AIM:Prenatal maternal infections may impair infant brain development. This study investigated the effect of maternal infections with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during pregnancy on infant neurodevelopment by assessing general movements (GMs). METHODS:Infants were recruited for this multicenter prospective cohort study from LMU University Hospital sites in Munich after birth or during routine visits. GMs were recorded and assessed between 1 July 2022 and 31 January 2023, using the Hadders-Algra method. Odds ratios for abnormal GMs were calculated for infants with parent-reported prenatal SARS-CoV-2 exposure compared to unexposed controls. Specific GM subgroups were analysed at preterm, writhing, and fidgety ages. RESULTS:The study comprised 114 exposed infants (55.3% male) and 92 controls (54.3% male). There were no significant differences between the groups at birth. Two of the mothers were infected twice and one of them required hospitalisation. GMs were assessed at a mean corrected age (CA) of 4 weeks. The odds ratios showed no significant differences in GM quality between exposed infants and controls in either the total group or the subgroups. CONCLUSION:Prenatal exposure to SARS-CoV-2 did not affect early neurodevelopment, which was determined by GM quality. Further studies should include long-term outcomes. TRIAL REGISTRATION:The study was registered at the German Clinical Trial Register (ID: DRKS00029247; https://drks.de/search/de/trial/DRKS00029247).

Anxiety and depression are highly prevalent among Syrian refugees. Anxiety and depression during pregnancy may impair infant neurodevelopment. This study evaluated whether potential maternal anxiety and depression in Syrian refugee and native Turkish mothers were associated with less favourable neonatal neurodevelopment. Cross-sectional study. Turkish (n = 64) and Syrian (n = 17) term-born infants (37–41 weeks’ gestation) referred to a level II-III neonatal intensive care unit in Izmir were assessed shortly after birth (median 5 days) together with their mothers. The Test of Infant Motor Performance (TIMP) was the primary outcome measure. In addition, we evaluated crying behaviour during the TIMP-assessment and performed General Movements Assessment (GMA). Mothers completed Beck Anxiety and Beck Depression Inventories in their native languages. Univariate and multivariate statistics were applied. Perinatal social characteristics of both groups were similar. TIMP scores of Syrian infants were significantly lower than those of Turkish infants (45.53 (SD 7.10) vs. 51.59 (SD 8.59), respectively (p = 0.009)). Sixteen Turkish infants (25

Background: The Balance Error Scoring System (BESS) is a commonly used method for clinically evaluating balance after traumatic brain injury. The utilization of force plates, characterized by their cost-effectiveness and portability, facilitates the integration of instrumentation into the BESS protocol. Despite the enhanced precision associated with instrumented measures, there remains a need to determine the clinical significance and feasibility of such measures within pediatric cohorts. Objective: To report a comprehensive set of posturographic measures obtained during instrumented BESS and to examine the concurrent validity, reliability, and feasibility of instrumented BESS in the pediatric point of care setting. Methods: Thirty-seven participants (18 female; aged 13.32 ± 3.31 years) performed BESS while standing on a force plate to simultaneously compute stabilometric measures (instrumented BESS). Ellipse area (EA), path length (PL), and sway velocity (VM) were obtained for each of the six BESS positions and compared with the respective BESS scores. Additionally, the effects of sex and age were explored. A second BESS repetition was performed to evaluate the test–retest reliability. Feedback questionnaires were handed out after testing to evaluate the feasibility of the proposed protocol. Results: The BESS total score was 20.81 ± 6.28. While there was no statistically significant age or sex dependency in the BESS results, instrumented posturography demonstrated an age dependency in EA, VM, and PL. The one-leg stance on a soft surface resulted in the highest BESS score (8.38 ± 1.76), EA (218.78 cm2 ± 168.65), PL (4386.91 mm ± 1859.00), and VM (21.93 mm/s ± 9.29). The Spearman’s coefficient displayed moderate to high correlations between the EA (rs = 0.429–0.770, p = 0.001–0.009), PL (rs = 0.451–0.809, p = 0.001–0.006), and VM (rs = 0.451–0.809, p = 0.001–0.006) when compared with the BESS scores for all testing positions, except for the one-leg stance on a soft surface. The BESS total score significantly correlated during the first and second repetition (rs = 0.734, p ≤ 0.001), as did errors during the different testing positions (rs = 0.489–0.799, p ≤ 0.001–0.002), except during the two-legged stance on a soft surface. VM and PL correlated significantly in all testing positions (rs = 0.465–0.675, p ≤ 0.001–0.004; (rs = 0.465–0.675, p ≤ 0.001–0.004), as did EA for all positions except for the two-legged stance on a soft surface (rs = 0.392–0.581, p ≤ 0.001–0.016). A total of 92% of participants stated that the instructions for the testing procedure were very well-explained, while 78% of participants enjoyed the balance testing, and 61% of participants could not decide whether the testing was easy or hard to perform. Conclusions: Instrumented posturography may complement clinical assessment in investigating postural control in children and adolescents. While the BESS score only allows for the consideration of a total score approximating postural control, instrumented posturography offers several parameters representing the responsiveness and magnitude of body sway as well as a more differentiated analysis of movement trajectory. Concise instrumented posturography protocols should be developed to augment neuropediatric assessments in cases where a deficiency in postural control is suspected, potentially stemming from disruptions in the processing of visual, proprioceptive, and/or vestibular information.

PURPOSE: This pooled analysis of data from three Phase 3 studies investigated the effects of incobotulinumtoxinA on spasticity-related pain (SRP) in children/adolescents with uni-/bilateral cerebral palsy (CP). METHODS: Children/adolescents (ambulant and non-ambulant) were evaluated for SRP on increasingly difficult activities/tasks 4 weeks after each of four incobotulinumtoxinA injection cycles (ICs) using the Questionnaire on Pain caused by Spasticity (QPS; six modules specific to lower limb [LL] or upper limb [UL] spasticity and respondent type [child/adolescent, interviewer, or parent/caregiver]). IncobotulinumtoxinA doses were personalized, with all doses pooled for analysis. RESULTS: QPS key item responses were available from 331 and 155 children/adolescents with LL- and UL-spasticity, respectively, and 841/444 (LL/UL) of their parents/caregivers. IncobotulinumtoxinA efficacy was evident with the first IC. Efficacy was sustained and became more robust with further subsequent ICs. By Week 4 of the last (i.e. fourth) IC, 33.8–53.3% of children/adolescents reported complete SRP relief from their baseline pain for respective QPS items. Children/adolescents reported reductions in mean LL SRP intensity at levels that surpassed clinically meaningful thresholds. Similarly, parents/caregivers observed complete SRP relief and less frequent SRP with incobotulinumtoxinA. Similar results were found for UL SRP. CONCLUSION: These findings indicate that incobotulinumtoxinA could bring considerable benefit to children/adolescents with spasticity by reducing SRP, even during strenuous activities.

Background Impaired selective motor control, weakness and spasticity represent the key characteristics of motor disability in the context of bilateral spastic cerebral palsy. Independent walking ability is an important goal and training of the gluteal muscles can improve endurance and gait stability. Combining conventional physical excercises with a neuromodulatory, non-invasive technique like repetitive neuromuscular magnetic stimulation probably enhances effects of the treatment. This prospective study aimed to assess the clinical effects of repetitive neuromuscular magnetic stimulation in combination with a personalized functional physical training offered to children and adolescents with bilateral spastic cerebral palsy. Methods Eight participants Gross Motor Function Classification System level II and III (10.4 ± 2y5m; 50% Gross Motor Function Classification System level II) received a personalized intervention applying functional repetitive neuromuscular magnetic stimulation (12 sessions within 3 weeks; 12,600 total stimuli during each session). At baseline and follow up the following assessments were performed: 10-m-walking-test, 6-min-walking-test, GMFM-66. Six weeks after the end of treatment the patient-reported outcome measure Gait Outcome Assessment List was completed. Results GMFM-66 total score improved by 1.4% (p = 0.002), as did scoring in domain D for standing (1.9%, p = 0.109) and domain E for walking, jumping and running (2.6%, p = 0.021). Gait speed or distance walked during 6 min did not improve from baseline to follow up. Patient-reported outcome showed improvement in 4 patients in altogether 14 ratings. Caregiver-reported outcome reported benefits in 3 participants in altogether 10 ratings. Conclusion Repetitive neuromuscular magnetic stimulation promises to be a meaningful, non-invasive treatment approach for children and adolescents with bilateral spastic cerebral palsy that could be offered in a resource-efficient manner to a broad number of patients. To further investigate the promising effects of repetitive neuromuscular magnetic stimulation and its mechanisms of action, larger-scaled, controlled trials are needed as well as comprehensive neurophysiological investigations.

Sialorrhea is defined as a chronic excessive flow of saliva from the mouth, often with adverse consequences for health and quality of life of patients. In addition to currently used non-drug treatment and systemic drugs, intraglandular Botulinum Neurotoxin A (BoNT/A) injections have been examined in case studies, controlled trials and clinical practice. Two pivotal Phase III trials recently led to market approval in the USA and EU for IncobotulinumtoxinA [Xeomin®, IncoBoNT/A, Clostridium botulinum neurotoxin type A (150 kD), free from complexing proteins, Merz Pharmaceuticals GmbH] for treatment of chronic sialorrhea in adults and pediatric patients. This review provides a multidisciplinary approach to discuss the current state of sialorrhea therapy as well as benefits and current limitations of BoNT/A injections. A consensus regarding treatment recommendations made available to physicians in Germany in 2022 has now been updated here for presentation to an international audience. This review provides a framework including a flow chart for patient selection, recommendations for dosing and the injection process, as well as a discussion of therapeutic goals, long-term benefits and safety aspects. This review is aimed at supporting physicians in developing multidisciplinary and individualized treatment approaches to achieve optimal benefits for patients.

Non-invasive neurostimulation as an adjunctive intervention to task-specific motor training is an approach to foster motor performance in patients affected by upper motor neuron syndrome (UMNS). Here, we present first-line data of repetitive neuromuscular magnetic stimulation (rNMS) in combination with personalized task-specific physical exercises targeting the tibialis anterior muscle to improve ankle dorsiflexion (functional rNMS (frNMS)). The main objective of this pilot study was to assess the feasibility in terms of adherence to frNMS, safety and practicability of frNMS, and satisfaction with frNMS. First, during 10 training sessions, only physical exercises were performed (study period (SP) A). After a 1 week break, frNMS was delivered during 10 sessions (SPC). Twelve children affected by UMNS (mean age 8.9 ± 1.6 years) adhered to 93% (SPA) and 94% (SPC) of the sessions, and omittance was not related to the intervention itself in any case. frNMS was safe (no AEs reported in 88% of sessions, no AE-related discontinuation). The practicability of and satisfaction with frNMS were high. Patient/caregiver-reported outcomes revealed meaningful benefits on the individual level. The strength of the ankle dorsiflexors (MRC score) clinically meaningfully increased in four participants as spasticity of ankle plantar flexors (Tardieu scores) decreased in four participants after SPC. frNMS was experienced as a feasible intervention for children affected by UMNS. Together with the beneficial effects achieved on the individual level in some participants, this first study supports further real-world, large-scale, sham-controlled investigations to investigate the specific effects and distinct mechanisms of action of frNMS.

Background: For children and adolescents affected by bilateral spastic cerebral palsy (BSCP), non-invasive neurostimulation with repetitive neuromuscular magnetic stimulation (rNMS) combined with physical exercises, conceptualized as functional rNMS (frNMS), represents a novel treatment approach. Methods: In this open-label study, six children and two adolescents (10.4 ± 2.5 years) with BSCP received a frNMS intervention targeting the gluteal muscles (12 sessions within 3 weeks). Results: In 77.1% of the sessions, no side effects were reported. In 16.7%, 6.3% and 5.2% of the sessions, a tingling sensation, feelings of pressure/warmth/cold or very shortly lasting pain appeared, respectively. frNMS was highly accepted by families (100% adherence) and highly feasible (97.9% of treatment per training protocol). A total of 100% of participants would repeat frNMS, and 87.5% would recommend it. The Canadian Occupational Performance Measure demonstrated clinically important benefits for performance in 28% and satisfaction in 42% of mobility-related tasks evaluated by caregivers for at least one follow-up time point (6 days and 6 weeks post intervention). Two patients accomplished goal attainment for one mobility-related goal each. One patient experienced improvement for both predefined goals, and another participant experienced improvement in one and outreach of the other goal as assessed with the goal attainment scale. Conclusions: frNMS is a safe and well-accepted neuromodulatory approach that could improve the quality of life, especially in regard to activity and participation, of children and adolescents with BSCP. Larger-scaled studies are needed to further explore the effects of frNMS in this setting.

To analyze growth patterns of children with CP between countries; to examine differences in growth; and to assess the fit of growth charts. Cross-sectional study in children with CP from 2 to 19 years old, 399 from Argentina and 400 from Germany. Growth measures were converted into z-scores and compared to WHO reference and US CP growth charts. Generalized Linear Model was used to analyze the growth expressed as mean z-scores. 799 children. Mean age 9 years (± 4). Compared to the WHO reference, the decrease in Height z-scores (HAZ) with age in Argentina (− 0.144/year) was double that in Germany (− 0.073/year). For children in GMFCS IV–V, BMI z-scores (BMIZ) decreased with age (− 0.102/year). Using the US CP charts, both countries showed decreasing HAZ with age, in Argentina (− 0.066/year) and in Germany (− 0.032/year). BMIZ increased more among children with feeding tubes (0.062/year), similar in both countries. Argentinian children with oral feeding decrease their Weight z-score (WAZ) by − 0.553 compared to their peers. With WHO charts BMIZ presented an excellent fit for GMFCS I–III. HAZ presents a poor fit to growth references. BMIZ and WAZ presented a good fit to US CP Charts. Growth differences due to ethnicity also act in children with CP, and are related to motor impairment, age and feeding modality, possibly reflecting differences in environment or health care.

Zusammenfassung Der arteriell ischämische Schlaganfall im Kindes- und Jugendalter gehört zu den zeitkritischsten Notfällen in der Pädiatrie. Dennoch wird er häufig mit einer oft prognostisch relevanten Zeitverzögerung diagnostiziert. Gründe dafür liegen neben der geringen Awareness auch in der zuweilen unspezifischen klinischen Präsentation mit einer herausfordernden Breite kritischer Differenzialdiagnosen sowie in der Fläche noch wenig verzahnter Akutversorgungsstrukturen. Gleichwohl zeigen grundsätzlich die beim Erwachsenen etablierten Revaskularisationsstrategien auch beim Kind ihre möglichen, zum Teil spektakulären Erfolge. Es gilt also, diese nach Möglichkeit auch den betroffenen Kindern zur Verfügung zu stellen, auch wenn hier derzeit ein nicht annähernd vergleichbarer Grad an Evidenz erreicht ist. Postakut ist die ätiologische Aufarbeitung durch die größere Bandbreite zu bedenkender Risikofaktoren besonders komplex, muss aber in der Lage sein, das individuelle Risikoprofil mit Sekundärprophylaxe, Rezidivrisiko und Outcome präzise zu identifizieren. Die Langzeitbetreuung im multiprofessionellen, interdisziplinären Team muss die biopsychosozialen Aspekte des Kindes in seiner jeweiligen Entwicklungsphase berücksichtigen und damit eine bestmögliche Integration des Kindes in sein soziales und schulisches, später berufliches Umfeld realisieren.

To compare growth patterns during infancy, childhood and adolescence in children with unilateral and bilateral cerebral palsy (CP) phenotype and to assess the association with gross motor impairment, dysphagia and gestational age. We retrospectively studied 389 children with CP from a single center population in Munich, Germany. 1536 measurements of height and weight were tabulated and z-scored from 6 to 180 months of age. Generalized linear mixed model were used to examine the association between growth, GMFCS, dysphagia and gestational age by CP phenotype. Children with unilateral CP tend to grow similarly to their typically developed peers. In the main effect model, bilateral CP phenotype was significantly associated with decreased mean z-scores for height (β [95% CI] − 0.953 [− 1.145, − 0.761], p < 0.001), weight (− 0.999 [− 1.176, − 0.807], p < 0.001) and BMI (β [95% CI] − 0.437 [− 0.799, − 0.075]), compared with unilateral CP phenotype. This association remained significant in the interaction models. The height-for-age z-scores, weight-for-age decreased z-scores and BMI-for-age z-scores of children with bilateral CP and GMFCS III–V or dysphagia decreased more significantly than those of children with unilateral CP. Preterm birth was not significantly associated with decreased growth in height, weight and BMI. Reduced growth in children with bilateral CP was strongly associated with moderate to severe impairment in gross motor function (GMFCS III–V) and dysphagia.

PURPOSE: A large prospective database from three Phase 3 studies allowed the study of spasticity-related pain (SRP) in pediatric cerebral palsy (CP). METHODS: Baseline (pretreatment) SRP data occurring during different activities in children/adolescents (aged 2–17 years, ambulant/nonambulant) with uni-/bilateral spastic CP was obtained using the Questionnaire on Pain caused by Spasticity (QPS; six modules specific to spasticity level [lower limb (LL) or upper limb (UL)] and type of respondent [child/adolescent, interviewer, or parent/caregiver]). RESULTS: At baseline, 331 children/adolescents with LL- and 155 with UL-spasticity completed at least one key item of their modules; LL/UL QPS modules of parent/caregivers were at least partially completed (key items) by 841/444 parents/caregivers. SRP with at least one activity at baseline was self-reported in 81.9% /69.7% (LLs/ULs) of children/adolescents with spasticity. Parents/caregivers observed LL/UL SRP behaviors in 85.9% /77.7% of their children, with multiple body regions affected. SRP negatively affected the great majority of the children in various ways. Child/adolescent-reported mean SRP intensity and parent/caregiver-observed mean SRP behavior frequencies were higher for LLs than ULs, and the level of SRP increased with more physically demanding activities. CONCLUSION: These data suggest SRP is more common and intense in pediatric CP than generally thought, emphasizing the need for effective, long-term pain management.

IncobotulinumtoxinA, a pure botulinumtoxinA formulation, is free of accessory proteins. This analysis provides pooled safety data from phase 3 trials of children/adolescents (2–17 years), investigating incobotulinumtoxinA for the treatment of spasticity associated with cerebral palsy (at doses ≤20 U/kg (max. 500 U) per injection cycle (IC) for ≤6 ICs; three trials) or sialorrhea associated with neurologic disorders (at total doses of 20–75 U per IC for ≤4 ICs; one trial) for ≤96 weeks. Safety endpoints included the incidences of different types of treatment-emergent adverse events (TEAEs) and immunogenicity. IncobotulinumtoxinA dose groups were combined. Of 1159 patients (mean age 7.3 years, 60.4% males) treated with incobotulinumtoxinA, 3.9% experienced treatment-related TEAEs, with the most common being injection site reactions (1.3%) (both indications), muscular weakness (0.7%) (spasticity), and dysphagia (0.2%) (sialorrhea). Two patients (0.2%) experienced a treatment-related treatment-emergent serious adverse event, and 0.3% discontinued the study due to treatment-related TEAEs. No botulinumtoxinA-naïve patients developed neutralizing antibodies (NAbs) after incobotulinumtoxinA. All children/adolescents with known pre-treatment status and testing positive for Nabs at final visit (n = 7) were previously treated with a botulinumtoxinA other than incobotulinumtoxinA. IncobotulinumtoxinA was shown to be safe, with very few treatment-related TEAEs in a large, diverse cohort of children/adolescents with chronic conditions requiring long-term treatment and was without new NAb formation in treatment-naïve patients.

BACKGROUND Spinal Muscular Atrophy (SMA) is the most common neurodegenerative disease in childhood. New therapeutic interventions have been developed to interrupt rapid motor deterioration. The current standard of clinical evaluation for severely weak infants is the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND), originally developed for SMA type 1. This test however, remains subjective and requires extensive training to be performed reliably. OBJECTIVE Proof of principle of the motion tracking method for capturing complex movement patterns in ten children with SMA. METHODS We have developed a system for tracking full-body motion in infants (KineMAT) using a commercially available, low-cost RGB-depth sensor. Ten patients with SMA (2-46 months of age; CHOP INTEND score 10-50) were recorded for 2 minutes during unperturbed spontaneous whole-body activity. Five predefined motion parameters representing 56 degrees of freedom of upper, lower extremities and trunk joints were correlated with CHOP INTEND scores using Pearson product momentum correlation (r). Test-retest analysis in two patients used descriptive statistics. RESULTS 4/5 preselected motion parameters highly correlated with CHOP INTEND: 1. Standard deviation of joint angles (r = 0.959, test-retest range 1.3-1.9%), 2. Standard deviation of joint position (r = 0.933, test-retest range 2.9%), 3. Absolute distance of hand/foot travelled (r = 0.937, test-retest range 6-10.5%), 4. Absolute distance of hand/foot travelled against gravity (r = 0.923; test-retest range 4.8-8.5%). CONCLUSIONS Markerless whole-body motion capture using the KineMAT proved to objectively capture motor performance in infants and children with SMA across different severity and ages.

Background: Mutations in SOX6 have recently been recognized as a new molecular cause of neurodevelopmental disorders characterized by intellectual disability, behavioral changes, and nonspecific facial and digital skeletal abnormalities. To date, <25 cases have been reported in the literature. Methods and Findings: Here we report a new case of SOX6-associated neurodegeneration and expand the phenotype to include ceratoconus. The clinical picture consisted of early onset mildly reduced intellectual function, facial asymmetry, and dystonic tremor of hands and neck, substantially improved by levodopa. Skeletal abnormalities included scoliosis and hypertrophy of the mandibular coronoid process. A heterozygous de novo loss-of-function variant in SOX6 (c.277 C>T. p.Arg93*) was molecularly confirmed which leads to truncation of the SOX6 protein in its N-terminus, upstream of any known functional domain. Conclusion: SOX6-associated neurodevelopmental delayis ultrarare with less than 25 cases described in the literature. We report a new case who presented with early-onset mildly reduced intellectual function, facial asymmetry, skeletal abnormalities and dystonic tremor of hands and neck, substantially improved by levodopa. Given the therapeutic implications, SOX6 mutations should be considered in patients with complex dystonia parkinsonism.

BackgroundMotor impairment due to spasticity, weakness, and insufficient selective motor control is a key feature of cerebral palsy (CP). For standing and walking, the gluteal muscles play an important role. Physical therapy represents an evidence-based treatment to promote strength and endurance but may be limited to address selective motor control. Treatment incorporating neurostimulating techniques may increase the therapeutic benefits in these situations.PurposeThe aim of this case report was to evaluate the feasibility, safety and clinical effects of a customized protocol of functional repetitive neuromuscular magnetic stimulation (frNMS).MethodsThis case report describes a frNMS protocol applied to the gluteal muscles in an 8-year old boy with bilateral spastic CP. The protocol combines 12 sessions of customized physiotherapeutic exercises with simultaneous electromagnetic stimulation.ResultsfrNMS protocol was adhered to as planned, no relevant adverse events were observed. At day fourafter the intervention the patient reported clinical benefits and improvements of standing and walking assessed by Gross Motor Function Measure dimensions D (+5.1%) and E (+4.2%) were documented. Body sway as measured by center of pressure displacement during posturography decreased.ConclusionClinical studies are warranted to assess effects of frNMS and its mechanisms of action in a controlled setting.