers to how the nervous system translates incoming sensory information about body motion into motor commands to activate muscles. In healthy adults, muscle activity in response to backward support-surface translations during standing can be reconstructed by center of mass (CoM) feedback, i.e., by a linear combination of delayed (due to neural transmission times) CoM displacement, velocity, and acceleration. The level of muscle activity in relation to changes in CoM kinematics, i.e., the feedback gains, provides a metric of the sensitivity of the muscle response to CoM perturbations. RESEARCH QUESTION: Can CoM feedback explain reactive muscle activity in children with CP, yet with higher feedback gains than in TD children? METHODS: We perturbed standing balance by backward support-surface translations of different magnitudes in 20 children with CP and 20 age-matched TD children and investigated CoM feedback pathways underlying reactive muscle activity in the triceps surae and tibialis anterior. RESULTS: Reactive muscle activity could be reconstructed by delayed feedback of CoM kinematics and hence similar sensorimotor pathways might underlie balance control in children with CP and TD children. However, sensitivities of both agonistic and antagonistic muscle activity to CoM displacement and velocity were higher in children with CP than in TD children. The increased sensitivity of balance correcting responses to CoM movement might explain the stiffer kinematic response, i.e., smaller CoM movement, observed in children with CP. SIGNIFICANCE: The sensorimotor model used here provided unique insights into how CP affects neural processing underlying balance control. Sensorimotor sensitivities might be a useful metric to diagnose balance impairments.

Ex vivo adult stem cell characterization from multiple muscles in ambulatory children with cerebral palsy during early development of contractures.

Cerebral palsy (CP) is one of the most common conditions leading to lifelong childhood physical disability. Literature reported previously altered muscle properties such as lower number of satellite cells (SCs), with altered fusion capacity. However, these observations highly vary among studies, possibly due to heterogeneity in patient population, lack of appropriate control data, methodology and different assessed muscle. In this study we aimed to strengthen previous observations and to understand the heterogeneity of CP muscle pathology. Myogenic differentiation of SCs from the Medial Gastrocnemius (MG) muscle of patients with CP (n = 16, 3-9 years old) showed higher fusion capacity compared to age-matched typically developing children (TD, n = 13). Furthermore, we uniquely assessed cells of two different lower limb muscles and showed a decreased myogenic potency in cells from the Semitendinosus (ST) compared to the MG (TD: n = 3, CP: n = 6). Longitudinal assessments, one year after the first botulinum toxin treatment, showed slightly reduced SC representations and lower fusion capacity (n = 4). Finally, we proved the robustness of our data, by assessing in parallel the myogenic capacity of two samples from the same TD muscle. In conclusion, these data confirmed previous findings of increased SC fusion capacity from MG muscle of young patients with CP compared to age-matched TD. Further elaboration is reported on potential factors contributing to heterogeneity, such as assessed muscle, CP progression and reliability of primary outcome parameters.

Single-event multilevel surgery, but not botulinum toxin injections normalize joint loading in cerebral palsy patients.

BACKGROUND: Many patients with cerebral palsy present a pathologic gait pattern, which presumably induces aberrant musculoskeletal loading that interferes with natural bone growth, causing bone deformations on the long term. Botulinum toxin interventions and single-event multilevel surgeries are used to restore the gait pattern, assuming that a normal gait pattern restores musculoskeletal loading and thus prevents further bone deformation. However, it is unknown if these interventions are able to restore musculoskeletal loading. Hence, we investigated the impact of botulinum toxin injections and single-event multilevel surgery on musculoskeletal loading. METHODS: Gait data collected in 93 children with bilateral cerebral palsy, which included pre- and post multi-level botulinum toxin (49 children) and single-event multilevel surgery (44 children) assessments, and 15 typically developing children were retrospectively processed using a musculoskeletal modelling workflow to calculate joint angles, moments, muscle and joint contact force magnitudes and orientations. Differences from the typically developing waveform were expressed by a root-mean square difference were compared using paired t-tests for each intervention separately (alpha <0.05). FINDINGS: Botulinum toxin induced significant changes in the joint angles, but did not improve the muscle and joint contact forces. Single-event multilevel surgery induced significant kinematic and kinetic changes, which were associated with improved muscle and joint contact forces. INTERPRETATION: The present results indicate that botulinum toxin injections were not able to restore normal gait kinematics nor musculoskeletal loading, whereas single-event multilevel surgery did successfully restore both. Therefore, single-event multilevel surgery might be protective against the re-occurrence of bone deformation on the longer term.

Treatment of non-idiopathic clubfeet with the Ponseti method: a systematic review.

PURPOSE: Although non-idiopathic clubfeet were long thought to be resistant to non-surgical treatment methods, more studies documenting results on treatment of these feet with the Ponseti method are being published. The goal of this systematic review is to summarize current evidence on treatment of non-idiopathic clubfeet using the Ponseti method. METHODS: PubMed and Limo were searched, reference lists of eligible studies were screened and studies that met the inclusion criteria were included. Data on average number of casts, Achilles tendon tenotomy (ATT), initial correction, recurrence, successful treatment at final follow-up and complications were pooled. The Methodological Index for Non-Randomized Studies was used to assess the methodological quality of the selected studies. RESULTS: In all, 11 studies were included, yielding a total of 374 non-idiopathic and 801 idiopathic clubfeet. Non-idiopathic clubfeet required more casts (7.2 versus 5.4) and had a higher rate of ATT (89.4% versus 75.7%). Furthermore, these feet had a higher recurrence rate (43.3% versus 11.5%) and a lower rate of successful treatment at final follow-up (69.3% versus 95.0%). Complications were found in 20.3% of the non--idiopathic cohort. When comparing results between clubfeet associated with myelomeningocele and arthrogryposis, the first group presented with a lower number of casts (5.4 -versus 7.2) and a higher rate of successful treatment at final follow-up (81.8% versus 58.2%). CONCLUSION: The Ponseti method is a valuable and non-invasive option in the primary treatment of non-idiopathic clubfeet in young children. Studies with longer follow-up are necessary to evaluate its long-term effect. LEVEL OF EVIDENCE: Level III - systematic review of Level-III studies.This work meets the requirements of the PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and -Meta-Analyses).

European consensus on the concepts and measurement of the pathophysiological neuromuscular responses to passive muscle stretch.

BACKGROUND AND PURPOSE: To support clinical decision-making in central neurological disorders, a physical examination is used to assess responses to passive muscle stretch. However, what exactly is being assessed is expressed and interpreted in different ways. A clear diagnostic framework is lacking. Therefore, the aim was to arrive at unambiguous terminology about the concepts and measurement around pathophysiological neuromuscular response to passive muscle stretch. METHODS: During two consensus meetings, 37 experts from 12 European countries filled online questionnaires based on a Delphi approach, followed by plenary discussion after rounds. Consensus was reached for agreement ≥75%. RESULTS: The term hyper-resistance should be used to describe the phenomenon of impaired neuromuscular response during passive stretch, instead of for example 'spasticity' or 'hypertonia'. From there, it is essential to distinguish non-neural (tissue-related) from neural (central nervous system related) contributions to hyper-resistance. Tissue contributions are elasticity, viscosity and muscle shortening. Neural contributions are velocity dependent stretch hyperreflexia and non-velocity dependent involuntary background activation. The term 'spasticity' should only be used next to stretch hyperreflexia, and 'stiffness' next to passive tissue contributions. When joint angle, moment and electromyography are recorded, components of hyper-resistance within the framework can be quantitatively assessed. CONCLUSIONS: A conceptual framework of pathophysiological responses to passive muscle stretch is defined. This framework can be used in clinical assessment of hyper-resistance and will improve communication between clinicians. Components within the framework are defined by objective parameters from instrumented assessment. These parameters need experimental validation in order to develop treatment algorithms based on the aetiology of the clinical phenomena.

Instrumented assessment of the effect of Botulinum Toxin-A in the medial hamstrings in children with cerebral palsy.

This study examined the sensitivity of an instrumented spasticity assessment of the medial hamstrings (MEH) in children with cerebral palsy (CP). Nineteen children received Botulinum Toxin type A (BTX-A) injections in the MEH. Biomechanical (position and torque) and electrophysiological (surface electromyography, EMG) signals were integrated during manually-performed passive stretches of the MEH at low, medium and high velocity. Signals were examined at each velocity and between stretch velocities, and compared pre and post BTX-A (43 ± 16 days). Average change between pre and post BTX-A was interpreted in view of the minimal detectable change (MDC) calculated from previously published reliability results. Improvements greater than the MDC were found for nearly all EMG-parameters and for torque parameters at high velocity and at high versus low velocity (p<0.03), however large inter-subject variability was noted. Moderate correlations were found between the improvement in EMG and in torque (r=0.52, p<0.05). Biomechanical and electrophysiological parameters proved to be adequately sensitive to assess the response to treatment with BTX-A. Furthermore, studying both parameters at different velocities improves our understanding of spasticity and of the physiological effect of selective tone-reduction. This not only provides a clinical validation of the instrumented assessment, but also opens new avenues for further spasticity research.

Divergent in vitro and in vivo lipid peroxidation in the postprandial phase of patients with type I diabetes mellitus.

OBJECTIVE: The two- to fourfold higher risk of cardiovascular disease in diabetes mellitus is more strongly predicted by the postprandial than by the fasting blood glucose and lipids. We aimed to investigate the impact of postprandial changes in serum lipoprotein fractions on lipid peroxidation in type I diabetes mellitus (T1DM). DESIGN: This was a prospective observational study. SETTING: The study was performed at Antwerp University Hospital, Belgium. SUBJECTS: Twenty-three well-controlled T1DM patients were included. INTERVENTION: Patients received a standard breakfast and lunch (>50% energy as fat). Blood was sampled at fasting (F), after the post-breakfast hyperglycemic peak (BP), just before lunch (B), after the post-lunch hyperglycemic peak (LP), after the post-lunch dale (LD) and 5 h after lunch (L) for the measurement of serum lipids, lipoprotein subfraction composition, alpha-tocopherol and lipid peroxidation in vivo and in vitro. RESULTS: Serum triacylglycerols (Tgs) increased (from 1.03+/-0.40 at F to 1.60+/-0.87 mmol/l at LP, P=0.001), but cholesterol decreased by 12% in parallel with alpha-tocopherol (from 4.43+/-0.76 at F to 4.12+/-0.82 micromol/mmol total lipid at B, P=0.006). Although plasma malondialdehyde increased from 1.02+/-0.36 at F to 1.14+/-0.40 micromol/L at LP, P=0.03, copper-induced in vitro peroxidation decreased in the low-density lipoprotein and high-density lipoprotein fractions. CONCLUSIONS: In well-controlled T1DM patients moderate postprandial increases in serum Tgs are accompanied by a relative deficiency in alpha-tocopherol. Lipid peroxidation in vivo increases but cannot be ascribed to changes in the susceptibility of lipoproteins to copper-induced in vitro peroxidation.

Scoliosis.

Scoliosis is a structural lateral curvature of the spine with a rotatory component. Imaging in scoliosis is important. Most cases of scoliosis are idiopathic, and imaging is used routinely in monitoring the changes of the deformity that take place during growth. Imaging is also crucial in determining the underlying etiology in non-idiopathic cases of scoliosis and is used in pre- and postoperative monitoring.

Does vitamin C supplementation influence the levels of circulating oxidized LDL, sICAM-1, sVCAM-1 and vWF-antigen in healthy male smokers?

OBJECTIVE: To examine the effects of vitamin C supplementation on the concentration of oxidation markers, in particular, circulating oxidized LDL (OxLDL) and on endothelial activation markers. DESIGN: Randomized double-blind, placebo-controlled crossover trial. SETTING: Belgian population of the city of Leuven. SUBJECTS: A total of 34 healthy male smokers aged 26-73 y. INTERVENTION: Smokers were randomly assigned to receive either vitamin C (250 mg twice daily) or placebo capsules, each to be taken for 4 weeks. After a 1-week washout period, participants then crossed over to the alternative capsules for further 4 weeks. MEAN OUTCOME MEASURES: Markers of oxidation (bilirubin, uric acid, alpha-tocopherol, retinol, malondialdehyde, circulating Oxidized LDL (OxLDL)) and markers of endothelial activation (sICAM-1, sVCAM-1, vWF-antigen) were analysed. RESULTS: Plasma ascorbate concentrations significantly increased from 46.6+/-17.6 to 70.1+/-21.2 mumol/l after a 4-week treatment with 500 mg vitamin C per day. The other plasma antioxidants concentrations, including bilirubin, uric acid, alpha-tocopherol and retinol, were similar in both treatment periods. Vitamin C did not change plasma malondialdehyde and circulating OxLDL compared with placebo (vitamin C 0.73+/-0.25 mg/dl OxLDL; placebo 0.72+/-0.21 mg/dl OxLDL). After vitamin C supplementation, neither sICAM-1 and sVCAM-1 levels nor the concentration of vWF-antigen significantly differed from placebo condition. CONCLUSIONS: Oral supplementation of vitamin C is not associated with changes in markers of oxidation or endothelial activation in healthy male smokers.

Does functional treatment of idiopathic clubfoot reduce the indication for surgery? Call for a widely accepted rating system.

We present our experience of treatment by physiotherapy, continuous passive motion and strapping in a series of 100 clubfeet classified on a scale of severity according to Dimeglio. Twenty-five percent were good after conservative treatment, and 75% required an operation. There were no recurrences or additional procedures. Before the introduction of the functional treatment in our department, 100% required some sort of surgical intervention and 51% required an additional procedure. In comparison with the results published by Dimeglio et al., the greatest discordance is observed in grade 2 clubfeet.