Risk Factors for Perinatal Arterial Ischemic Stroke: A Machine Learning Approach.

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.

Broadening the Spectrum of SLC22A5 Phenotype: Primary Carnitine Deficiency Presenting with Focal Myoclonus.

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.

Early intervention programmes for infants at high risk of atypical neurodevelopmental outcome.

The purpose of this review is to present a new framework, EI SMART (early intervention: sensorimotor development, attention and regulation, relationships, and therapist support) for identifying key components that could contribute to more effective interventions for infants at high risk of atypical neurodevelopmental outcome. We present a clinical consensus of current challenges and themes in early intervention, based on multidisciplinary group discussions, including parents of high-risk infants, supported by a literature review. Components to include in early intervention programmes are: (1) promotion of self-initiated, developmentally appropriate motor activity; (2) supporting infant self-regulation and the development of positive parent-infant relationships; and (3) promotion of early communication skills, parent coaching, responsive parenting, and supporting parental mental well-being. Such multimodal programmes may need to be evaluated as a package. WHAT THIS PAPER ADDS: Early intervention programmes should address sensorimotor development, attention, self-regulation, and early communication skills. Therapist input to the programme should include parent coaching and support for parental mental well-being.

PROGRAMAS DE INTERVENCIÓN TEMPRANA PARA LACTANTES CON ALTO RIESGO DE TRATARNOS DEL DESARROLLO NEUROLÓGICO: El propósito de esta revisión es presentar un nuevo marco, EI SMART (intervención temprana: desarrollo sensoriomotor, atención y regulación, relaciones y apoyo del terapeuta) para identificar componentes clave que podrían contribuir a intervenciones más efectivas para los bebés con alto riesgo de desarrollar un trastorno del neurodesarrollo. Presentamos un consenso clínico de los desafíos y temas actuales en la intervención temprana, basados ​​en discusiones grupales multidisciplinares, incluidos los padres de bebés con alto riesgo, respaldados por una revisión de la literatura. Los componentes para incluir en los programas de intervención temprana son (1) la promoción de actividades motoras autoiniciadas y apropiadas para el desarrollo; (2) apoyar la autorregulación infantil y el desarrollo de relaciones positivas entre padres e infantes; (3) promoción de las habilidades de comunicación temprana, entrenamiento de padres, crianza responsable y apoyo al bienestar mental de los padres. Es posible que dichos programas multimodales deban evaluarse como un paquete terapéutico.

PROGRAMAS DE INTERVENÇÃO PRECOCE PARA CRIANÇAS EM ALTO RISCO DE RESULTADO ANORMAL DO DESENVOLVIMENTO: O propósito desta revisão é apresentar um novo formato: EI SMART (intervenção precoce: desenvolvimento sensóriomotor, atenção e regulação, relacionamentos, e apoio do terapeuta) para identificar componentes centrais que podem contribuir para intervenções mais efetivas em lactentes de alto risco. Apresentamos um consenso clínico dos desafios correntes e temas em intervenção precoce, com base em discussões interdisciplinares, incluindo pais de lactentes de alto risco, com apoio de uma revisão de literatura. Os componentes a serem incluídos em programas de intervenção precoce são 1) promoção de atividade motora auto-iniciada apropriada para o desenvolvimento; 2) suporte para a auto-regulação do lactente e desenvolvimento de relações pais-filhos positivas; 3) promoção de habilidades precoces de comunicação, suporte aos pais, parentalidade responsável, e suporte ao bem estar mental dos pais. Tais programas multimodais podem precisar ser avaliados em forma de um pacote.

Current Therapeutic Management of Perinatal Stroke with a Focus on the Upper Limb: A Cross-Sectional Survey of UK Physiotherapists and Occupational Therapists.

AIM: To determine current UK pediatric physiotherapist (PT) and occupational therapist (OT) management of perinatal stroke. DESIGN: Web-based cross-sectional survey. METHODS: Participants were members of the Association of Paediatric Chartered Physiotherapists and Occupational Therapists specialist section: children young people and families working with infants. Items covered prioritization of referrals, assessments, therapy approaches aimed at the upper limb, and parental support. RESULTS: 179 therapists responded. 87.2% of PTs and 63.0% of OTs managed infants with perinatal stroke. Infants with clinical signs of motor dysfunction at referral were prioritized for early initial assessment. The most frequently used assessments were the Alberta Infant Motor Scale (AIMS) and Bayley Scales of Infant Development (BSID). Of PTs and OTs, 41.9 and 40.0% used no standardized assessments. Frequently used therapy interventions were Bobath/Neurodevelopmental Therapy (NDT), positioning aids and passive movements. 88.1% of therapists would choose a bilateral rather than unilateral (affected side) therapy approach for infants with perinatal stroke aged up to 6 months. Of PTs and OTs, 56.9 and 57.1% provided psychological support to families. CONCLUSIONS: Assessment and provision of therapy services following perinatal stroke is variable. Increased use of standardized assessments and centralized data collection regarding service provision for high-risk infants is recommended.

Human neural stem cells dispersed in artificial ECM form cerebral organoids when grafted in vivo.

Human neural stem cells (hNSC) derived from induced pluripotent stem cells can be differentiated into neurons that could be used for transplantation to repair brain injury. In this study we dispersed such hNSC in a three-dimensional artificial extracellular matrix (aECM) and compared their differentiation in vitro and following grafting into the sensorimotor cortex (SMC) of postnatal day (P)14 rat pups lesioned by localised injection of endothelin-1 at P12. After 10-43 days of in vitro differentiation, a few cells remained as PAX6+ neuroprogenitors but many more resembled post-mitotic neurons expressing doublecortin, ß-tubulin and MAP2. These cells remained dispersed throughout the ECM, but with extended long processes for over 50 µm. In vivo, by 1 month post grafting, cells expressing human specific markers instead organised into cerebral organoids: columns of tightly packed PAX6 co-expressing progenitor cells arranged around small tubular lumen in rosettes, with a looser network of cells with processes around the outside co-expressing markers of immature neurons including doublecortin, and CTIP2 characteristic of corticofugal neurons. Host cells also invaded the graft including microglia, astrocytes and endothelial cells forming blood vessels. By 10 weeks post-grafting, the organoids had disappeared and the aECM had started to break down with fewer transplanted cells remaining. In vitro, cerebral organoids form in rotating incubators that force oxygen and nutrients to the centre of the structures. We have shown that cerebral organoids can form in vivo; intrinsic factors may direct their organisation including infiltration by host blood vessels.

The Tyneside Pegboard Test: development, validation, and observations in unilateral cerebral palsy.

AIM: The aims of this study were twofold: first, to develop and validate a timed test of unimanual and bimanual dexterity suitable for those with disability affecting hand function; second, to explore relationships between unimanual and bimanual completion times. METHOD: We developed the Tyneside Pegboard Test (TPT), an electronically timed test with three peg sizes, incorporating an asymmetrical bimanual task. Nine hundred and seventy-four participants (455 males, 519 females; age range 4-80y) provided normative data. Test-retest reliability and construct validity were assessed (50 adults: 14 males, 36 females; 15-73y) on two occasions 2 weeks apart. Bimanual and unimanual completion times were measured in 87 children (51 males, 36 females) with unilateral cerebral palsy (CP) and 498 individuals in a comparison group (238 males, 260 females; 5-15y). RESULTS: The comparison group showed an asymmetrical U-shaped relationship between completion times and age. Intraclass correlation coefficients ranged from 0.74 to 0.91, indicating moderate test-retest reliability. There was a negative relationship between average TPT bimanual times and Purdue pegboard bimanual scores (Spearman's rho -0.611, degrees of freedom 44, p<0.001). Children with unilateral CP had greater prolongation of bimanual than unimanual completion times compared with the comparison group (mean difference 20.31s, 95% confidence interval 18.13-22.49, p<0.001). INTERPRETATION: The TPT is accessible for those with impaired hand function. Children with unilateral CP demonstrated disproportionate bimanual deficits, even allowing for unimanual dexterity: this has implications for therapy. WHAT THIS PAPER ADDS: We developed an adapted, electronically timed 9-hole pegboard test. Our modifications facilitate use by those with disability affecting hand function. The test incorporates an asymmetrical bimanual task. Children with unilateral cerebral palsy showed disproportionate bimanual dexterity deficits even allowing for unimanual dexterity.

Structural connectivity in a paediatric case of anarchic hand syndrome.

BACKGROUND: "Anarchic hand" is a rare condition characterised by non-volitional, goal-directed movements of one arm. We report a case with analysis of structural and functional connectivity. CASE PRESENTATION: A 15 year old girl developed intermittent symptoms of intermanual conflict or anarchic hand as a result of traumatic brain injury during which she sustained a callosal bleed. Resting-state fMRI and DTI tractography were performed at a stage when symptoms had largely resolved. CONCLUSION: Structural connectivity between homologous superior frontal areas and functional connectivity between homologous posterior cingulate areas were significantly reduced, which may have contributed to causation. Tractography demonstrated new indirect connections between supplementary motor areas via the cerebellum, which we propose contributed to symptom resolution.

Early intervention after perinatal stroke: opportunities and challenges.

Perinatal stroke is the most common cause of hemiplegic cerebral palsy. No standardized early intervention exists despite evidence for a critical time window for activity-dependent plasticity to mould corticospinal tract development in the first few years of life. Intervention during this unique period of plasticity could mitigate the consequences of perinatal stroke to an extent not possible with later intervention, by preserving the normal pattern of development of descending motor pathways. This article outlines the broad range of approaches currently under investigation. Despite significant progress in this area, improved early detection and outcome prediction remain important goals.

Non-invasive ventilation for severe bronchiolitis: analysis and evidence.

OBJECTIVES: (1) To examine whether infants with severe bronchiolitis, fulfilling criteria for further respiratory support, could be managed outside a Pediatric Intensive Care Unit (PICU) with non-invasive ventilation (NIV) alone. (2) To study the characteristics, clinical course and outcome of NIV responders and non responders to assess safety and efficacy and inform guideline construction. HYPOTHESIS: Infants with severe bronchiolitis can be safely managed with NIV outside a PICU. STUDY DESIGN: Retrospective case review. PATIENT SELECTION: Cohort of infants with objective evidence of severe bronchiolitis requiring respiratory support nursed in a Pediatric High Dependency Unit (PHDU) and/or Intensive Care Unit (ICU) between 2001 and 2007. METHODOLOGY: Analysis of patient characteristics and respiratory parameters at admission and initiation of ventilation, changes after 2 and 4 hr of NIV or invasive ventilation, complications, short and long-term outcomes were analyzed. RESULTS: One thousand and thirty-five infants with bronchiolitis were admitted with 67 ventilation episodes identified from 65 patients. Fifty-five episodes, including 34 with apnea, were treated exclusively with NIV. Six infants failed to respond and were invasively ventilated. Six patients were invasively ventilated at presentation. Non-responders had a significantly higher rate of bacterial infection. Significant improvements in respiratory parameters in responders occurred by 2 hr and sustained at 4 hr. Duration of hospital stay, ventilation requirement and oxygen requirement were significantly shorter in responders. Short and longer-term follow up data did not identify any adverse effects related to NIV. CONCLUSIONS: NIV was effective in 80% of infants receiving respiratory support for severe bronchiolitis.

Cystic fibrosis presenting with bilateral facial palsy.

A 15-week old male infant presented with bilateral lower motor neuron facial palsy of unknown cause. Subsequently his growth deteriorated and he developed progressively worsening cough and wheeze. A diagnosis of cystic fibrosis was confirmed and hypovitaminosis A detected. Improvement of the facial palsy was noted following standard management of cystic fibrosis including vitamin A supplementation.