Associations of Neonatal Noncardiac Surgery with Brain Structure and Neurodevelopment: A Prospective Case-Control Study.

OBJECTIVE: To examine the associations of neonatal noncardiac surgery with newborn brain structure and neurodevelopment at 2 years of age. STUDY DESIGN: Infants requiring neonatal noncardiac surgery for congenital diaphragmatic hernia, esophageal atresia, or anterior abdominal wall defect were compared with infants who did not require surgery, matched for sex, gestation at birth, and postmenstrual age at magnetic resonance imaging. Cerebral magnetic resonance imaging was performed at a mean (SD) postmenstrual age of 41.6 (1.7) weeks. Images were assessed qualitatively for brain maturation and injury and quantitatively for measures of brain size, cerebrospinal fluid spaces, and global abnormality. Neurodevelopment was then assessed at 2 years using the Bayley Scales of Infant and Toddler Development, 3rd edition. RESULTS: Infants requiring surgery (n = 39) were 5.9 times (95% CI, 1.9-19.5; P < .01) more likely to have delayed gyral maturation and 9.8 times (95% CI, 1.2-446; P = .01) more likely to have white matter signal abnormalities compared with controls (n = 39). Cases were more likely to have higher global abnormality scores, smaller biparietal diameters, and larger ventricular sizes than controls. Infants who had surgery had lower mean composite scores in the language (mean difference, -12.5; 95% CI, -22.4 to -2.7) and motor domains (mean difference, -13.4; 95% CI, -21.1 to -5.6) compared with controls. CONCLUSIONS: Infants requiring neonatal noncardiac surgery have smaller brains with more abnormalities compared with matched controls and have associated neurodevelopmental impairment at 2 years of age. Prospective studies with preoperative and postoperative imaging would assist in determining the timing of brain injury.

Neonatal neuroimaging after repair of congenital diaphragmatic hernia and long-term neurodevelopmental outcome.

Objective: Previous outcome reports of congenital diaphragmatic hernia (CDH) have described neuroimaging anomalies and neurodevelopmental impairment. However, the link between imaging and outcome has not been described. We aimed to determine whether routine postoperative neonatal neuroimaging in infants with CDH detects later neurodevelopmental impairment. Methods: In a prospective cohort study within a clinical service in The Royal Children's Hospital Newborn Intensive Care. Cerebral ultrasound was performed in 81 children and MRI in 57 children who subsequently underwent neurodevelopmental follow-up after surgery for CDH. MRI scans were analyzed using a scoring system designed to identify injury, maturation and volume loss. Neurodevelopmental assessment occurred at 2 years (48) and neurocognitive assessment at 5 years (26) and/or 8 years (27). Brain imaging scores corrected for gestational age at scan time were correlated with outcome measures, adjusting for known clinical confounders. Results: Clinically significant findings were identified on MRI of 16 (28%) infants. Mean scores were in the normal range for all domains assessed at each age. Language impairment was seen in 23% at 2 years and verbal intellectual impairment in 25% at 8 years. Mean cognitive scores were lower in 2-year-old children with white matter injury on MRI (p=0.03). Mean motor scores were lower in 2-year-old children with brain immaturity (p=0.01). Associations between MRI and 5-year and 8-year assessments were no longer significant when adjusting for known clinical confounders. Conclusions: Neuroimaging abnormalities were associated with worse neurodevelopment at 2 years, but not with later neurocognitive outcomes, after accounting for clinical risk factors.

Cognition and behaviour in children with congenital abdominal wall defects.

AIM: To characterise neurodevelopment at age two years and cognition and behaviour at age five years in children born with abdominal wall defects (gastroschisis or exomphalos). STUDY DESIGN: Participants were treated as neonates for gastroschisis or exomphalos and invited for routine clinical follow-up at ages two and five years. Thirty-nine two year-olds and 20 five year-olds with gastroschisis and 20 two year-olds and 10 five year-olds with exomphalos returned for age-appropriate assessments of development (two years) and intellectual functioning (IQ), executive function, and behavioural problems. Results were compared with normative data from the tests and published data from local term-born children. RESULTS: For both gastroschisis and exomphalos two year-olds, neurodevelopment was in line with the test normative data, but below the level of local normative data for all domains (effect sizes from -0.4 to -1.4 standard deviations). At five years, children with gastroschisis performed similarly to the normative mean for IQ but had high rates of various executive functioning problems on parent report (18-41% compared with 7% expected from norms). There was also a tendency for increased frequency of internalising problems (33% compared with normative expectation of 16%). Five year-olds with exomphalos also performed similarly to the normative mean for IQ and had low rates of executive and behavioural problems. CONCLUSIONS: Survivors of gastroschisis and exomphalos may be at risk of poor neurodevelopment in toddlerhood, depending on the reference group, and children with gastroschisis may be particularly at risk for executive functioning difficulties despite an IQ within normal limits.

Successful subcutaneous glucagon use for persistent hypoglycaemia in congenital hyperinsulinism.

Abstract Congenital hyperinsulinism (CHI) results from inappropriate excessive insulin secretion by the beta cells in the pancreas. A wide clinical spectrum of disease exists and a genetic diagnosis is now possible for approximately 50% of affected children. We describe a patient with atypical diffuse CHI caused by mosaic ABCC8 mutation inheritance, unmasked by paternal uniparental disomy. Hypoglycaemia persisted despite two subtotal pancreatectomies and trials of diazoxide and nifedipine were unsuccessful. Octreotide resulted in anaphylaxis, precluding its use. Continuous subcutaneous glucagon infusion was successful in restoring normoglycaemia and attenuating weight gain, with concomitant improvement of developmental milestones. No adverse effects have been encountered after >12 months of therapy. Administration problems (e.g., line crystallisation) may complicate continuous glucagon therapy; hence a practical description of infusion constitution is included. We recommend consideration of continuous subcutaneous glucagon infusion as a therapeutic option for persistent refractory hypoglycaemia in CHI.

"Stiff neonate" with mitochondrial DNA depletion and secondary neurotransmitter defects.

Mitochondrial disorders comprise a heterogenous group. A neonate who presented with episodes of severe truncal hypertonia and apnea progressed to a hypokinetic rigid syndrome characterized by hypokinesia, tremulousness, profound head lag, absent suck and gag reflexes, brisk deep tendon reflexes, ankle and jaw clonus, and evidence of autonomic dysfunction. Analysis of cerebrospinal fluid neurotransmitters from age 7 weeks demonstrated low levels of amine metabolites (homovanillic acid and 5-hydroxyindoleacetic acid), tetrahydrobiopterin, and pyridoxal phosphate. Mitochondrial DNA quantitative studies on muscle homogenate demonstrated a mitochondrial DNA depletion disorder. Respiratory chain enzymology demonstrated decreased complex IV activity. Screening for mitochondrial DNA rearrangement disorders and sequencing relevant mitochondrial genes produced negative results. No clinical or biochemical response to treatment with pyridoxal phosphate, tetrahydrobiopterin, or l-dopa occurred. The clinical course was progressive, and the patient died at age 19 months. Mitochondrial disorders causing secondary neurotransmitter diseases are usually severe, but are rarely reported. This diagnosis should be considered in neonates or infants who present with hypertonia, hypokinesia rigidity, and progressive neurodegeneration.