BACKGROUND:Hypoxic ischaemic encephalopathy (HIE) is the most frequently occurring neonatal brain injury in term-born infants. Families affected by HIE can face significant breastfeeding and lactation challenges. AIMS:This systematic review aims to improve our understanding of these challenges and identify potential solutions by answering the question: What factors influence breastfeeding and lactation outcomes after neonatal HIE? METHODS:This systematic review used a convergent integrated analysis mixed methods design. Eleven databases were searched for qualitative, quantitative, and mixed methods papers meeting specified criteria (e.g., born ≥ 34 weeks gestation) in November 2022 and again in July 2023 and April 2025. Full methods are registered on PROSPERO https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023375506. Of the 3393 titles and abstracts screened, 455 were identified for full-text screening and 10 were included in the review. An additional seven papers were found via reference lists and citation checking, resulting in a total of 17 included studies. RESULTS:Five categories of potentially influencing factors were identified: infant medical factors, neuroprotective interventions, feeding during therapeutic hypothermia, support for expressing milk, and parent-infant closeness in the neonatal phase. However, significant evidence gaps were demonstrated, including the influence of environmental and social factors, interventions for lactation support and breastfeeding skills, and qualitative and mixed methods studies specifically focused on breastfeeding and lactation following neonatal HIE. CONCLUSION:Current research is insufficient to inform our understanding of factors influencing breastfeeding and lactation outcomes following HIE. High-quality breastfeeding and lactation-specific research is urgently needed to inform information sharing and intervention development for HIE-affected families.

BACKGROUND:Cerebral Palsy (CP) is an umbrella term for a group of permanent postural and movement conditions caused by non-progressive damage to the developing brain. Infants not identified with risk factors for CP around the time of birth are usually referred on from primary care after six months of age, essentially precluding early therapy. Candidacy, a seven-step dynamic theory, describes how individuals negotiate their eligibility for medical attention with themselves, others, and health services. This study aims to explore the CP diagnostic journey for community identified infants using the concept of candidacy. METHODS:Data was combined from two studies: an online survey of caregivers of children with CP about their earliest concerns and diagnosis journeys (n=255), and a series of interviews to support the development of a new tool to facilitate earlier identification of infants with emerging motor difficulties (11 parents, 11 health care professionals [HCPs]). A deductive thematic analysis was used with a semantic, critical realist approach. An initial analysis was framed by the Andersen Model of Total Patient delay, and then conceptualised using Candidacy. RESULTS:Participants had difficulties identifying whether their child needed medical attention, prompting online searches, and seeking advice from family and friends. HCP adjudications led to immediate or delayed referral, in which families continued their searches, reappearing at services until a referral was made. Once referred, families faced poor operating conditions, such as long waiting times. After learning the diagnosis criteria, participants began making requests for referral and navigated to private services if requests were denied. Participants felt that more information on infant development from a reliable source was needed to support new parents in raising their concerns to aid earlier identification. CONCLUSION:Participants identified personal lack of infant development knowledge as being the limiting factor to earlier referral. Further research is needed to develop materials relevant for the UK and to understand General Practitioner perspectives regarding provision of such materials.

Paired box 2 (PAX2)-related disorder, also known as renal coloboma syndrome, is a variably penetrant autosomal dominant condition, associated with renal and ophthalmological abnormalities. We report a child withPAX2-related disorder who presented atypically with acute ataxia on a background of stage 3 chronic kidney disease. Extensive biochemical, radiological and gene agnostic rapid trio exome sequencing was non-diagnostic. Identification of bilateral optic disc colobomas in the proband and his father raised the suspicion of an inheritedPAX2-related disorder. No causative variants were identified on a focused review of the filtered genomic data. Given the strong suspicion of an inherited monogenic disorder, whole genome trio sequencing was requested. Analysis assuming incomplete penetrance identified a paternally inheritedPAX2microdeletion encompassing exon 4. This case adds to evidence of a broaderPAX2-associated phenotype. It highlights the importance of a clinical genetics and mainstream interface when navigating and interpreting genetic testing.

To assess the clinical service provision of neonatal follow-up services in the UK in line with UK National Institute for Health and Care Excellence (NICE) guideline NG72, ‘Developmental follow-up of children and young people born preterm’. Design: Online survey. Setting: Neonatal units in England, Scotland and Wales (n = 187) in July– September 2022. Participants: Lead neonatal clinicians for neurodevelopmental follow-up. Responses were received from 154 neonatal units, representing 82 What this study hopes to add. How this study might affect research, practice, or policy.

Poor manual skills in children with Developmental Coordination Disorder (DCD) may be dependent on task complexity and due to difficulties in the automatization phase of the motor learning process. Increased task demands and the dual-task paradigm can be used to test these hypotheses. OBJECTIVES:We aim to investigate (1) manual dexterity abilities using increased levels of difficulty; (2) dual tasking using an experimental protocol of the Tyneside Pegboard Test (TPT). METHOD:Sixteen children with DCD and 16 age-matched typically developing (TD) children were included. Various experimental conditions of the TPT (unimanual, bimanual and dual task) were administered. The dual-task paradigm comprised a primary unimanual task and a cognitive task (auditory non-verbal task). Parents were asked to fill out the eConners questionnaire to report attentional difficulties. Repeated measures ANOVAs were used to compare possible differences in effects on the performance of the groups. Pearson correlation coefficients were calculated between dual-task performance and ADHD index of the eConners questionnaire. RESULTS:Children with DCD performed significantly worse in all task conditions (unimanual, bimanual, dual task) compared to TD children. In unimanual and bimanual conditions, they did no not present a higher impact of task constraints. Dual-task performances did not have a differential effect on groups and were not interfered by attentional difficulties. CONCLUSIONS:Children with DCD exhibit a general slowness in all TPT tasks. Our findings do not support the automatization deficit hypothesis.

The original description of cerebral palsy (CP) contained case histories suggesting that perinatal environmental stressors resulted in brain injury and neurodevelopmental disability. While there are clear associations between environmental impact on brain development and CP, recent studies indicate an 11% to 40% incidence of monogenic conditions in patients given a diagnosis of CP. A genetic diagnosis supports the delivery of personalized medicine. In this review, we describe how the Wnt pathway exemplifies our understanding of pathophysiology related to a gene variant (CTNNB1) found in some children diagnosed with CP. We cover studies undertaken to establish the baseline prevalence of monogenic conditions in populations attending CP clinics. We list factors indicating increased likelihood of a genomic diagnosis; and we highlight the need for a comprehensive, accurate, genotype-phenotype reference data set to aid variant interpretation in CP cohorts. We also consider the wider societal implications of genomic management of CP including significance of the diagnostic label, benefits and pitfalls of a genetic diagnosis, logistics, and cost.

BACKGROUND AND OBJECTIVES:Perinatal arterial ischemic stroke (PAIS) is a focal vascular brain injury presumed to occur between the fetal period and the first 28 days of life. It is the leading cause of hemiparetic cerebral palsy. Multiple maternal, intrapartum, delivery, and fetal factors have been associated with PAIS, but studies are limited by modest sample sizes and complex interactions between factors. Machine learning approaches use large and complex data sets to enable unbiased identification of clinical predictors but have not yet been applied to PAIS. We combined large PAIS data sets and used machine learning methods to identify clinical PAIS factors and compare this data-driven approach with previously described literature-driven clinical prediction models. METHODS:Common data elements from 3 registries with patients with PAIS, the Alberta Perinatal Stroke Project, Canadian Cerebral Palsy Registry, International Pediatric Stroke Study, and a longitudinal cohort of healthy controls (Alberta Pregnancy Outcomes and Nutrition Study), were used to identify potential predictors of PAIS. Inclusion criteria were term birth and idiopathic PAIS (absence of primary causative medical condition). Data including maternal/pregnancy, intrapartum, and neonatal factors were collected between January 2003 and March 2020. Common data elements were entered into a validated random forest machine learning pipeline to identify the highest predictive features and develop a predictive model. Univariable analyses were completed post hoc to assess the relationship between each predictor and outcome. RESULTS:A machine learning model was developed using data from 2,571 neonates, including 527 cases (20%) and 2,044 controls (80%). With a mean of 21 features selected, the random forest machine learning approach predicted the outcome with approximately 86.5% balanced accuracy. Factors that were selected a priori through literature-driven variable selection that were also identified as most important by the machine learning model were maternal age, recreational substance exposure, tobacco exposure, intrapartum maternal fever, and low Apgar score at 5 minutes. Additional variables identified through machine learning included in utero alcohol exposure, infertility, miscarriage, primigravida, meconium, spontaneous vaginal delivery, neonatal head circumference, and 1-minute Apgar score. Overall, the machine learning model performed better (area under the curve [AUC] 0.93) than the literature-driven model (AUC 0.73). DISCUSSION:Machine learning may be an alternative, unbiased method to identify clinical predictors associated with PAIS. Identification of previously suggested and novel clinical factors requires cautious interpretation but supports the multifactorial nature of PAIS pathophysiology. Our results suggest that identification of neonates at risk of PAIS is possible.

Introduction Early intervention (Ei) is recommended for infants at high risk of neurodevelopmental challenges. Ei SMART is an evidence-based clinical reasoning framework supporting infant development by integrating Sensory, Motor, Attention and regulation, and Relational development through healthcare professionals (HCPs) and parents working Together. Aim: To evaluate learning outcomes following Ei SMART training. Methods 34 staff members from one UK neonatal operational delivery network participated in face-to-face training, co-produced and co-presented by parents and HCPs via online modules/tutorials. Participants completed pre/post-training surveys. Questions quantified self-perceived understanding of Infant Development & Well-Being, Parent/Family Support and Engagement, and Staff Engagement & Well-Being. Total and Domain scores were compared pre/post-training. Results 33/34(97%) respondents completed both pre-and post-training surveys; one respondent was excluded (incomplete data). Median (IQR) post-training score was significantly increased (152(22) v 108(26) (p < 0.001), as were domain scores. Conclusion Ei SMART training provided measurable improvements in perceived learning for HCPs.

The English version of this invited editorial is available at: https://doi.org/10.1111/dmcn.15452.

The English version of this invited editorial is available at: https://doi.org/10.1111/dmcn.15452 .

Primary carnitine deficiency (PCD) is caused by pathogenic variants of the SLC22A5 gene, which encodes a transmembrane protein that functions as a high affinity carnitine transporter. Carnitine is essential for the transport of acyl-CoA, produced from fatty acids, into the mitochondria where they are oxidised to produce energy. We present the case history of an 8-year-old boy who presented with fever, lethargy, focal rhythmic (3 Hz) left wrist twitching, and severe encephalopathy. MRI brain showed basal ganglia involvement. Metabolic investigations revealed low serum carnitine; whole genome sequencing confirmed compound heterozygous SLC22A5 mutations. With carnitine replacement, intensive care support, and neurorehabilitation, he made a remarkable recovery, regaining independent breathing, speech, mobility, and hand use. Seizure presentation in PCD is rare and presentation with sustained focal myoclonus has not been previously reported. This case expands the known phenotype of PCD. Prompt carnitine replacement is imperative.

Background The adoption of video calls during the pandemic is seen as an innovation opportunity in early intervention occupational and physiotherapy delivery for infants with cerebral palsy. The aim of this work is to explore parent and therapist perspectives of communication and learning in early intervention via video calls, and co-produce knowledge for guidance of telehealth service delivery. Methods Data were taken from the larger ‘Optimise EI’ study. Data collection commenced prior to the pandemic. The flexibility of grounded theory methods enabled the exploration of parent and therapist engagement via video calls as it occurred naturalistically. Data are drawn from interviews (n=30) and focus groups (n=2) involving 14 parents and 15 therapists, and including two video cases, where multimodal interaction analysis was also undertaken. Results Parents reported increased engagement challenges relating to communication and learning due to interaction complexities via video calls. Video calls removed certain communication modes meaning that other modes were amplified to compensate. For example, parents were required to perform supplementary commentary while enacting therapeutic play with their child for the observing therapist. Visual information on video calls is critical for effective communication and learning because accurate interpretation is needed to undertake embodied actions. The simultaneous responsibility on parents to direct the camera while conducting the therapeutic activities created a particular challenge for visual interpretation. Camera positioning required constant parent awareness and decision making to accommodate the therapist’s visual perspective to ensure ongoing shared understanding of events. Traditional therapist-parent roles were disrupted by video calls. Positively, parents were more actively involved. Yet, parents reflected that the higher logistical requirements, in enhanced performative roles as ‘Actor-Directors’, detracted from their learning. Conclusion This research outlines the challenges that parents and therapists face to collaborative learning via video calls, which needs further consideration to optimise the potential of this format.

Many disorders encountered by neurologists are rare, life-changing, and not currently preventable. There are others that most of us do not encounter due to global public health strategies such as vaccination against polio. Then there are conditions we come across occasionally, which make us re-examine the role of policy in prevention. Two of these are late-onset vitamin K deficiency bleeding (VKDB) and bilirubin encephalopathy. Late-onset VKDB usually presents with intracranial bleeding in exclusively breastfed infants who have not received vitamin K supplementation. Mortality and morbidity are high. VKDB is essentially preventable with vitamin K supplementation, except in infants with liver disease. Vitamin K administration can be via a single intramuscular dose or one of various oral regimens. The American Academy of Pediatrics (AAP) policy statement recommends intramuscular administration.1 This is not surprising given the potential for vomiting, poor intestinal absorption, or lack of administration of oral doses. The AAP references high-quality information about VKDB for parents (https://www.cdc.gov/ncbddd/vitamink/index.html) and lists key discussion points in their supplement. Vitamin K supplementation is not mentioned in the 2021 National Institute for Health and Care Excellence (NICE) postnatal care guideline (NG194), though the 2021 antenatal care guideline (NG201) recommends that supplementation is discussed. UK-based neonatal units vary in their approach to prophylaxis, strategies also vary across Europe.2 Hospitals differ in the level of detail provided in written information regarding the risks associated with VKDB. This has implications for those refusing intramuscular administration and for compliance with oral regimens. Standardization of information provision and use of intramuscular vitamin K as the default approach seem achievable: a change in UK policy in this direction should be strongly considered. The risk of harm seems low: a previously reported association between intramuscular vitamin K and increased cancer risk was not replicable. Bilirubin encephalopathy (kernicterus) is a devastating consequence of severe neonatal jaundice. Typical features include choreoathetoid cerebral palsy, sensorineural hearing loss, and upward gaze paresis, often with preserved cognition. Neuroimaging shows signal change in the globus pallidus. Haemolysis is a major risk factor: guidelines for prevention and management of isoimmune haemolytic disease are well-established, and kernicterus is now rare. Nomograms exist indicating which jaundiced neonates should receive phototherapy or exchange transfusion based on serum bilirubin level, age (in hours), gestational age, and neurotoxicity risk factors. However, a major variation in policy relates to screening via measurement of bilirubin levels in the first days of life. The 2015 UK National Screening Committee report, prepared by Bazian Ltd., led to a recommendation against universal screening for kernicterus. In contrast, the 2022 AAP Clinical Practice Guideline states that bilirubin levels should be measured in all neonates between 24 hours and 48 hours after birth or before discharge, whichever is earlier.3 A large study from the Kaiser Permanente data set provides illuminating data on kernicterus over a 16-year period.4 Neurological outcomes of infants with at least one bilirubin measurement above the level recommended for exchange transfusion (‘exposed’) were compared with a sample of unexposed infants. Of those unexposed, none developed kernicterus. Of those exposed, three had kernicterus: two (both with gestational age of 36–37 weeks) had glucose-6-phosphate dehydrogenase (G6PD) deficiency and the third had suffered hypoxic-ischaemic damage. All three had bilirubin levels well above the limit for exchange transfusion. The risks of exchange transfusion are well-known, but recently an association between phototherapy and a small increase in epilepsy risk was identified.5 Where does this leave the prevention of kernicterus? Swift identification and management of neonates with G6PD deficiency would likely help, if it were possible, but what about universal bilirubinometry? The National Screening Committee website indicates that their recommendation regarding kernicterus is due to be updated. Wide consultation will be welcomed. Not required.

Access the whole slide scan at http://image.upmc.edu:8080/NeuroPathology/BPA/BPA-20-11-288/view.apml. A term-born boy presented at age 2 months with the first episode of focal seizure, involving the left leg, and concern from a few weeks of age regarding delayed development. There was antenatal polyhydramnios without accompanying foetal abnormalities. He had never fixed, followed or cried. He was the first child of non-consanguineous parents with no relevant family history. Examination revealed weight <0.4th centile, length 9th centile, relative macrocephaly (50th centile), generalised hypertonia and absent oculocephalic reflexes with spared pupillary responses. He could suck but not grimace to stimuli. Hypertelorism and mild micrognathia were noted. MRI with contrast showed disseminated, bilateral white matter changes with frontal sparing (Figure 1, Panel A), leptomeningeal and brain stem enhancement. Post-contrast enhancement was prominent in areas, including the optic chiasm, mammillary bodies and tectum (Figure 1, Panel B). There were no intramedullary lesions, although there was enhancement along the surface of the conus medullaris and the cauda equina. Cerebral aqueduct narrowing with lateral and third ventricle hydrocephalus was present. Electroencephalogram (EEG) showed a diffusely slowed background, with runs of seizure activity. Craniotomy, brain biopsy and third ventriculostomy were performed. Brain biopsy was small, taken from the tuber cinereum. The biopsy showed glial tissue and Rosenthal-like granular intracytoplasmic deposits in the cell bodies, which raised a broad list of differential diagnoses. However, the biopsy material was limited and in the context of the clinical picture, a low-grade glioma remained a possible diagnosis. No BRAF mutation in exon 15 or KIAA1549:BRAF fusion transcript was detected. Re-biopsy was considered however not performed as there was a high risk of morbidity including damage to visual pathways. Our patient was commenced on vincristine and carboplatin, which is standard first-line chemotherapy for low-grade glioma. He had tolerable chemotherapy side effects including culture-positive febrile neutropenia treated with intravenous antibiotics. The patient experienced recurrent seizures over 8 wk manifested by left eye deviation and tonic upper limb posturing, worsening white matter changes and hydrocephalus, requiring a ventriculoperitoneal shunt. Subsequent EEGs demonstrated frequent sustained seizure activity from different hemispheric foci. Nasogastric feeding was commenced as a result of feed intolerance and vomiting. He deteriorated further with status epilepticus, requiring anticonvulsants, intubation and ventilation. Following extensive discussion with the team and the family, ventilatory support was withdrawn and the patient expired. At autopsy, the brain showed mild cortical atrophy and dilated lateral ventricles with periventricular leukomalacia. The third ventricle was dilated and the aqueduct narrowed. Diffuse subcortical white matter change was seen in the parietal and temporal regions of the cerebrum, hypothalamic-chiasmatic region, basal ganglia, thalamus and sub-insular regions, with focal cystic degeneration. The cerebellum and brain stem were pale and appeared yellow, granular and cavitary (Figure 2, Panels A,B). Brain weight was 749 g (Box 1). Perivascular Rosenthal fibres were seen, together with prominent subpial Rosenthal fibres, occasional glial cells with eosinophilic granules (Figure 2, Panel C [20× magnification], Panel D [40× magnification]). Subependymal regions and subpial areas also contained astrocytic cells with granular eosinophilic inclusions (figures not shown). Representative sections of the supratentorial pathology, stained with Luxol fast blue combined with periodic acid-Schiff (LFB-PAS), show characteristic blue staining of Rosenthal fibres (Right parietal lobe, Figure 2, Panels E,F). Neonatal Alexander disease. The clinical presentation, atypical imaging and biopsy findings caused diagnostic uncertainty, leading to a decision to treat as low-grade glioma pending definitive diagnosis. Genetic testing, available post-mortem, demonstrated a GFAP pathogenic germline variant (c.716G>T p.(Arg239Leu)). Characteristic pathological features at autopsy included Rosenthal fibres in astrocyte cell bodies. Parental testing in his asymptomatic mother showed maternal somatic mosaicism for this variant, with potential implications for maternal health and future pregnancies. Therefore, the autopsy findings and germline GFAP sequencing sent prior to death confirmed Alexander disease. Alexander disease is an autosomal-dominant leukodystrophy caused by a mutation in the GFAP gene, which leads to gain of function and accumulation of abnormal protein that impairs astrocyte function [1]. Typical clinical features of neonatal Alexander disease are hydrocephalus, because of cerebral aqueduct stenosis, and persistent seizures as seen in our case [2]. The mutation is common de novo [1] and to our knowledge, maternal somatic mosaicism has not been previously reported. The specific finding of Rosenthal-like granular intracytoplasmic deposits in the cell bodies from the biopsy raised the possibility of Alexander disease. Rosenthal fibres can be found in low-grade glial tumours, reactive gliosis, focal cortical dysplasia, fucosidosis, giant axonal neuropathy and Alexander disease. The presence of Rosenthal-like material in astrocyte cell bodies (as well as the more usual cell processes) is typical of Alexander disease [3]. The atypical radiological findings led to the consideration of neoplasia or a metabolic disorder. The rapidly progressive imaging changes, associated contrast enhancement and lack of frontal involvement were more suggestive of malignancy. The bilateral symmetrical involvement and age of onset were however against a diffuse neoplastic process and more consistent with a metabolic disorder. Clinicians and pathologists need to consider Alexander disease in cases where bilateral widespread white matter changes are observed in association with Rosenthal fibres. In addition, the presence of Rosenthal-like granular glial inclusions in biopsies merits consideration of Alexander disease, even if characteristic Rosenthal fibres are absent. Diffuse leptomeningeal enhancement and lack of frontal leukoencephalopathy were atypical for Alexander disease and raised concern for a disseminated malignancy. Suggestive features for Alexander disease in this case were contrast enhancement in the brainstem, optic chiasm and meninges and especially Rosenthal fibres and Rosenthal-like inclusions in astrocyte cell bodies. Early use of genetic testing is recommended for diagnostic certainty, to guide patient management and parental counselling. The authors have no conflicts of interest to declare. Marion K Mateos drafted and revised the manuscript, with input from all authors. Nikhil Birdi and Dipayan Mitra generated the radiology case images and commentary. Anna P. Basu provided neurology input. Michael Wright provided genetic expertise regarding the germline variant. Abhijit Joshi, Srinivas Annavarapu and Thomas S. Jacques provided pathology input and review. Abhijit Joshi and Srinivas Annavarapu generated the pathology case images. Simon Bailey provided expert clinical oversight. All authors approved the final manuscript. Details for the germline GFAP pathogenic variant are included in the text.

Spanish , Portuguese & French translation of this Invited Editorial is available in the online issue. Video Podcast: https://youtu.be/DL8Eq7I6MxQ

BACKGROUND AND OBJECTIVES:Pathogenic STXBP1 variants cause a severe early-onset developmental and epileptic encephalopathy (STXBP1-DEE). We aimed to investigate the natural history of STXBP1-DEE in adults focusing on seizure evolution, the presence of movement disorders, and the level of functional (in)dependence.METHODS:In this observational study, patients with a minimum age of 18 years carrying a (likely) pathogenic STXBP1 variant were recruited through medical genetics departments and epilepsy centers. Treating clinicians completed clinical questionnaires and performed semistructured video examinations while performing tasks from the (modified) Unified Parkinson Disease Rating Scale when possible.RESULTS:Thirty adult patients were included for summary statistics, with video recordings available for 19 patients. The median age at last follow-up was 24 years (range 18-58 years). All patients had epilepsy, with a median onset age of 3.5 months. At last follow-up, 80% of adults had treatment-resistant seizures despite long periods of seizure freedom in 37%. Tonic-clonic, focal, and tonic seizures were most frequent in adults. Epileptic spasms, an unusual feature beyond infancy, were present in 3 adults. All individuals had developmental impairment. Periods of regression were present in 59% and did not always correlate with flare-ups in seizure activity. Eighty-seven percent had severe or profound intellectual disability, 42% had autistic features, and 65% had significant behavioral problems. Video examinations showed gait disorders in all 12 patients able to walk, including postural abnormalities with external rotation of the feet, broad-based gait, and asymmetric posture/dystonia. Tremor, present in 56%, was predominantly of the intention/action type. Stereotypies were seen in 63%. Functional outcome concerning mobility was variable ranging from independent walking (50%) to wheelchair dependence (39%). Seventy-one percent of adults were nonverbal, and all were dependent on caregivers for most activities of daily living.DISCUSSION:STXBP1-DEE warrants continuous monitoring for seizures in adult life. Periods of regression are more frequent than previously established and can occur into adulthood. Movement disorders are often present and involve multiple systems. Although functional mobility is variable in adulthood, STXBP1-DEE frequently leads to severe cognitive impairments and a high level of functional dependence. Understanding the natural history of STXBP1-DEE is important for prognostication and will inform future therapeutic trials.