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Disruption of basal lamina components in neuromotor synapses of children with spastic quadriplegic cerebral palsy.

ABSTRACT: Cerebral palsy (CP) is a static encephalopathy occurring when a lesion to the developing brain results in disordered movement and posture. Patients present with sometimes overlapping spastic, athetoid/dyskinetic, and ataxic symptoms. Spastic CP, which is characterized by stiff muscles, weakness, and poor motor control, accounts for ?80% of cases. The detailed mechanisms leading to disordered movement in spastic CP are not completely understood, but clinical experience and recent studies suggest involvement of peripheral motor synapses. For example, it is recognized that CP patients have altered sensitivities to drugs that target neuromuscular junctions (NMJs), and protein localization studies suggest that NMJ microanatomy is disrupted in CP. Since CP originates during maturation, we hypothesized that NMJ disruption in spastic CP is associated with retention of an immature neuromotor phenotype later in life. Scoliosis patients with spastic CP or idiopathic disease were enrolled in a prospective, partially-blinded study to evaluate NMJ organization and neuromotor maturation. The localization of synaptic acetylcholine esterase (AChE) relative to postsynaptic acetylcholine receptor (AChR), synaptic laminin ?2, and presynaptic vesicle protein 2 (SV2) appeared mismatched in the CP samples; whereas, no significant disruption was found between AChR and SV2. These data suggest that pre- and postsynaptic NMJ components in CP children were appropriately distributed even though AChE and laminin ?2 within the synaptic basal lamina appeared disrupted. Follow up electron microscopy indicated that NMJs from CP patients appeared generally mature and similar to controls with some differences present, including deeper postsynaptic folds and reduced presynaptic mitochondria. Analysis of maturational markers, including myosin, syntrophin, myogenin, and AChR subunit expression, and telomere lengths, all indicated similar levels of motor maturation in the two groups. Thus, NMJ disruption in CP was found to principally involve components of the synaptic basal lamina and subtle ultra-structural modifications but appeared unrelated to neuromotor maturational status.

SUBMITTER: Robinson KG

PROVIDER: S-EPMC3745387 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Disruption of basal lamina components in neuromotor synapses of children with spastic quadriplegic cerebral palsy.

Robinson Karyn G KG Mendonca Janet L JL Militar Jaimee L JL Theroux Mary C MC Dabney Kirk W KW Shah Suken A SA Miller Freeman F Akins Robert E RE

PloS one 20130816 8

Cerebral palsy (CP) is a static encephalopathy occurring when a lesion to the developing brain results in disordered movement and posture. Patients present with sometimes overlapping spastic, athetoid/dyskinetic, and ataxic symptoms. Spastic CP, which is characterized by stiff muscles, weakness, and poor motor control, accounts for ∼80% of cases. The detailed mechanisms leading to disordered movement in spastic CP are not completely understood, but clinical experience and recent studies suggest ...[more]

PMID: 23976945

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Project description:AimTo compare anterior and posterior standing balance reactions, as measured by single-stepping thresholds, in children with and without spastic cerebral palsy (CP).MethodSeventeen ambulatory children with spastic CP (eight males, nine females) and 28 typically developing children (13 males, 15 females; age range 5-12y, mean [SD] 9y 2mo [2y 3mo]), were included in this cross-sectional, observational study. Balance reaction skill was quantified as anterior and posterior single-stepping thresholds, or the treadmill-induced perturbations that consistently elicited a step in that direction. In order to understand the underlying mechanisms of between-group differences in stepping thresholds, dynamic stability was quantified using the minimum margin of stability. Ankle muscle activation latency, magnitude, and co-contraction were assessed with surface electromyography.ResultsWe observed an age and group interaction for anterior thresholds (p=0.001, partial η2 =0.24). At older (≈11y; p<0.001, partial η2 =0.48), but not younger (≈7y; p=0.33, partial η2 =0.02) ages, typically developing children had larger anterior thresholds than those with CP. In response to near-threshold anterior perturbations, older typically developing children recovered from more instability than their peers with CP (p=0.004, partial η2 =0.18). Older children had no between-group differences in ankle muscle activity. No between-group differences were observed in posterior thresholds.InterpretationThe effects of CP on balance reactions are age- and direction-specific. Older typically developing children are more able or willing to withhold a step when unstable.What this paper addsChildren with spastic cerebral palsy have age- and direction-specific balance-reaction impairments. Lower anterior stepping thresholds were observed in older, but not younger children. Older typically developing children withheld a forward step at higher levels of instability. No between-group differences were seen in posterior stepping thresholds.

Project description:The pendulum test assesses quadriceps spasticity by dropping the lower leg of a relaxed patient from the horizontal position and observing limb movement. The first swing excursion (FS) decreases with increasing spasticity severity. Our recent simulation study suggests that the reduced initial swing results from muscle short-range stiffness and its interaction with reflex hyper-excitability. Short-range stiffness emerges from the thixotropic behavior of muscles where fiber stiffness upon stretch increases when the muscle is held isometric. Fiber stiffness might thus be higher during the first swing of the pendulum test than during consecutive swings. In addition, it has recently been suggested that muscle spindle firing reflects fiber force rather than velocity and therefore, reflex activity might depend on fiber stiffness. If this hypothesized mechanism is true, we expect to observe larger first swing excursions and reduced reflex muscle activity when the leg is moved rather than kept isometric before release, especially in patients with increased reflex activity. We performed the pendulum test in 15 children with cerebral palsy (CP) and 15 age-matched typically developing (TD) children in two conditions. In the hold condition, the leg was kept isometric in the extended position before release. In the movement condition, the leg was moved up and down before release to reduce the contribution of short-range stiffness. Knee kinematics and muscle activity were recorded. Moving the leg before release increased first swing excursion (p < 0.001) and this increase was larger in children with CP (21°) than in TD children (8°) (p < 0.005). In addition, pre-movement delayed reflex onset by 87 ms (p < 0.05) and reduced reflex activity as assessed through the area under the curve of rectus femoris electromyography (p < 0.05) in children with CP. The movement history dependence of pendulum kinematics and reflex activity supports our hypothesis that muscle short-range stiffness and its interaction with reflex hyper-excitability contribute to joint hyper-resistance in spastic CP. Our results have implications for standardizing movement history in clinical tests of spasticity and for understanding the role of spasticity in functional movements, where movement history differs from movement history in clinical tests.

Project description:The interaction between brain damage and motor function is not yet fully understood in children with spastic cerebral palsy (CP). Therefore, a semi-quantitative MRI (sqMRI) scale was used to explore whether identified brain lesions related to functional abilities and gait pathology in this population. A retrospective cohort of ambulatory children with spastic CP was selected [N = 104; 52 bilateral (bCP) and 52 unilateral (uCP)]. Extent and location-specific scores were defined according to the sqMRI scale guidelines. The gross motor function classification system (GMFCS), the gait profile score (GPS), GPSs per motion plane, gait variable scores (GVS) and multiple-joint (MJ) gait patterns were related to brain lesion scores. In all groups, the global total brain scores correlated to the GPS (total: r s = 0.404, p ≤ 0.001; bCP: r s = 0.335, p ≤ 0.05; uCP: r s = 0.493, p ≤ 0.001). The global total hemispheric scores correlated to the GMFCS (total: r s = 0.392, p ≤ 0.001; bCP: r s = 0.316, p ≤ 0.05; uCP: r s = 0.331, p ≤ 0.05). The laterality scores of the hemispheres in the total group correlated negatively to the GMFCS level (r s = -0.523, p ≤ 0.001) and the GVS-knee sagittal (r s = -0.311, p ≤ 0.01). Lesion location, for the total group demonstrated positive correlations between parietal lobe involvement and the GPS (r s = 0.321, p ≤ 0.001) and between periventricular layer damage and the GMFCS (r s = 0.348, p ≤ 0.001). Involvement of the anterior part of the corpus callosum (CC) was associated with the GVS-hip sagittal in all groups (total: r pb = 0.495, p ≤ 0.001; bCP: r pb = 0.357, p ≤ 0.05; uCP: r pb = 0.641, p ≤ 0.001). The global total hemispheric and laterality of the hemispheres scores differentiated between the minor and both the extension (p ≤ 0.001 and p ≤ 0.001) and flexion (p = 0.016 and p = 0.013, respectively) MJ patterns in the total group. Maximal periventricular involvement and CC intactness were associated with extension patterns (p ≤ 0.05 and p ≤ 0.001, respectively). Current findings demonstrated relationships between brain structure and motor function as well as pathological gait, in this cohort of children with CP. These results might facilitate the timely identification of gait pathology and, ultimately, guide individualized treatment planning of gait impairments in children with CP.

Dataset Information

Disruption of basal lamina components in neuromotor synapses of children with spastic quadriplegic cerebral palsy.

Publications

Disruption of basal lamina components in neuromotor synapses of children with spastic quadriplegic cerebral palsy.

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