Early administration of umbilical cord blood cells following brief high tidal volume ventilation in preterm sheep: a cautionary tale.

BACKGROUND: Umbilical cord blood (UCB) cells are a promising treatment for preterm brain injury. Access to allogeneic sources of UCB cells offer the potential for early administration to optimise their therapeutic capacities. As preterm infants often require ventilatory support, which can contribute to preterm brain injury, we investigated the efficacy of early UCB cell administration following ventilation to reduce white matter inflammation and injury. METHODS: Preterm fetal sheep (0.85 gestation) were randomly allocated to no ventilation (SHAM; n = 5) or 15 min ex utero high tidal volume ventilation. One hour following ventilation, fetuses were randomly allocated to i.v. administration of saline (VENT; n = 7) or allogeneic term-derived UCB cells (24.5 ± 5.0 million cells/kg; VENT + UCB; n = 7). Twenty-four hours after ventilation, lambs were delivered for magnetic resonance imaging and post-mortem brain tissue collected. Arterial plasma was collected throughout the experiment for cytokine analyses. To further investigate the results from the in vivo study, mononuclear cells (MNCs) isolated from human UCB were subjected to in vitro cytokine-spiked culture medium (TNFα and/or IFNγ; 10 ng/mL; n = 3/group) for 16 h then supernatant and cells collected for protein and mRNA assessments respectively. RESULTS: In VENT + UCB lambs, systemic IFNγ levels increased and by 24 h, there was white matter neuroglial activation, vascular damage, reduced oligodendrocytes, and increased average, radial and mean diffusivity compared to VENT and SHAM. No evidence of white matter inflammation or injury was present in VENT lambs, except for mRNA downregulation of OCLN and CLDN1 compared to SHAM. In vitro, MNCs subjected to TNFα and/or IFNγ displayed both pro- and anti-inflammatory characteristics indicated by changes in cytokine (IL-18 & IL-10) and growth factor (BDNF & VEGF) gene and protein expression compared to controls. CONCLUSIONS: UCB cells administered early after brief high tidal volume ventilation in preterm fetal sheep causes white matter injury, and the mechanisms underlying these changes are likely dysregulated responses of the UCB cells to the degree of injury/inflammation already present. If immunomodulatory therapies such as UCB cells are to become a therapeutic strategy for preterm brain injury, especially after ventilation, our study suggests that the inflammatory state of the preterm infant should be considered when timing UCB cells administration.

The Temporal Relationship between Blood-Brain Barrier Integrity and Microglial Response following Neonatal Hypoxia Ischemia.

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.

Diagnostic utility of exome sequencing followed by research reanalysis in human brain malformations.

This study aimed to determine the diagnostic yield of singleton exome sequencing and subsequent research-based trio exome analysis in children with a spectrum of brain malformations seen commonly in clinical practice. We recruited children ≤ 18 years old with a brain malformation diagnosed by magnetic resonance imaging and consistent with an established list of known genetic causes. Patients were ascertained nationally from eight tertiary paediatric centres as part of the Australian Genomics Brain Malformation Flagship. Chromosome microarray was required for all children, and those with pathogenic copy number changes were excluded. Cytomegalovirus polymerase chain reaction on neonatal blood spots was performed on all children with polymicrogyria with positive patients excluded. Singleton exome sequencing was performed through a diagnostic laboratory and analysed using a clinical exome sequencing pipeline. Undiagnosed patients were followed up in a research setting, including reanalysis of the singleton exome data and subsequent trio exome sequencing. A total of 102 children were recruited. Ten malformation subtypes were identified with the commonest being polymicrogyria (36%), pontocerebellar hypoplasia (14%), periventricular nodular heterotopia (11%), tubulinopathy (10%), lissencephaly (10%) and cortical dysplasia (9%). The overall diagnostic yield for the clinical singleton exome sequencing was 36%, which increased to 43% after research follow-up. The main source of increased diagnostic yield was the reanalysis of the singleton exome data to include newly discovered gene-disease associations. One additional diagnosis was made by trio exome sequencing. The highest phenotype-based diagnostic yields were for cobblestone malformation, tubulinopathy and lissencephaly and the lowest for cortical dysplasia and polymicrogyria. Pathogenic variants were identified in 32 genes, with variants in 6/32 genes occurring in more than one patient. The most frequent genetic diagnosis was pathogenic variants in TUBA1A. This study shows that over 40% of patients with common brain malformations have a genetic aetiology identified by exome sequencing. Periodic reanalysis of exome data to include newly identified genes was of greater value in increasing diagnostic yield than the expansion to trio exome. This study highlights the genetic and phenotypic heterogeneity of brain malformations, the importance of a multidisciplinary approach to diagnosis and the large number of patients that remain without a genetic diagnosis despite clinical exome sequencing and research reanalysis.

Distinct manifestations and potential mechanisms of seizures due to cortical versus white matter injury in children.

PURPOSE: To study seizure manifestations and outcomes in children with cortical versus white matter injury, differences potentially explaining variability of epilepsy in children with cerebral palsy. METHODS: In this population-based retrospective cohort study, MRIs of children with cerebral palsy due to ischemia or haemorrhage were classified according to presence or absence of cortical injury. MRI findings were then correlated with history of neonatal seizures, seizures during childhood, epilepsy syndromes, and seizure outcomes. RESULTS: Of 256 children studied, neonatal seizures occurred in 57 and seizures during childhood occurred in 93. Children with neonatal seizures were more likely to develop seizures during childhood, mostly those with cortical injury. Cortical injury was more strongly associated with (1) developing seizures during childhood, (2) more severe epilepsy syndromes (infantile spasms syndrome, focal epilepsy, Lennox-Gastaut syndrome), and (3) less likelihood of reaching > 2 years without seizures at last follow-up, compared to children without cortical injury. Children without cortical injury, mainly those with white matter injury, were less likely to develop neonatal seizures and seizures during childhood, and when they did, epilepsy syndromes were more commonly febrile seizures and self-limited focal epilepsies of childhood, with most achieving > 2 years without seizures at last follow-up. The presence of cortical injury also influenced seizure occurrence, severity, and outcome within the different predominant injury patterns of the MRI Classification System in cerebral palsy, most notably white matter injury. CONCLUSIONS: Epileptogenesis is understood with cortical injury but not well with white matter injury, the latter potentially related to altered postnatal white matter development or myelination leading to apoptosis, abnormal synaptogenesis or altered thalamic connectivity of cortical neurons. These findings, and the potential mechanisms discussed, likely explain the variability of epilepsy in children with cerebral palsy and epilepsy following early-life brain injury in general.

Neuroprotective Action of Tacrolimus before and after Onset of Neonatal Hypoxic-Ischaemic Brain Injury in Rats.

(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.

Developmental regression in children: Current and future directions.

Developmental regression describes when a child loses previously established skills, such as the ability to speak words and is most recognised in neurodevelopmental conditions including Autism; Developmental Epileptic Encephalopathies, such as Landau Kleffner syndrome, and genetic conditions such as Rett syndrome and Phelan McDermid syndrome. Although studies have reported developmental regression for over 100 years, there remain significant knowledge gaps within and between conditions that feature developmental regression. The certainty of evidence from earlier work has been limited by condition-specific studies, retrospective methodology, and inconsistency in the definitions and measures used for classification. Given prior limitations in the field, there is a paucity of knowledge about neurocognitive mechanisms, trajectories and outcomes for children with developmental regression, and their families. Here we provide a comprehensive overview, synthesise key definitions, clinical measures, and aetiological clues associated with developmental regression and discuss impacts on caregiver physical and mental health to clarify challenges and highlight future directions in the field.

Clinical actionability of genetic findings in cerebral palsy.

Background and objectives: Single gene mutations are increasingly recognized as causes of cerebral palsy (CP) phenotypes, yet there is currently no standardized framework for measuring their clinical impact. We evaluated Pathogenic/Likely Pathogenic (P/LP) variants identified in individuals with CP to determine how frequently genetic testing results would prompt changes in care. Methods: We analyzed published P/LP variants in OMIM genes identified in clinical (n = 1,345 individuals) or research (n = 496) cohorts using exome sequencing of CP patients. We established a working group of clinical and research geneticists, developmental pediatricians, genetic counselors, and neurologists and performed a systematic review of existing literature for evidence of clinical management approaches linked to genetic disorders. Scoring rubrics were adapted, and a modified Delphi approach was used to build consensus and establish the anticipated impact on patient care. Overall clinical utility was calculated from metrics assessing outcome severity if left untreated, safety/practicality of the intervention, and anticipated intervention efficacy . Results: We found 140/1,841 (8%) of individuals in published CP cohorts had a genetic diagnosis classified as actionable , defined as prompting a change in clinical management based on knowledge related to the genetic etiology. 58/243 genes with P/LP variants were classified as actionable; 16 had treatment options targeting the primary disease mechanism , 16 had specific prevention strategies , and 26 had specific symptom management recommendations. The level of evidence was also graded according to ClinGen criteria; 44.6% of interventions had evidence class "D" or below. The potential interventions have clinical utility with 97% of outcomes being moderate-high severity if left untreated and 62% of interventions predicted to be of moderate-high efficacy . Most interventions (71%) were considered moderate-high safety/practicality . Discussion: Our findings indicate that actionable genetic findings occur in 8% of individuals referred for genetic testing with CP. Evaluation of potential efficacy , outcome severity , and intervention safety / practicality indicates moderate-high clinical utility of these genetic findings. Thus, genetic sequencing to identify these individuals for precision medicine interventions could improve outcomes and provide clinical benefit to individuals with CP. The relatively limited evidence base for most interventions underscores the need for additional research.

Intrathecal magnesium delivery for Mg++-insensitive NMDA receptor activity due to GRIN1 mutation.

BACKGROUND: Mutations in the NMDA receptor are known to disrupt glutamatergic signaling crucial for early neurodevelopment, often leading to severe global developmental delay/intellectual disability, epileptic encephalopathy, and cerebral palsy phenotypes. Both seizures and movement disorders can be highly treatment-refractory. RESULTS: We describe a targeted ABA n-of-1 treatment trial with intrathecal MgSO4, rationally designed based on the electrophysiologic properties of this gain of function mutation in the GRIN1 NMDA subunit. CONCLUSION: Although the invasive nature of the trial necessitated a short-term, non-randomized, unblinded intervention, quantitative longitudinal neurophysiologic monitoring indicated benefit, providing class II evidence in support of intrathecal MgSO4 for select forms of GRIN disorders.

Redefining cerebral palsies as a diverse group of neurodevelopmental disorders with genetic aetiology.

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.

Some children with idiopathic toe walking display sensory processing difficulties but not all: A systematic review.

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.

Paroxysmal Nonepileptic Events in Children With Epilepsy and Cerebral Palsy.

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.

Multi-omics identifies large mitoribosomal subunit instability caused by pathogenic MRPL39 variants as a cause of pediatric onset mitochondrial disease.

MRPL39 encodes one of 52 proteins comprising the large subunit of the mitochondrial ribosome (mitoribosome). In conjunction with 30 proteins in the small subunit, the mitoribosome synthesizes the 13 subunits of the mitochondrial oxidative phosphorylation (OXPHOS) system encoded by mitochondrial Deoxyribonucleic acid (DNA). We used multi-omics and gene matching to identify three unrelated individuals with biallelic variants in MRPL39 presenting with multisystem diseases with severity ranging from lethal, infantile-onset (Leigh syndrome spectrum) to milder with survival into adulthood. Clinical exome sequencing of known disease genes failed to diagnose these patients; however quantitative proteomics identified a specific decrease in the abundance of large but not small mitoribosomal subunits in fibroblasts from the two patients with severe phenotype. Re-analysis of exome sequencing led to the identification of candidate single heterozygous variants in mitoribosomal genes MRPL39 (both patients) and MRPL15. Genome sequencing identified a shared deep intronic MRPL39 variant predicted to generate a cryptic exon, with transcriptomics and targeted studies providing further functional evidence for causation. The patient with the milder disease was homozygous for a missense variant identified through trio exome sequencing. Our study highlights the utility of quantitative proteomics in detecting protein signatures and in characterizing gene-disease associations in exome-unsolved patients. We describe Relative Complex Abundance analysis of proteomics data, a sensitive method that can identify defects in OXPHOS disorders to a similar or greater sensitivity to the traditional enzymology. Relative Complex Abundance has potential utility for functional validation or prioritization in many hundreds of inherited rare diseases where protein complex assembly is disrupted.

Harnessing neuroplasticity to improve motor performance in infants with cerebral palsy: a study protocol for the GAME randomised controlled trial.

INTRODUCTION: Cerebral palsy (CP) is the most common physical disability of childhood worldwide. Historically the diagnosis was made between 12 and 24 months, meaning data about effective early interventions to improve motor outcomes are scant. In high-income countries, two in three children will walk. This evaluator-blinded randomised controlled trial will investigate the efficacy of an early and sustained Goals-Activity-Motor Enrichment approach to improve motor and cognitive skills in infants with suspected or confirmed CP. METHODS AND ANALYSIS: Participants will be recruited from neonatal intensive care units and the community in Australia across four states. To be eligible for inclusion infants will be aged 3-6.5 months corrected for prematurity and have a diagnosis of CP or 'high risk of CP' according to the International Clinical Practice Guideline criteria. Eligible participants whose caregivers consent will be randomly allocated to receive usual care or weekly sessions at home from a GAME-trained study physiotherapist or occupational therapist, paired with a daily home programme, until age 2. The study requires 150 participants per group to detect a 0.5 SD difference in motor skills at 2 years of age, measured by the Peabody Developmental Motor Scales-2. Secondary outcomes include gross motor function, cognition, functional independence, social-emotional development and quality of life. A within-trial economic evaluation is also planned. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Sydney Children's Hospital Network Human Ethics Committee in April 2017 (ref number HREC/17/SCHN/37). Outcomes will be disseminated through peer-reviewed journal publications, presentations at international conferences and consumer websites. TRIAL REGISTRATION NUMBER: ACTRN12617000006347.

Acceptability of neural stem cell therapy for cerebral palsy: survey of the Australian cerebral palsy community.

BACKGROUND: Neural stem cells (NSCs) have the potential to engraft and replace damaged brain tissue, repairing the damaged neonatal brain that causes cerebral palsy (CP). There are procedures that could increase engraftment of NSCs and may be critical for efficacy, but hold notable risks. Before clinical trials progress, it is important to engage with the CP community to understand their opinions. The aim of this study was to determine the acceptability of NSC therapy for CP in the CP community. METHODS: Australian residents with CP and parents/carers of those with CP completed a questionnaire to determine their willingness to use NSCs from three sources (fetal, embryonic and induced pluripotent stem cells) and their willingness to undergo accompanying procedures (neurosurgery, immunosuppression) that carry potential risks. To further explore their views, participants also answered free text questions about their ethical concerns regarding the source of NSCs and their perceptions of meaningful outcomes following NSC treatment. RESULTS: In total, 232 responses were analyzed. Participants were willing to use NSCs from all three cell sources and were willing to undergo NSC therapy despite the need for neurosurgery and immunosuppression. Participants identified a range of outcome domains considered important following NSC treatment including gross motor function, quality of life, independence and cognitive function. CONCLUSIONS: Hypothetical NSC therapy was acceptable to the Australian CP community. This study has identified important findings from the CP community which can be used to inform future NSC research, including the design of clinical trials which may help to increase recruitment, compliance and participant satisfaction.

Epilepsy syndromes in cerebral palsy: varied, evolving and mostly self-limited.

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.

Persistent Inflammation in Cerebral Palsy: Pathogenic Mediator or Comorbidity? A Scoping Review.

Research has established inflammation in the pathogenesis of brain injury and the risk of developing cerebral palsy (CP). However, it is unclear if inflammation is solely pathogenic and primarily contributes to the acute phase of injury, or if inflammation persists with consequence in CP and may therefore be considered a comorbidity. We conducted a scoping review to identify studies that analyzed inflammatory biomarkers in CP and discuss the role of inflammation in the pathogenesis of CP and/or as a comorbidity. Twelve included studies reported a range of analytes, methods and biomarkers, including indicators of inflammatory status, immune function and genetic changes. The majority of controlled studies concluded that one or more systemic biomarkers of inflammation were significantly different in CP versus controls; most commonly serum or plasma cytokines such as tumor necrosis factor, Interleukin (IL)-6 and IL-10. In addition, differences in inflammation were noted in distinct subgroups of CP (e.g., those with varying severity). The available evidence supports the pathogenic role of inflammation and its ongoing role as a comorbidity of CP. This review shows that inflammation may persist for decades, driving functional impairment across development and into adulthood. However, inflammation is complex, thus further research will increase our understanding.

Making waves: The changing tide of cerebral palsy.

Cerebral palsy (CP) is a broad diagnosis unbound by aetiology and is based on a clinical examination demonstrating abnormalities of movement or posture. CP represents a static neurological condition, provided that neurodegenerative conditions, leukoencephalopathies and neuromuscular disorders are excluded. In paediatrics, the genetic conditions associated with CP are rapidly increasing, with primary and overlapping neurodevelopmental conditions perhaps better categorised by the predominant clinical feature such as CP, intellectual disability, autism spectrum disorder or epilepsy. Progress in molecular genetics may challenge what constitutes CP, but a genetic diagnosis does not negate the CP diagnosis. As clinicians working in the field, we discuss the changing tide of CP. Neuroimaging provides essential information through pattern recognition and demonstration of static brain changes. We present examples of children where a layered clinical diagnosis or dual aetiologies are appropriate. We also present examples of children with genetic causes of CP to highlight the challenges and limitations of neuroimaging to provide an aetiological diagnosis. In consultation with a geneticist, access to genomic testing (exome or genome sequencing) is now available in Australia under Medicare billing for children under the age of 10 with dysmorphic features, one or more major structural organ anomalies, (an evolving) intellectual disability or global developmental delay. We encourage the uptake of genomic testing in CP, because it can be difficult to tell whether a child has an environmental or genetic cause for CP. A specific genetic diagnosis may change patient management, reduce guilt and enable more distinctive research in the future to assist with understanding disease mechanisms.

Ganaxolone versus Phenobarbital for Neonatal Seizure Management.

OBJECTIVE: Seizures are more common in the neonatal period than at any other stage of life. Phenobarbital is the first-line treatment for neonatal seizures and is at best effective in approximately 50% of babies, but may contribute to neuronal injury. Here, we assessed the efficacy of phenobarbital versus the synthetic neurosteroid, ganaxolone, to moderate seizure activity and neuropathology in neonatal lambs exposed to perinatal asphyxia. METHODS: Asphyxia was induced via umbilical cord occlusion in term lambs at birth. Lambs were treated with ganaxolone (5mg/kg/bolus then 5mg/kg/day for 2 days) or phenobarbital (20mg/kg/bolus then 5mg/kg/day for 2 days) at 6 hours. Abnormal brain activity was classified as stereotypic evolving (SE) seizures, epileptiform discharges (EDs), and epileptiform transients (ETs) using continuous amplitude-integrated electroencephalographic recordings. At 48 hours, lambs were euthanized for brain pathology. RESULTS: Asphyxia caused abnormal brain activity, including SE seizures that peaked at 18 to 20 hours, EDs, and ETs, and induced neuronal degeneration and neuroinflammation. Ganaxolone treatment was associated with an 86.4% reduction in the number of seizures compared to the asphyxia group. The total seizure duration in the asphyxia+ganaxolone group was less than the untreated asphyxia group. There was no difference in the number of SE seizures between the asphyxia and asphyxia+phenobarbital groups or duration of SE seizures. Ganaxolone treatment, but not phenobarbital, reduced neuronal degeneration within hippocampal CA1 and CA3 regions, and cortical neurons, and ganaxolone reduced neuroinflammation within the thalamus. INTERPRETATION: Ganaxolone provided better seizure control than phenobarbital in this perinatal asphyxia model and was neuroprotective for the newborn brain, affording a new therapeutic opportunity for treatment of neonatal seizures. ANN NEUROL 2022;92:1066-1079.