Russell C. Dale

Description:Background: We aimed to describe the clinical spectrum and burden of COVID-19-associated neurologic disease in Australian children. Methods: We extracted Australian national sentinel site surveillance data on COVID-19-associated neurologic disease in children hospitalized in the Paediatric Active Enhanced Disease Surveillance network, 2020-2023. Neurologic complications included encephalitis, encephalopathy, Guillain-Barre syndrome, seizures and cerebrovascular accident among others. We calculated the proportion of hospitalized pediatric COVID-19 cases associated with neurologic disease and described the spectrum of presentations including clinical features and severity. We calculated incidence rates of neurologic disease within COVID-19 variant eras among hospitalized patients. Results: We identified 311 cases of SARS-CoV-2 infection with neurologic disease among 4616 hospitalized pediatric cases of COVID-19 reported through the surveillance network, representing 5.3 cases per 100 pediatric COVID-19 admissions. The most common COVID-19-associated neurologic presentations were seizures (n = 215), including febrile seizures. Nonspecific encephalopathy (n = 62), encephalitis, Guillain-Barre Syndrome, acute cerebellar syndromes, acute demyelinating encephalomyelitis and cerebrovascular accident were also reported. Almost 60% of children were ≤4 years, approximately 30% had pre-existing neurologic conditions and almost half had other medical comorbidities. COVID-19-associated neurologic complications infrequently led to death, although 25% (n = 2/8) of children with COVID-19 encephalitis died. The incidence rate of COVID-19-associated neurologic disease was lowest during the late Omicron era. Conclusions: Neurologic complications among COVID-19 hospitalized children are relatively frequent. While most neurologic complications are transient, including seizures, encephalitis remains a cause of significant morbidity. Children with pre-existing neurologic disease and other comorbidities are at higher risk.

Description:Sensory dysregulation impacts multiple areas within the everyday lives of young people with tic disorders. Although research indicates contextual and emotional factors worsen sensory dysregulation and impact tic expression, there is a paucity of qualitative studies investigating the interplay between sensory experiences and tics in young people. Thus, the purpose of this study was to explore the sensory experiences that reduce or exacerbate tics from the perspectives of young people and their parent(s). A qualitative descriptive method was used. Semi-structured interviews were conducted with 10 young people with tic disorders and their parent(s). Thematic analysis was used to analyse the data. Three overarching themes were identified: sensory experiences associated with tics; environmental contexts that reduce or exacerbate tics; and occupational participation as a method of focus and distraction. This study highlights the sensory experiences that reduce or exacerbate tics are unique to the individual. This indicates the need for a holistic approach that considers personal, environmental and occupational factors that may assist young people to better understand their sensory needs, identity safe sensory environments and participate in meaningful occupations to reduce tics.

Description:Mesenchymal stromal cells (MSCs) have been under clinical investigation for the treatment of cerebral palsy (CP) for over a decade. However, the field has been limited by study heterogeneity and variable reports of efficacy. We conducted a scoping review of published and registered reports of MSC treatment for CP, with meta-analysis of Gross Motor Function Measure (GMFM) outcomes to summarize research and provide future recommendations. Thirty published reports and 10 registered trials were identified, including 1292 people with CP receiving MSCs. Most received ≥2 doses (72%) of umbilical cord tissue MSCs (75%), intrathecally (40%) or intravenously (38%), and 31% were treated via compassionate/Expanded access. MSC treatment was safe and meta-analyses demonstrated that MSCs conferred significant improvements in GMFM at 3 - (1.05 (0.19-1.92), p = 0.02), 6 - (0.97 (0.30-1.64), p = 0.005) and 12 months (0.99 (0.30-1.67), p = 0.005) post-treatment. Whilst MSCs are safe and improve GMFM outcomes in CP with large effect sizes, study and participant variability continues to confound data interpretation and limits subgroup analyses. With no published Phase 3 trials and high rates of compassionate access, the field would benefit from well-designed trials with unified outcomes. Additionally, data sharing to enable Individual Participant Data Meta-Analysis would support the determination of optimal source, route and dose to progress towards regulatory approval.

Description:Objective: DNA variations in the NF-kappa-B essential modulator (NEMO) gene are linked to incontinentia pigmenti (IP) and also immunodeficiency and autoinflammatory conditions. Some patients with IP present with neonatal vasculitis-like brain changes, although pathogenesis is unclear. We investigated cell-specific gene expression in a neonate with IP, who had encephalopathy, seizures, and vasculitis-like brain changes, and responded to steroid treatment. Methods: Single-cell RNA (ribonucleic acid) sequencing (scRNAseq), using the HIVE single-cell system, was performed on a neonate with IP, before and after steroid treatment, compared with a sex-matched healthy control toddler. Results: A total of 20,411 cells were sequenced and clustered into 10 cell types. In IP compared with control, upregulated significant gene set enrichment analysis gene ontology pathways (FDR <0.05) included defense response, complement activation, humoral immune response, and phagocytosis across all cell types. After steroid treatment, these pathways were predominantly downregulated in monocytes and neutrophils. The upregulated genes in IP that became downregulated after steroid treatment were interferon-related genes, oligoadenylate synthases, and immunoglobulin genes. Conclusions: IP-associated loss of NEMO function is associated with a proinflammatory phenotype, that is moderated by steroids. scRNAseq provides a rationale for immune modulation in an n = 1 setting and valuable insights into the pathogenesis and therapeutics of this rare disease.

Description:Heterozygous mutations in KMT2B are associated with an early-onset, progressive and often complex dystonia (DYT28). Key characteristics of typical disease include focal motor features at disease presentation, evolving through a caudocranial pattern into generalized dystonia, with prominent oromandibular, laryngeal and cervical involvement. Although KMT2B-related disease is emerging as one of the most common causes of early-onset genetic dystonia, much remains to be understood about the full spectrum of the disease. We describe a cohort of 53 patients with KMT2B mutations, with detailed delineation of their clinical phenotype and molecular genetic features. We report new disease presentations, including atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype. In addition to the previously reported systemic features, our study has identified co-morbidities, including the risk of status dystonicus, intrauterine growth retardation, and endocrinopathies. Analysis of this study cohort (n = 53) in tandem with published cases (n = 80) revealed that patients with chromosomal deletions and protein truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants. Eighteen individuals had detailed longitudinal data available after insertion of deep brain stimulation for medically refractory dystonia. Median age at deep brain stimulation was 11.5 years (range: 4.5-37.0 years). Follow-up after deep brain stimulation ranged from 0.25 to 22 years. Significant improvement of motor function and disability (as assessed by the Burke Fahn Marsden's Dystonia Rating Scales, BFMDRS-M and BFMDRS-D) was evident at ł months, 1 year and last follow-up (motor, P = 0.001, P = 0.004, and P = 0.012; disability, P = 0.009, P = 0.002 and P = 0.012). At 1 year post-deep brain stimulation, >50% of subjects showed BFMDRS-M and BFMDRS-D improvements of >30%. In the long-term deep brain stimulation cohort (deep brain stimulation inserted for >5 years, n = 8), improvement of >30% was maintained in 5/8 and 3/8 subjects for the BFMDRS-M and BFMDRS-D, respectively. The greatest BFMDRS-M improvements were observed for trunk (53.2%) and cervical (50.5%) dystonia, with less clinical impact on laryngeal dystonia. Improvements in gait dystonia decreased from 20.9% at 1 year to 1ł.2% at last assessment; no patient maintained a fully independent gait. Reduction of BFMDRS-D was maintained for swallowing (52.9%). Five patients developed mild parkinsonism following deep brain stimulation. KMT2B-related disease comprises an expanding continuum from infancy to adulthood, with early evidence of genotype-phenotype correlations. Except for laryngeal dysphonia, deep brain stimulation provides a significant improvement in quality of life and function with sustained clinical benefit depending on symptoms distribution.