Objective To determine the relationship between brain abnormalities on newborn magnetic resonance imaging (MRI) and neurodevelopmental impairment at 7 years of age in very preterm children. Study ...design A total of 223 very preterm infants (<30 weeks of gestation or <1250 g) born at Melbourne's Royal Women's Hospital had a brain MRI scan at term equivalent age. Scans were scored using a standardized system that assessed structural abnormality of cerebral white matter, cortical gray matter, deep gray matter, and cerebellum. Children were assessed at 7 years on measures of general intelligence, motor functioning, academic achievement, and behavior. Results One hundred eighty-six very preterm children (83%) had both an MRI at term equivalent age and a 7-year follow-up assessment. Higher global brain, cerebral white matter, and deep gray matter abnormality scores were related to poorer intelligence quotient (IQ) ( P s < .01), spelling ( P s < .05), math computation ( P s < .01), and motor function ( P s < .001). Higher cerebellum abnormality scores were related to poorer IQ ( P = .001), math computation ( P = .018), and motor outcomes ( P = .001). Perinatal, neonatal, and social confounders had little effect on the relationships between the MRI abnormality scores and outcomes. Moderate-severe global abnormality on newborn MRI was associated with a reduction in IQ (−6.9 points), math computation (−7.1 points), and motor (−1.9 points) scores independent of the other potential confounders. Conclusions Structured evaluation of brain MRI at term equivalent is predictive of outcome at 7 years of age, independent of clinical and social factors.
Abnormalities on magnetic resonance imaging scans are common both before and after surgery for congenital heart disease in early infancy. The aim of this study was to prospectively investigate the ...nature, timing, and consequences of brain injury on magnetic resonance imaging in a cohort of young infants undergoing surgery for congenital heart disease both with and without cardiopulmonary bypass.
A total of 153 infants undergoing surgery for congenital heart disease at <8 weeks of age underwent serial magnetic resonance imaging scans before and after surgery and at 3 months of age, as well as neurodevelopmental assessment at 2 years of age. White matter injury (WMI) was the commonest type of injury both before and after surgery. It occurred in 20% of infants before surgery and was associated with a less mature brain. New WMI after surgery was present in 44% of infants and at similar rates after surgery with or without cardiopulmonary bypass. The most important association was diagnostic group (P<0.001). In infants having arch reconstruction, the use and duration of circulatory arrest were significantly associated with new WMI. New WMI was also associated with the duration of cardiopulmonary bypass, postoperative lactate level, brain maturity, and WMI before surgery. Brain immaturity but not brain injury was associated with impaired neurodevelopment at 2 years of age.
New WMI is common after surgery for congenital heart disease and occurs at the same rate in infants undergoing surgery with and without cardiopulmonary bypass. New WMI is associated with diagnostic group and, in infants undergoing arch surgery, the use of circulatory arrest.
ObjectiveHistorical cohort studies have reported adverse neurodevelopment following cardiac surgery during early infancy. Advances in surgical techniques and perioperative care have coincided with ...updating of neurodevelopmental assessment tools. We aimed to determine perioperative risk factors for impaired neurodevelopment at 2 years following surgery for congenital heart disease (CHD) in early infancy.Design and patientsWe undertook a prospective longitudinal study of 153 full-term infants undergoing surgery for CHD before 2 months of age. Infants were excluded if they had a genetic syndrome associated with neurodevelopmental impairment.Outcome measuresPredefined perioperative parameters were recorded and infants were classified according to cardiac anatomy. At 2 years, survivors were assessed using the Bayley Scales of Infant Development-III.ResultsAt 2 years, 130 children (98% of survivors) were assessed. Mean cognitive, language and motor scores were 93.4±13.6, 93.6±16.1 and 96.8±12.5 respectively (100±15 norm). Twenty (13%) died and 12 (9%) survivors had severe impairment (score <70), mostly language (8%). The lowest scores were in infants born with single ventricle physiology with obstruction to the pulmonary circulation who required a neonatal systemic-to-pulmonary artery shunt. Additional risk factors for impairment included reduced gestational age, postoperative elevation of lactate or S100B and repeat cardiac surgery.ConclusionsIn the modern era of infant cardiac surgery and perioperative care, children continue to demonstrate neurodevelopmental delays. The use of updated assessment tools has revealed early language dysfunction and relative sparing of motor function. Ongoing follow-up is critical in this high-risk population.
Abstract
Background
Perinatal infection/inflammation is associated with a high risk for neurological injury and neurodevelopmental impairment after birth. Despite a growing preclinical evidence base, ...anti-inflammatory interventions have not been established in clinical practice, partly because of the range of potential targets. We therefore systematically reviewed preclinical studies of immunomodulation to improve neurological outcomes in the perinatal brain and assessed their therapeutic potential.
Methods
We reviewed relevant studies published from January 2012 to July 2023 using PubMed, Medline (OvidSP) and EMBASE databases. Studies were assessed for risk of bias using the SYRCLE risk of bias assessment tool (PROSPERO; registration number CRD42023395690).
Results
Forty preclinical publications using 12 models of perinatal neuroinflammation were identified and divided into 59 individual studies. Twenty-seven anti-inflammatory agents in 19 categories were investigated. Forty-five (76%) of 59 studies reported neuroprotection, from all 19 categories of therapeutics. Notably, 10/10 (100%) studies investigating anti-interleukin (IL)-1 therapies reported improved outcome, whereas half of the studies using corticosteroids (5/10; 50%) reported no improvement or worse outcomes with treatment. Most studies (49/59, 83%) did not control core body temperature (a known potential confounder), and 25 of 59 studies (42%) did not report the sex of subjects. Many studies did not clearly state whether they controlled for potential study bias.
Conclusion
Anti-inflammatory therapies are promising candidates for treatment or even prevention of perinatal brain injury. Our analysis highlights key knowledge gaps and opportunities to improve preclinical study design that must be addressed to support clinical translation.
Postoperative apnea is a complication in young infants. Awake regional anesthesia (RA) may reduce the risk; however, the evidence is weak. The General Anesthesia compared to Spinal anesthesia study ...is a randomized, controlled trial designed to assess the influence of general anesthesia (GA) on neurodevelopment. A secondary aim is to compare rates of apnea after anesthesia.
Infants aged 60 weeks or younger, postmenstrual age scheduled for inguinal herniorrhaphy, were randomized to RA or GA. Exclusion criteria included risk factors for adverse neurodevelopmental outcome and infants born less than 26 weeks gestation. The primary outcome of this analysis was any observed apnea up to 12 h postoperatively. Apnea assessment was unblinded.
Three hundred sixty-three patients were assigned to RA and 359 to GA. Overall, the incidence of apnea (0 to 12 h) was similar between arms (3% in RA and 4% in GA arms; odds ratio OR, 0.63; 95% CI, 0.31 to 1.30, P = 0.2133); however, the incidence of early apnea (0 to 30 min) was lower in the RA arm (1 vs. 3%; OR, 0.20; 95% CI, 0.05 to 0.91; P = 0.0367). The incidence of late apnea (30 min to 12 h) was 2% in both RA and GA arms (OR, 1.17; 95% CI, 0.41 to 3.33; P = 0.7688). The strongest predictor of apnea was prematurity (OR, 21.87; 95% CI, 4.38 to 109.24), and 96% of infants with apnea were premature.
RA in infants undergoing inguinal herniorrhaphy reduces apnea in the early postoperative period. Cardiorespiratory monitoring should be used for all ex-premature infants.
Preterm infants commonly have transient hypothyroxinemia of prematurity after birth, which has been associated with deficits in general intellectual functioning, memory, attention, and academic ...achievement. However, research has predominantly focused on thyroxine levels in the first 2 weeks of life and outcomes are limited to the preschool period. Our objective was to evaluate the relationships between free thyroxine (fT₄) levels over the first 6 weeks after very preterm (VPT) birth with cognitive functioning and brain development at age 7 years.
A total of 83 infants born VPT (<30 weeks' gestation) had fT₄ concentrations measured postnatally and 2- and 6-week area under the curve (AUC) summary measures were calculated. Follow-up at age 7 years included a neuropsychological assessment and brain MRI. Univariable and multivariable regression modeling was used where AUC for fT₄ was the main predictor of neurodevelopmental outcome at age 7 years.
Multivariable modeling revealed that higher, not lower, postnatal fT₄ levels (2-week AUC) were associated with poorer cognitive performances at age 7 years on tasks of verbal learning (P = .02), verbal memory (P = .03), and simple reaction time (P < .001). A similar pattern of results was found when the 6-week AUC was examined. No significant associations between postnatal fT₄ levels and brain volumes at age 7 years were identified.
Results are contradictory to previous observations and suggest that after adjustment for confounders, higher postnatal fT₄ levels in VPT infants, rather than lower levels, may be a marker of adverse neuropsychological development in childhood.
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
Objective
To study the epilepsy syndromes among the severe epilepsies of infancy and assess their incidence, etiologies, and outcomes.
Methods
A population‐based cohort study was undertaken of severe ...epilepsies with onset before age 18 months in Victoria, Australia. Two epileptologists reviewed clinical features, seizure videos, and electroencephalograms to diagnose International League Against Epilepsy epilepsy syndromes. Incidence, etiologies, and outcomes at age 2 years were determined.
Results
Seventy‐three of 114 (64%) infants fulfilled diagnostic criteria for epilepsy syndromes at presentation, and 16 (14%) had "variants" of epilepsy syndromes in which there was one missing or different feature, or where all classical features had not yet emerged. West syndrome (WS) and "WS‐like" epilepsy (infantile spasms without hypsarrhythmia or modified hypsarrhythmia) were the most common syndromes, with a combined incidence of 32.7/100 000 live births/year. The incidence of epilepsy of infancy with migrating focal seizures (EIMFS) was 4.5/100 000 and of early infantile epileptic encephalopathy (EIEE) was 3.6/100 000. Structural etiologies were common in "WS‐like" epilepsy (100%), unifocal epilepsy (83%), and WS (39%), whereas single gene disorders predominated in EIMFS, EIEE, and Dravet syndrome. Eighteen (16%) infants died before age 2 years. Development was delayed or borderline in 85 of 96 (89%) survivors, being severe–profound in 40 of 96 (42%). All infants with EIEE or EIMFS had severe–profound delay or were deceased, but only 19 of 64 (30%) infants with WS, "WS‐like," or "unifocal epilepsy" had severe–profound delay, and only two of 64 (3%) were deceased.
Significance
Three quarters of severe epilepsies of infancy could be assigned an epilepsy syndrome or "variant syndrome" at presentation. In this era of genomic testing and advanced brain imaging, diagnosing epilepsy syndromes at presentation remains clinically useful for guiding etiologic investigation, initial treatment, and prognostication.
Purpose
Perioperative brain injury is common in young infants undergoing cardiac surgery. We aimed to determine the relationship between perioperative electrical seizures, the background pattern of ...amplitude-integrated electroencephalography (aEEG) and 2-year neurodevelopmental outcome in young infants undergoing surgery for congenital heart disease.
Methods
A total of 150 newborn infants undergoing cardiac surgery underwent aEEG monitoring prior to and during surgery, and for 72 h postoperatively. Two blinded assessors reviewed the aEEGs for seizure activity and background pattern. Survivors underwent neurodevelopmental outcome assessment using the Bayley Scales of Infant Development (3rd edn.) at 2 years.
Results
The median age at surgery was 7 days (IQR 4–11). Cardiopulmonary bypass was used in 83 %. Perioperative electrical seizures occurred in 30 %, of whom 1/4 had a clinical correlate, but were not associated with 2-year outcome. Recovery to a continuous background occurred at a median 6 (3–13) h and sleep–wake cycling recovered at 21 (14–30) h. Prolonged aEEG recovery was associated with increased mortality and worse neurodevelopmental outcome. Failure of the aEEG to recover to a continuous background by 48 postoperative hours was associated with impairment in all outcome domains (
p
< 0.05). Continued abnormal aEEG at 7 postoperative days was highly associated with mortality (
p
< 0.001).
Conclusions
Perioperative seizures were common in this cohort of infants but did not impact on 2-year neurodevelopmental outcome. Delayed recovery in aEEG background was associated with increased risk of early mortality and worse neurodevelopment. Ongoing monitoring of the survivors is essential to determine the longer-term significance of these findings.
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