Safety and Feasibility of Functional Repetitive Neuromuscular Magnetic Stimulation of the Gluteal Muscles in Children and Adolescents with Bilateral Spastic Cerebral Palsy.

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.

Anti-PF4 immunothrombosis without proximate heparin or adenovirus vector vaccine exposure.

ABSTRACT: Platelet-activating anti-platelet factor 4 (PF4)/heparin antibodies and anti-PF4 antibodies cause heparin-induced thrombocytopenia (HIT) and vaccine-induced immune thrombocytopenia and thrombosis (VITT), respectively. Diagnostic and treatment considerations differ somewhat between HIT and VITT. We identified patients with thrombocytopenia and thrombosis without proximate heparin exposure or adenovirus-based vaccination who tested strongly positive by PF4/polyanion enzyme-immunoassays and negative/weakly positive by heparin-induced platelet activation (HIPA) test but strongly positive by PF4-induced platelet activation (PIPA) test (ie, VITT-like profile). We tested these patients by a standard chemiluminescence assay that detects anti-PF4/heparin antibodies found in HIT (HemosIL AcuStar HIT-IgG(PF4-H)) as well as a novel chemiluminescence assay for anti-PF4 antibodies found in VITT. Representative control sera included an exploratory anti-PF4 antibody-positive but HIPA-negative/weak cohort obtained before 2020 (n = 188). We identified 9 patients with a clinical-pathological profile of a VITT-like disorder in the absence of proximate heparin or vaccination, with a high frequency of stroke (arterial, n = 3; cerebral venous sinus thrombosis, n = 4), thrombocytopenia (median platelet count nadir, 49 × 109/L), and hypercoagulability (greatly elevated D-dimer levels). VITT-like serological features included strong reactivity by PIPA (aggregation <10 minutes in 9/9 sera) and positive testing in the novel anti-PF4 chemiluminescence assay (3/9 also tested positive in the anti-PF4/heparin chemiluminescence assay). Our exploratory cohort identified 13 additional patient sera obtained before 2020 with VITT-like anti-PF4 antibodies. Platelet-activating VITT-like anti-PF4 antibodies should be considered in patients with thrombocytopenia, thrombosis, and very high D-dimer levels, even without a proximate exposure to heparin or adenovirus vector vaccines.

Functional Repetitive Neuromuscular Magnetic Stimulation (frNMS) Targeting the Tibialis Anterior Muscle in Children with Upper Motor Neuron Syndrome: A Feasibility Study.

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.

Addressing gross motor function by functional repetitive neuromuscular magnetic stimulation targeting to the gluteal muscles in children with bilateral spastic cerebral palsy: benefits of functional repetitive neuromuscular magnetic stimulation targeting the gluteal muscles.

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.

First detected geographical cluster of BoDV-1 encephalitis from same small village in two children: therapeutic considerations and epidemiological implications.

BACKGROUND: The Borna disease virus (BoDV-1) is an emerging zoonotic virus causing severe and mostly fatal encephalitis in humans. METHODS AND RESULTS: A local cluster of fatal BoDV-1 encephalitis cases was detected in the same village three years apart affecting two children. While the first case was diagnosed late in the course of disease, a very early diagnosis and treatment attempt facilitated by heightened awareness was achieved in the second case. Therapy started as early as day 12 of disease. Antiviral therapy encompassed favipiravir and ribavirin, and, after bioinformatic modelling, also remdesivir. As the disease is immunopathogenetically mediated, an intensified anti-inflammatory therapy was administered. Following initial impressive clinical improvement, the course was also fatal, although clearly prolonged. Viral RNA was detected by qPCR in tear fluid and saliva, constituting a possible transmission risk for health care professionals. Highest viral loads were found post mortem in the olfactory nerve and the limbic system, possibly reflecting the portal of entry for BoDV-1. Whole exome sequencing in both patients yielded no hint for underlying immunodeficiency. Full virus genomes belonging to the same cluster were obtained in both cases by next-generation sequencing. Sequences were not identical, indicating viral diversity in natural reservoirs. Specific transmission events or a common source of infection were not found by structured interviews. Patients lived 750m apart from each other and on the fringe of the settlement, a recently shown relevant risk factor. CONCLUSION: Our report highlights the urgent necessity of effective treatment strategies, heightened awareness and early diagnosis. Gaps of knowledge regarding risk factors, transmission events, and tailored prevention methods become apparent. Whether this case cluster reflects endemicity or a geographical hot spot needs further investigation.

Targeted Molecular Strategies for Genetic Neurodevelopmental Disorders: Emerging Lessons from Dravet Syndrome.

Dravet syndrome is a severe developmental and epileptic encephalopathy mostly caused by heterozygous mutation of the SCN1A gene encoding the voltage-gated sodium channel α subunit Nav1.1. Multiple seizure types, cognitive deterioration, behavioral disturbances, ataxia, and sudden unexpected death associated with epilepsy are a hallmark of the disease. Recently approved antiseizure medications such as fenfluramine and cannabidiol have been shown to reduce seizure burden. However, patients with Dravet syndrome are still medically refractory in the majority of cases, and there is a high demand for new therapies aiming to improve behavioral and cognitive outcome. Drug-repurposing approaches for SCN1A-related Dravet syndrome are currently under investigation (i.e., lorcaserin, clemizole, and ataluren). New therapeutic concepts also arise from the field of precision medicine by upregulating functional SCN1A or by activating Nav1.1. These include antisense nucleotides directed against the nonproductive transcript of SCN1A with the poison exon 20N and against an inhibitory noncoding antisense RNA of SCN1A. Gene therapy approaches such as adeno-associated virus-based upregulation of SCN1A using a transcriptional activator (ETX101) or CRISPR/dCas technologies show promising results in preclinical studies. Although these new treatment concepts still need further clinical research, they offer great potential for precise and disease modifying treatment of Dravet syndrome.

Expression of the Phosphatase Ppef2 Controls Survival and Function of CD8+ Dendritic Cells.

Apoptotic cell death of Dendritic cells (DCs) is critical for immune homeostasis. Although intrinsic mechanisms controlling DC death have not been fully characterized up to now, experimentally enforced inhibition of DC-death causes various autoimmune diseases in model systems. We have generated mice deficient for Protein Phosphatase with EF-Hands 2 (Ppef2), which is selectively expressed in CD8+ DCs, but not in other related DC subtypes such as tissue CD103+ DCs. Ppef2 is down-regulated rapidly upon maturation of DCs by toll-like receptor stimuli, but not upon triggering of CD40. Ppef2-deficient CD8+ DCs accumulate the pro-apoptotic Bcl-2-like protein 11 (Bim) and show increased apoptosis and reduced competitve repopulation capacities. Furthermore, Ppef2-/- CD8+ DCs have strongly diminished antigen presentation capacities in vivo, as CD8+ T cells primed by Ppef2-/- CD8+ DCs undergo reduced expansion. In conclusion, our data suggests that Ppef2 is crucial to support survival of immature CD8+ DCs, while Ppef2 down-regulation during DC-maturation limits T cell responses.