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This study aims to determine if children follow the same cortical activation patterns as adults when responding to two‐point discrimination sensory stimuli during functional magnetic resonance imaging (fMRI). We recruited 15 children with typical development, aged between 8 and 16 years. These participants were asked to complete a two‐point discrimination test (task block) while undergoing an fMRI scan. In the two‐point stimulus test, strong activation compared to baseline was observed in the left and right frontal orbital cortex. The inferior parietal lobe also exhibited activity, particularly on the right side, with activation in both the supramarginal and angular gyri. Further activity was evident in the left supramarginal gyrus and the left paracingulate gyrus. This novel study on fMRI two‐point discrimination testing in children shows the activation patterns in key brain regions involved in somatosensory discrimination and decision making. Practical Applications: This study provides crucial normative data on cortical activation patterns during two‐point discrimination testing in typically developing children. Such data serve as a valuable reference point for future research investigating sensory processing and cognitive function in pediatric populations. Researchers can use these findings to establish benchmarks and compare cortical activation patterns in children with neurodevelopmental conditions. This information is essential for exploring pathology, which may affect tactile sensation techniques and developing targeted interventions tailored to individual needs in pediatric treatment. Additionally, it lays the groundwork for further exploration into the neural mechanisms underpinning somatosensory discrimination, potentially leading to advancements in understanding and treating sensory‐related disorders in children. [ABSTRACT FROM AUTHOR]

Childhood conditions that feature developmental regression are poorly understood. Phenotype–genotype characterization and diagnostic yield data are needed to inform clinical decision‐making. The aim of this study was to report the conditions featuring developmental regression and assess diagnostic yields of investigations. A retrospective chart review of children presenting with developmental regression to a tertiary pediatric genetic clinic between 2018 and 2021 was performed. Of 99 children, 30% (n = 30) had intellectual disability (ID), 21% (n = 21) were autistic, 39% (n = 39) were autistic with ID, and 9% (n = 9) did not have ID or autism. Thirty‐two percent (n = 32) of children received a new diagnosis, including eight molecular findings not previously reported to feature developmental regression. Of the children investigated, exome sequencing (ES) provided the highest diagnostic yield (51.1%, n = 24/47), highest (63.6%, n = 14/22) for children with ID, 50% for autistic children with ID (n = 6/12) and children without autism or ID (n = 3/6), and 14.3% (n = 1/7) for autistic children without ID. We highlight the conditions that feature developmental regression and report on novel phenotypic expansions. The high diagnostic yield of ES, regardless of autism or ID diagnosis, indicates the presence of developmental regression as an opportunity to identify the cause, including for genetic differences not previously reported to include regression. [ABSTRACT FROM AUTHOR]

Blood–brain barrier (BBB) dysfunction and neuroinflammation are key mechanisms of brain injury. We performed a time-course study following neonatal hypoxia–ischemia (HI) to characterize these events. HI brain injury was induced in postnatal day 10 rats by single carotid artery ligation followed by hypoxia (8% oxygen, 90 min). At 6, 12, 24, and 72 h (h) post-HI, brains were collected to assess neuropathology and BBB dysfunction. A significant breakdown of the BBB was observed in the HI injury group compared to the sham group from 6 h in the cortex and hippocampus (p < 0.001), including a significant increase in albumin extravasation (p < 0.0033) and decrease in basal lamina integrity and tight-junction proteins. There was a decrease in resting microglia (p < 0.0001) transitioning to an intermediate state from as early as 6 h post-HI, with the intermediate microglia peaking at 12 h (p < 0.0001), which significantly correlated to the peak of microbleeds. Neonatal HI insult leads to significant brain injury over the first 72 h that is mediated by BBB disruption within 6 h and a transitioning state of the resident microglia. Key BBB events coincide with the appearance of the intermediate microglial state and this relationship warrants further research and may be a key target for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Objective: Variants in several potassium channel genes, including KCNA1 and KCNA2, cause Developmental and Epileptic Encephalopathies (DEEs). We investigated whether variants in KCNA3, another mammalian homologue of the Drosophila shaker family and encoding for Kv1.3 subunits, can cause DEE. Methods: Genetic analysis of study individuals was performed by routine exome or genome sequencing, usually of parent‐offspring trios. Phenotyping was performed via a standard clinical questionnaire. Currents from wild‐type and/or mutant Kv1.3 subunits were investigated by whole‐cell patch‐clamp upon their heterologous expression. Results: Fourteen individuals, each carrying a de novo heterozygous missense variant in KCNA3, were identified. Most (12/14; 86%) had DEE with marked speech delay with or without motor delay, intellectual disability, epilepsy, and autism spectrum disorder. Functional analysis of Kv1.3 channels carrying each variant revealed heterogeneous functional changes, ranging from "pure" loss‐of‐function (LoF) effects due to faster inactivation kinetics, depolarized voltage‐dependence of activation, slower activation kinetics, increased current inactivation, reduced or absent currents with or without dominant‐negative effects, to "mixed" loss‐ and gain‐of‐function (GoF) effects. Compared to controls, Kv1.3 currents in lymphoblasts from 1 of the proband displayed functional changes similar to those observed upon heterologous expression of channels carrying the same variant. The antidepressant drug fluoxetine inhibited with similar potency the currents from wild‐type and 1 of the Kv1.3 GoF variant. Interpretation: We describe a novel association of de novo missense variants in KCNA3 with a human DEE, and provide evidence that fluoxetine might represent a potential targeted treatment for individuals carrying variants with significant GoF effects. ANN NEUROL 2024;95:365–376 [ABSTRACT FROM AUTHOR]

Umbilical cord blood cells have therapeutic potential for neurological disorders, through a paracrine mechanism of action. A greater understanding of the safety and immunological effects of allogeneic donor cord blood cells in the context of a healthy recipient immune system, such as in cerebral palsy, is needed. This study aimed to determine how quickly donor cord blood cells were cleared from the circulation in children with cerebral palsy who received a single intravenous infusion of 12/12 human leucocyte antigen (HLA)-matched sibling cord blood cells. Twelve participants with cerebral palsy aged 2–12 years received cord blood cell infusions as part of a phase I trial of umbilical blood infusion for cerebral palsy. Digital droplet PCR analysis of DNA copy number variants specific to donor and recipient was used to assess donor DNA clearance at five timepoints post-infusion, a surrogate measure of cell clearance. Donor cells were cleared by 3 months post-infusion in 11/12 participants. When detected, donor DNA was at a fraction of 0.01–0.31% of total DNA with no signs of graft-versus-host disease in any participant. The donor DNA clearance times provided by this study have important implications for understanding the safety of allogeneic cord blood cell infusion for cerebral palsy and translational tissue engineering or regenerative medicine research in other disorders. [ABSTRACT FROM AUTHOR]

(1) Background: Neonatal brain injury can lead to permanent neurodevelopmental impairments. Notably, suppressing inflammatory pathways may reduce damage. To determine the role of neuroinflammation in the progression of neonatal brain injury, we investigated the effect of treating neonatal rat pups with the immunosuppressant tacrolimus at two time points: before and after hypoxic–ischaemic (HI)-induced injury. (2) Methods: To induce HI injury, postnatal day (PND) 10 rat pups underwent single carotid artery ligation followed by hypoxia (8% oxygen, 90 min). Pups received daily tacrolimus (or a vehicle) starting either 3 days before HI on PND 7 (pre-HI), or 12 h after HI (post-HI). Four doses were tested: 0.025, 0.05, 0.1 or 0.25 mg/kg/day. Pups were euthanised at PND 17 or PND 50. (3) Results: All tacrolimus doses administered pre-HI significantly reduced brain infarct size and neuronal loss, increased the number of resting microglia and reduced cellular apoptosis (p < 0.05 compared to control). In contrast, only the highest dose of tacrolimus administered post-HI (0.25 mg/kg/day) reduced brain infarct size (p < 0.05). All doses of tacrolimus reduced pup weight compared to the controls. (4) Conclusions: Tacrolimus administration 3 days pre-HI was neuroprotective, likely mediated through neuroinflammatory and cell death pathways. Tacrolimus post-HI may have limited capacity to reduce brain injury, with higher doses increasing rat pup mortality. This work highlights the benefits of targeting neuroinflammation during the acute injurious period. More specific targeting of neuroinflammation, e.g., via T-cells, warrants further investigation. [ABSTRACT FROM AUTHOR]

Cerebral palsy is a clinical descriptor covering a diverse group of permanent, non-degenerative disorders of motor function. Around one-third of cases have now been shown to have an underlying genetic aetiology, with the genetic landscape overlapping with those of neurodevelopmental disorders including intellectual disability, epilepsy, speech and language disorders and autism. Here we review the current state of genomic testing in cerebral palsy, highlighting the benefits for personalized medicine and the imperative to consider aetiology during clinical diagnosis. With earlier clinical diagnosis now possible, we emphasize the opportunity for comprehensive and early genomic testing as a crucial component of the routine diagnostic work-up in people with cerebral palsy. The diagnosis of cerebral palsy is currently made on clinical observations only and does not consider aetiology or pathology. Here, van Eyk and colleagues review the current state of genomic testing in cerebral palsy and highlight the benefits of a 'genotype-first' approach for this group of disorders. Key points: Currently, a clinical diagnosis of cerebral palsy (CP) is made on observation of signs and symptoms and does not consider aetiology or pathology. CP encompasses a clinically heterogeneous group of disorders — together referred to as cerebral palsies — with at least one-third of cases having a genetic aetiology. CP has a high degree of genetic overlap with neurodevelopmental disorders, such as intellectual disability, epilepsy and autism, and should itself be considered, at least partly, a genetic neurodevelopmental disorder. The presence of known cerebral palsy risk factors, such as prematurity and growth restriction, and the absence of other comorbid neurodevelopmental phenotypes, including intellectual disability and epilepsy, do not rule out a genetic aetiology. Diagnostic practice has not evolved with the fast-accumulating evidence for a genetic contribution to CP aetiology; the nomenclature for genetic cases and the circumstances under which a genetic diagnosis should negate the CP clinical diagnosis lack consensus. An aetiology-driven diagnosis of CP involving a 'genotype-first' approach will bring tangible benefits to individuals with CP through precision medicine and improved clinical management. [ABSTRACT FROM AUTHOR]

Aim: Idiopathic toe walking (ITW) is a diagnosis for children who toe walk without another diagnosis known to cause toe walking. Recent research has suggested that children with ITW may have mild motor planning challenges and sensory processing differences. The primary aim of this systematic review was to determine whether children diagnosed with ITW have differences in their sensory processing compared to typically developing children. Secondary aims included determining how sensory processing was assessed in this population and documenting the broad clinometric and psychometric properties of any assessment tools. Methods: MEDLINE, CINAHL, AMED and Embase were searched for relevant literature in English. Studies were eligible for inclusion if they described children aged 3 and 18 with idiopathic toe walking and reported a sensory processing domain. Results: Twelve articles met the inclusion criteria; however, only two papers included data permitting meta‐analysis. Meta‐analyses of vibration perception threshold using a random effect model were not significant (p = 0.31). Other data were synthesised by narrative and showed a high heterogeneity across multiple sensory processing domains. Conclusion: This study highlights that despite children with ITW often conceptualised as possessing sensory processing challenges, there is little evidence supporting this theory. Further research on sensory processing in children with this gait pattern is necessary. [ABSTRACT FROM AUTHOR]

Background: It is widely accepted that both autologous and alloplastic reconstruction are safe. A recent publication reported a significant association between textured implants and metastatic recurrence of breast cancer. This study aims to assess if the published results are reproducible in our cohort and to review the safety of breast reconstruction. Methods: This is a retrospective cohort study of adult patients undergoing mastectomy and either alloplastic or autologous breast reconstruction at a single quaternary hospital. Outcomes include disease free survival (DFS), local and recurrence free survival (LRRFS) and BIA‐ALCL. For time to event endpoints, unadjusted and multivariate adjusted hazard ratios (HRs) were estimated using Cox regression, and penalized Cox regression respectively. Results: Four hundred and twenty‐six patients of whom 187 underwent autologous reconstruction and 239 underwent alloplastic. There were 43 cancer recurrences (24 alloplastic and 19 autologous) and 14 local regional recurrences (8 alloplastic and 4 autologous). There were 26 deaths and no instances of BIA‐ALCL. Median follow‐up time was 4.7 years. No evidence of association was found between breast reconstruction method and DFS (HR 0.87 CI: 0.47–1.58). It is uncertain whether implant texture grade was associated with increased breast cancer recurrence (HR 2.17 CI: 0.65–7.52). Conclusion: Both autologous and alloplastic breast reconstruction have been carried out in our cohort and reconstructive modality was not associated with either reduced DFS or LRRFS. The results in this cohort show there is uncertainty between the use of textured breast implants and either local or distant breast cancer recurrence. [ABSTRACT FROM AUTHOR]

Aim: To investigate the relationship between motor ability and early social development in a cohort of preschool children with cerebral palsy (CP). Design: Population-based cohort study. Methods: Participants were 122 children with CP assessed at 18, 24 and 30 months, corrected age (ca). Motor ability was measured by the Gross Motor Function Classification System (GMFCS) with classification assigned by physiotherapists. The sample was representative of a population-based cohort (I=48, 38.4%, II=19, 15.2%, III=17, 13.6%, IV=22, 17.6% and V=19, 15.2%). Social development was measured by the Paediatric Evaluation of Disability Inventory (PEDI) and included capabilities in social interaction, social communication, interactive play and household/community tasks. Results: Cross-sectional analyses indicated a significant relationship between motor ability and social development at 18 months, F(4, 56) = 11.44, p less than 0.0001, [eta][superscript 2] = 0.45, at 24 months, F(4, 79) = 15.66, p less than 0.0001, [eta][superscript 2] = 0.44 and at 30 months, F(4, 76) = 16.06, p less than 0.0001, [eta][superscript 2] = 0.49. A longitudinal analysis with a subset of children (N = 24) indicated a significant interaction between age at assessment and GMFCS, F(2, 21) = 7.02, p = 0.005, [eta][superscript 2] = 0.40. Comparison with community norms indicated that at 18 months corrected age, 44.3% of the cohort was greater than two standard deviations below the mean (greater than 2SD) for social development and a further 27.9% of the cohort was greater than one standard deviation below the mean (greater than 1SD). Interpretation: There is a relationship between motor ability and social development in preschool children with CP. Children with CP may require support for social development in additional to physical interventions, from as early as 18 months. (Contains 3 tables and 1 figure.)

Objective: To determine the frequency of paroxysmal nonepileptic events in children with cerebral palsy due to brain injury who have epilepsy and to describe the factors associated with paroxysmal nonepileptic events. Methods: Retrospective, population-based study of children from the Victorian CP Register born 1999–2006. Neuroimaging, medical records, electroencephalograms (EEG), and EEG requests were analyzed. Results: Of the included 256 children, 87 had epilepsy. EEGs (with video correlation) were available for 82 of 87. Eighteen (18/82, 22%) had epileptic events captured on EEG. Twenty-one (21/82, 26%) had paroxysmal nonepileptic events captured on EEG. The majority (13/18, 77%) of children with epileptic events also had paroxysmal nonepileptic events captured. Ten parents and carers continued to report events as epileptic despite there being no ictal EEG correlate for specific events on multiple EEGs. There were no clear associations to identify which children would have ongoing paroxysmal nonepileptic events reported. Conclusions: Paroxysmal nonepileptic events were captured on EEG in one-fourth of children from this cerebral palsy cohort with epilepsy and available EEG. Half the parents and carers reported previously identified paroxysmal nonepileptic events as epileptic on subsequent EEGs, highlighting the need for clearer counseling so that parents better understand seizure semiology in children with EEG-proven paroxysmal nonepileptic events. [ABSTRACT FROM AUTHOR]

Seizures occur in approximately one-third of children with cerebral palsy. This study aimed to determine epilepsy syndromes in children with seizures and cerebral palsy due to vascular injury, anticipating that this would inform treatment and prognosis. We studied a population-based cohort of children with cerebral palsy due to prenatal or perinatal vascular injuries, born 1999–2006. Each child's MRI was reviewed to characterize patterns of grey and white matter injury. Children with syndromic or likely genetic causes of cerebral palsy were excluded, given their inherent association with epilepsy and our aim to study a homogeneous cohort of classical cerebral palsy. Chart review, parent interview and EEGs were used to determine epilepsy syndromes and seizure outcomes. Of 256 children, 93 (36%) had one or more febrile or afebrile seizures beyond the neonatal period and 87 (34%) had epilepsy. Children with seizures were more likely to have had neonatal seizures, have spastic quadriplegic cerebral palsy and function within Gross Motor Function Classification System level IV or V. Fifty-six (60%) children with seizures had electroclinical features of a self-limited focal epilepsy of childhood; we diagnosed these children with a self-limited focal epilepsy-variant given the current International League Against Epilepsy classification precludes a diagnosis of self-limited focal epilepsy in children with a brain lesion. Other epilepsy syndromes were focal epilepsy—not otherwise specified in 28, infantile spasms syndrome in 11, Lennox–Gastaut syndrome in three, genetic generalized epilepsies in two and febrile seizures in nine. No epilepsy syndrome could be assigned in seven children with no EEG. Twenty-one changed syndrome classification during childhood. Self-limited focal epilepsy-variant usually manifested with a mix of autonomic and brachio-facial motor features, and occipital and/or centro-temporal spikes on EEG. Of those with self-limited focal epilepsy-variant, 42/56 (75%) had not had a seizure for >2 years. Favourable seizure outcomes were also seen in some children with infantile spasms syndrome and focal epilepsy-not otherwise specified. Of the 93 children with seizures, at last follow-up (mean age 15 years), 61/91 (67%) had not had a seizure in >2 years. Children with cerebral palsy and seizures can be assigned specific epilepsy syndrome diagnoses typically reserved for normally developing children, those syndromes commonly being age-dependent and self-limited. Compared to typically developing children with epilepsy, self-limited focal epilepsy-variant occurs much more commonly in children with cerebral palsy and epilepsy. These findings have important implications for treatment and prognosis of epilepsy in cerebral palsy, and research into pathogenesis of self-limited focal epilepsy. [ABSTRACT FROM AUTHOR]