Preterm Sex Differences in Neurodevelopment and Brain Development From Early Life to 8 years.

OBJECTIVE: To examine sex differences in neurodevelopmental outcomes and brain development from early life to 8 years in males and females born preterm. STUDY DESIGN: This was a prospective cohort study of infants born very preterm (24-32 weeks' gestation) and followed to 8 years with standardized measures of neurodevelopment. Brain magnetic resonance imaging (MRI) scans were performed soon after birth, term-equivalent age, and 8 years. The relationship between sex, severe brain injury, early pain exposure, fractional anisotropy (FA), and neurodevelopmental outcomes were assessed using multivariable generalized estimating equations. RESULTS: Males (N=78) and females (N=66) were similar in clinical risk factors. Male sex was associated with lower cognitive scores (ß=-3.8, P=0.02) and greater motor impairment (OR=1.8, P=0.04) across time. Male sex was associated with lower superior white matter FA across time (ß=-0.01, P=0.04). Sex moderated the association between severe brain injury, early pain, and neurodevelopmental outcomes. With severe brain injury, males had lower cognitive scores at 3 years (P<0.001). With increasing pain, females had lower cognitive scores at 8 years (P=0.008), and males had greater motor impairment at 4.5 years (P=0.001) and 8 years (P=0.05). CONCLUSIONS: Males born preterm had lower cognitive scores and greater motor impairment compared with females, which were associated with differences in white matter maturation. The association between severe brain injury, early pain exposure, and neurodevelopmental outcomes was moderated by sex, indicating a differential response to early-life adversity in males and females born preterm.

Socioeconomic status moderates associations between hippocampal development and cognition in preterms.

OBJECTIVE: The hippocampus plays a critical role in cognitive networks. The anterior hippocampus is vulnerable to early-life stress and socioeconomic status (SES) with alterations persisting beyond childhood. How SES modifies the relationship between early hippocampal development and cognition remains poorly understood. This study examined associations between SES, structural and functional development of neonatal hippocampus, and 18-month cognition in very preterm neonates. METHODS: In total, 179 preterm neonates were followed prospectively. Structural and resting-state functional MRI were obtained early-in-life and at term-equivalent age (median 32.9 and 41.1 weeks post-menstrual age) to calculate anterior and posterior hippocampal volumes and hippocampal functional connectivity strength. Eighteen-month cognition was assessed via Bayley-III. Longitudinal statistical analysis using generalized estimating equations, accounting for birth gestational age, post-menstrual age at scan, sex, and motion, was performed. RESULTS: SES, measured as maternal education level, modified associations between anterior but not posterior hippocampal volumes and 18-month cognition (interaction term p = 0.005), and between hippocampal connectivity and cognition (interaction term p = 0.05). Greater anterior hippocampal volumes and hippocampal connectivity were associated with higher cognitive scores only in the lowest SES group. Maternal education alone did not predict neonatal hippocampal volume from early-in-life and term. INTERPRETATION: SES modified the relationship between neonatal hippocampal development and 18-month cognition in very preterm neonates. The lack of direct association between maternal education and neonatal hippocampal volumes indicates that socio-environmental factors beyond the neonatal period contribute to modifying the relationship between hippocampal development and cognition. These findings point toward opportunities to more equitably promote optimal neurodevelopmental outcomes in very preterm infants.

Prognostic Indicators of Reorientation of Care in Perinatal Hypoxic-Ischemic Encephalopathy Spectrum.

OBJECTIVE: To investigate the clinical, electrographic, and neuroimaging characteristics in neonates with perinatal hypoxic-ischemic encephalopathy (HIE) who undergo reorientation of care (ROC) using standardized scoring systems. STUDY DESIGN: A nested observational substudy within a prospective HIE cohort was conducted. Group 1 comprised infants whose parents received the medical recommendation for ROC, while Group 2 continued to receive standard care. Encephalopathy scores were monitored daily. Amplitude-integrated and continuous-video-integrated electroencephalogram (EEG) during therapeutic hypothermia were analyzed. Standardized scoring systems for cranial ultrasonography and post-rewarming brain MRI were deployed. RESULTS: The study included 165 infants, with 35 in Group 1 and 130 in Group 2. By day 3, all infants in Group 1 were encephalopathic with higher Thompson scores (median 13 [IQR 10-19] vs. 0 [IQR 0-3], p<0.001). Electrographic background normalization within 48 hours occurred in 3% of Group 1 compared with 46% of Group 2 (p<0.001). Sleep-wake cycling was not observed in Group 1 and emerged in 63% of Group 2 within the first 72 hours (p<0.001). The number of anti-seizure medications received was higher in Group 1 (median 3 [IQR, 2-4] vs. 0 [IQR, 0-1], respectively; p< 0.001). Group 1 had higher cranial ultrasound injury scores (median 4 [IQR 2-7] vs. 1 [IQR 0-1], p<0.001) within 48 hours and post-rewarming brain MRI injury scores (median 33 [range 20-51] vs. 4 [range 0-28], p<0.001). CONCLUSION: Neonates with perinatal HIE who underwent ROC presented with and maintained significantly more pronounced clinical manifestations, electrographic findings, and near-total brain injury as scored objectively on all modalities.

Associations and outcomes of prenatally detected rhombencephalosynapsis.

OBJECTIVE: To describe the association between prenatal imaging and neurodevelopmental outcomes of fetuses with rhombencephalosynapsis (RES). STUDY DESIGN: Thirty-four pregnancies complicated by RES were identified from our institutional databases based on US and/or MRI findings. Genetic testing results were gathered. In cases of termination of pregnancy, we studied the association between prenatal imaging and neuropathologic findings. For those who opted for expectant management, comprehensive developmental assessments and postnatal MRI imaging were evaluated. RESULTS: Over one third of fetuses in our cohort had complete RES. Common intracranial anomalies identified were mesencephalosynapsis, aqueduct stenosis and diencephalosynapsis. The degree of RES was not associated with the frequency of additional central nervous system anomalies. MRI had a good correlation with neuropathologic findings with regard to the degree of RES, aqueduct stenosis and mesencephalosynapsis. Postmortem autopsy showed that one third of our cases had VACTERL-H and almost all of those had complete RES. All liveborn neonates(n = 6) had aqueduct stenosis requiring ventriculoperitoneal shunting within days of delivery (median 5 days). While a large proportion of prenatally suspected complete RES were found to have partial RES on postnatal imaging, prenatal diagnosis of aqueduct stenosis remained unchanged. All children that were at least 2 years old (n = 3) had global developmental delay. CONCLUSION: Prenatal assessment of the RES severity is challenging and may be unreliable. Nevertheless, postnatal prognosis is poor for both complete and partial RES. Associated aqueductal stenosis, can be reliably assessed prenatally and this may contribute to worse postnatal prognosis than the degree of RES.

Add-On Deep Brain Stimulation versus Continued Vagus Nerve Stimulation for Childhood Epilepsy (ADVANCE): A Partially Randomized Patient Preference Trial.

Outcomes following vagus nerve stimulation (VNS) improve over years after implantation in children with drug-resistant epilepsy. The added value of deep brain stimulation (DBS) instead of continued VNS optimization is unknown. In a prospective, non-blinded, randomized patient preference trial of 18 children (aged 8-17 years) who did not respond to VNS after at least 1 year, add-on DBS resulted in greater seizure reduction compared with an additional year of VNS optimization (51.9% vs. 12.3%, p = 0.047). Add-on DBS also resulted in less bothersome seizures (p = 0.03), but no change in quality of life. DBS may be considered earlier for childhood epilepsy after non-response to VNS. ANN NEUROL 2024;96:405-411.

Change in Volumes and Location of Preterm White Matter Injury over a Period of 15 Years.

OBJECTIVE: To evaluate whether white matter injury (WMI) volumes and spatial distribution, which are important predictors of neurodevelopmental outcomes in preterm infants, have changed over a period of 15 years. STUDY DESIGN: Five hundred and twenty-eight infants born <32 weeks' gestational age from 2 sequential prospective cohorts (cohort 1: 2006 through 2012; cohort 2: 2014 through 2019) underwent early-life (median 32.7 weeks postmenstrual age) and/or term-equivalent-age MRI (median 40.7 weeks postmenstrual age). WMI were manually segmented for quantification of volumes. There were 152 infants with WMI with 74 infants in cohort 1 and 78 in cohort 2. Multivariable linear regression models examined change in WMI volume across cohorts while adjusting for clinical confounders. Lesion maps assessed change in WMI location across cohorts. RESULTS: There was a decrease in WMI volume in cohort 2 compared with cohort 1 (ß = -0.6, 95% CI [-0.8, -0.3], P < .001) with a shift from more central to posterior location of WMI. There was a decrease in clinical illness severity of infants across cohorts. CONCLUSIONS: We found a decrease in WMI volume and shift to more posterior location in very preterm infants over a period of 15 years. This may potentially reflect more advanced maturation of white matter at the time of injury which may be related to changes in clinical practice over time.

Consensus reporting guidelines to address gaps in descriptions of ultra-rare genetic conditions.

Genome-wide sequencing and genetic matchmaker services are propelling a new era of genotype-driven ascertainment of novel genetic conditions. The degree to which reported phenotype data in discovery-focused studies address informational priorities for clinicians and families is unclear. We identified reports published from 2017 to 2021 in 10 genetics journals of novel Mendelian disorders. We adjudicated the quality and detail of the phenotype data via 46 questions pertaining to six priority domains: (I) Development, cognition, and mental health; (II) Feeding and growth; (III) Medication use and treatment history; (IV) Pain, sleep, and quality of life; (V) Adulthood; and (VI) Epilepsy. For a subset of articles, all subsequent published follow-up case descriptions were identified and assessed in a similar manner. A modified Delphi approach was used to develop consensus reporting guidelines, with input from content experts across four countries. In total, 200 of 3243 screened publications met inclusion criteria. Relevant phenotypic details across each of the 6 domains were rated superficial or deficient in >87% of papers. For example, less than 10% of publications provided details regarding neuropsychiatric diagnoses and "behavioural issues", or about the type/nature of feeding problems. Follow-up reports (n = 95) rarely contributed this additional phenotype data. In summary, phenotype information relevant to clinical management, genetic counselling, and the stated priorities of patients and families is lacking for many newly described genetic diseases. The PHELIX (PHEnotype LIsting fiX) reporting guideline checklists were developed to improve phenotype reporting in the genomic era.

Fetal Hemodynamics, Early Survival, and Neurodevelopment in Patients With Cyanotic Congenital Heart Disease.

BACKGROUND: Fetuses with cyanotic congenital heart disease (CHD) exhibit profound fetal circulatory disturbances that may affect early outcomes. OBJECTIVES: This study sought to investigate the relationship between fetal hemodynamics and early survival and neurodevelopmental (ND) outcomes in patients with cyanotic CHD. METHODS: In this longitudinal observational study, fetuses with cyanotic CHD underwent late gestational fetal cardiovascular magnetic resonance (CMR) to measure vessel blood flow and oxygen content. Superior vena cava (SVC) flow was used as a proxy for cerebral blood flow. Primary outcomes were 18-month mortality and Bayley Scales of Infant Development-III assessment. RESULTS: A total of 144 fetuses with cyanotic CHD were assessed. By 18 months, 18 patients (12.5%) died. Early mortality was associated with reduced combined ventricular output (P = 0.01), descending aortic flow (P = 0.04), and umbilical vein flow (P = 0.03). Of the surviving patients, 71 had ND outcomes assessed. Cerebral oxygen delivery was the fetal hemodynamic variable most strongly associated with cognitive, language, and motor outcomes (P < 0.05). Fetal SVC flow was also associated with cognitive, language, and motor outcomes (P < 0.01), and it remained an independent predictor of cognitive (P = 0.002) and language (P = 0.04) outcomes after adjusting for diagnosis. Diminished SVC flow also performed better than other fetal CMR and echocardiographic predictors of cognitive ND delay (receiver-operating characteristic curve area: 0.85; SE 0.05). CONCLUSIONS: Among fetuses with cyanotic CHD, diminished fetal combined ventricular output is associated with mortality, whereas cerebral blood flow and oxygen delivery are associated with early cognitive, language, and motor development at 18 months of age. These results support the inclusion of fetal CMR to help identify patients at risk of adverse ND outcomes.

Size and Location of Preterm Brain Injury and Associations With Neurodevelopmental Outcomes.

BACKGROUND AND OBJECTIVES: We examined associations of white matter injury (WMI) and periventricular hemorrhagic infarction (PVHI) volume and location with 18-month neurodevelopment in very preterm infants. METHODS: A total of 254 infants born <32 weeks' gestational age were prospectively recruited across 3 tertiary neonatal intensive care units (NICUs). Infants underwent early-life (median 33.1 weeks) and/or term-equivalent-age (median 41.9 weeks) MRI. WMI and PVHI were manually segmented for quantification in 92 infants. Highest maternal education level was included as a marker of socioeconomic status and was defined as group 1 = primary/secondary school; group 2 = undergraduate degree; and group 3 = postgraduate degree. Eighteen-month neurodevelopmental assessments were completed with Bayley Scales of Infant and Toddler Development, Third Edition. Adverse outcomes were defined as a score of less than 85 points. Multivariable linear regression models were used to examine associations of brain injury (WMI and PVHI) volume with neurodevelopmental outcomes. Voxel-wise lesion symptom maps were developed to assess relationships between brain injury location and neurodevelopmental outcomes. RESULTS: Greater brain injury volume was associated with lower 18-month Motor scores (ß = -5.7, 95% CI -9.2 to -2.2, p = 0.002) while higher maternal education level was significantly associated with higher Cognitive scores (group 3 compared 1: ß = 14.5, 95% CI -2.1 to 26.9, p = 0.03). In voxel-wise lesion symptom maps, brain injury involving the central and parietal white matter was associated with an increased risk of poorer motor outcomes. DISCUSSION: We found that brain injury volume and location were significant predictors of motor, but not cognitive outcomes, suggesting that different pathways may mediate outcomes across domains of neurodevelopment in preterm infants. Specifically, assessing lesion size and location may allow for more accurate identification of infants with brain injury at highest risk of poorer motor outcomes. These data also highlight the importance of socioeconomic status in cognitive outcomes, even in preterm infants with brain injury.

Pain Exposure and Brain Connectivity in Preterm Infants.

Importance: Early-life exposure to painful procedures has been associated with altered brain maturation and neurodevelopmental outcomes in preterm infants, although sex-specific differences are largely unknown. Objective: To examine sex-specific associations among early-life pain exposure, alterations in neonatal structural connectivity, and 18-month neurodevelopment in preterm infants. Design, Setting, and Participants: This prospective cohort study recruited 193 very preterm infants from April 1, 2015, to April 1, 2019, across 2 tertiary neonatal intensive care units in Toronto, Canada. Structural connectivity data were available for 150 infants; neurodevelopmental outcomes were available for 123 infants. Data were analyzed from January 1, 2022, to December 31, 2023. Exposure: Pain was quantified in the initial weeks after birth as the total number of invasive procedures. Main Outcome and Measure: Infants underwent early-life and/or term-equivalent-age magnetic resonance imaging with diffusion tensor imaging to quantify structural connectivity using graph theory measures and regional connection strength. Eighteen-month neurodevelopmental outcomes were assessed with the Bayley Scales of Infant and Toddler Development, Third Edition. Stratifying by sex, generalized estimating equations were used to assess whether pain exposure modified the maturation of structural connectivity using an interaction term (early-life pain exposure × postmenstrual age [PMA] at scan). Generalized estimating equations were used to assess associations between structural connectivity and neurodevelopmental outcomes, adjusting for extreme prematurity and maternal education. Results: A total of 150 infants (80 [53%] male; median [IQR] gestational age at birth, 27.1 [25.4-29.0] weeks) with structural connectivity data were analyzed. Sex-specific associations were found between early-life pain and neonatal brain connectivity in female infants only, with greater early-life pain exposure associated with slower maturation in global efficiency (pain × PMA at scan interaction P = .002) and local efficiency (pain × PMA at scan interaction P = .005). In the full cohort, greater pain exposure was associated with lower global efficiency (coefficient, -0.46; 95% CI, -0.78, to -0.15; P = .004) and local efficiency (coefficient, -0.57; 95% CI, -1.04 to -0.10; P = .02) and regional connection strength. Local efficiency (coefficient, 0.003; 95% CI, 0.001-0.004; P = .005) and regional connection strength in the striatum were associated with cognitive outcomes. Conclusions and Relevance: In this cohort study of very preterm infants, greater exposure to early-life pain was associated with altered maturation of neonatal structural connectivity, particularly in female infants. Alterations in structural connectivity were associated with neurodevelopmental outcomes, with potential regional specificities.

KCTD7-related progressive myoclonic epilepsy: Report of 42 cases and review of literature.

OBJECTIVE: KCTD7-related progressive myoclonic epilepsy (PME) is a rare autosomal-recessive disorder. This study aimed to describe the clinical details and genetic variants in a large international cohort. METHODS: Families with molecularly confirmed diagnoses of KCTD7-related PME were identified through international collaboration. Furthermore, a systematic review was done to identify previously reported cases. Salient demographic, epilepsy, treatment, genetic testing, electroencephalographic (EEG), and imaging-related variables were collected and summarized. RESULTS: Forty-two patients (36 families) were included. The median age at first seizure was 14 months (interquartile range = 11.75-22.5). Myoclonic seizures were frequently the first seizure type noted (n = 18, 43.9%). EEG and brain magnetic resonance imaging findings were variable. Many patients exhibited delayed development with subsequent progressive regression (n = 16, 38.1%). Twenty-one cases with genetic testing available (55%) had previously reported variants in KCTD7, and 17 cases (45%) had novel variants in KCTD7 gene. Six patients died in the cohort (age range = 1.5-21 years). The systematic review identified 23 eligible studies and further identified 59 previously reported cases of KCTD7-related disorders from the literature. The phenotype for the majority of the reported cases was consistent with a PME (n = 52, 88%). Other reported phenotypes in the literature included opsoclonus myoclonus ataxia syndrome (n = 2), myoclonus dystonia (n = 2), and neuronal ceroid lipofuscinosis (n = 3). Eight published cases died over time (14%, age range = 3-18 years). SIGNIFICANCE: This study cohort and systematic review consolidated the phenotypic spectrum and natural history of KCTD7-related disorders. Early onset drug-resistant epilepsy, relentless neuroregression, and severe neurological sequalae were common. Better understanding of the natural history may help future clinical trials.

Neurodevelopmental outcomes at 18 months of children diagnosed with CHD compared to children born very preterm.

OBJECTIVE: To compare neurodevelopmental outcomes and parent behaviour ratings of children born term with CHD to children born very preterm. METHODS: A clinical research sample of 181 children (CHD [n = 81]; very preterm [≤32 weeks; n = 100]) was assessed at 18 months. RESULTS: Children with CHD and born very preterm did not differ on Bayley-III cognitive, language, or motor composite scores, or on expressive or receptive language, or on fine motor scaled scores. Children with CHD had lower ross motor scaled scores compared to children born very preterm (p = 0.047). More children with CHD had impaired scores (<70 SS) on language composite (17%), expressive language (16%), and gross motor (14%) indices compared to children born very preterm (6%; 7%; 3%; ps < 0.05). No group differences were found on behaviours rated by parents on the Child Behaviour Checklist (1.5-5 years) or the proportion of children with scores above the clinical cutoff. English as a first language was associated with higher cognitive (p = 0.004) and language composite scores (p < 0.001). Lower median household income and English as a second language were associated with higher total behaviour problems (ps < 0.05). CONCLUSIONS: Children with CHD were more likely to display language and motor impairment compared to children born very preterm at 18 months. Outcomes were associated with language spoken in the home and household income.

Antenatal diagnosis, neonatal brain volumes, and neurodevelopment in transposition of the great arteries.

AIM: To examine whether antenatal diagnosis modifies relationships between neonatal brain volumes and 18-month neurodevelopmental outcomes in children with transposition of the great arteries (TGA). METHOD: In a retrospective cohort of 139 children with TGA (77 antenatally diagnosed), we obtained total brain volumes (TBVs) on pre- (n = 102) and postoperative (n = 112) magnetic resonance imaging. Eighteen-month neurodevelopmental outcomes were assessed using the Bayley Scales of Infant and Toddler Development, Third Edition. Generalized estimating equations with interaction terms were used to determine whether antenatal diagnosis modified associations between TBVs and neurodevelopmental outcomes accounting for postmenstrual age at scan, brain injury, and ventricular septal defect. RESULTS: Infants with postnatal diagnosis had more preoperative hypotension (35% vs 14%, p = 0.004). The interactions between antenatal diagnosis and TBVs were significantly related to cognitive (p = 0.003) outcomes. Specifically, smaller TBVs were associated with lower cognitive scores in infants diagnosed postnatally; this association was attenuated in those diagnosed antenatally. INTERPRETATION: Antenatal diagnosis modifies associations between neonatal brain volume and 18-month cognitive outcome in infants with TGA. These findings suggest that antenatal diagnosis may be neuroprotective, possibly through improved preoperative clinical status. These data highlight the need to improve antenatal diagnosis rates. WHAT THIS PAPER ADDS: Antenatal diagnosis of transposition of the great arteries modified relationships between neonatal brain volume and neurodevelopment. Smaller brain volumes related to poorer cognitive scores with postnatal diagnosis only. There was more preoperative hypotension in the postnatal diagnosis group.

Neonatal Hypoxic-Ischemic Encephalopathy Spectrum: Severity-Stratified Analysis of Neuroimaging Modalities and Association with Neurodevelopmental Outcomes.

OBJECTIVE: To compare hypoxic-ischemic injury on early cranial ultrasonography (cUS) and post-rewarming brain magnetic resonance imaging (MRI) in newborn infants with hypoxic-ischemic encephalopathy (HIE) and to correlate that neuroimaging with neurodevelopmental outcomes. STUDY DESIGN: This was a retrospective cohort study of infants with mild, moderate, and severe HIE treated with therapeutic hypothermia and evaluated with early cUS and postrewarming MRI. Validated scoring systems were used to compare the severity of brain injury on cUS and MRI. Neurodevelopmental outcomes were assessed at 18 months of age. RESULTS: Among the 149 included infants, abnormal white matter (WM) and deep gray matter (DGM) hyperechogenicity on cUS in the first 48 hours after birth were more common in the severe HIE group than the mild HIE group (81% vs 39% and 50% vs 0%, respectively; P < .001). In infants with a normal cUS, 95% had normal or mildly abnormal brain MRIs. In infants with severely abnormal cUS, none had normal and 83% had severely abnormal brain MRIs. Total abnormality scores on cUS were higher in neonates with near-total brain injury on MRI than in neonates with normal MRI or WM-predominant injury pattern (adjusted P < .001 for both). In the multivariable model, a severely abnormal MRI was the only independent risk factor for adverse outcomes (OR: 19.9, 95% CI: 4.0-98.1; P < .001). CONCLUSION: The present study shows the complementary utility of cUS in the first 48 hours after birth as a predictive tool for the presence of hypoxic-ischemic injury on brain MRI.

Major Surgery, Brain Injury, and Neurodevelopmental Outcomes in Very Preterm Infants.

OBJECTIVES: We determined whether (1) major surgery is associated with an increased risk for brain injury and adverse neurodevelopment and (2) brain injury modifies associations between major surgery and neurodevelopment in very preterm infants. METHODS: Prospectively enrolled infants across 3 tertiary neonatal intensive care units underwent early-life and/or term-equivalent age MRI to detect moderate-severe brain injury. Eighteen-month neurodevelopmental outcomes were assessed with Bayley Scales of Infant and Toddler Development, third edition. Multivariable logistic and linear regressions were used to determine associations of major surgery with brain injury and neurodevelopment, adjusting for clinical confounders. RESULTS: There were 294 infants in this study. Major surgery was associated with brain injury (odds ratio 2.54, 95% CI 1.12-5.75, p = 0.03) and poorer motor outcomes (ß = -7.92, 95% CI -12.21 to -3.64, p < 0.001), adjusting for clinical confounders. Brain injury x major surgery interaction significantly predicted motor scores (p = 0.04): Lowest motor scores were in infants who required major surgery and had brain injury. DISCUSSION: There is an increased risk for brain injury and adverse motor outcomes in very preterm infants who require major surgery, which may be a marker of clinical illness severity. Routine brain MRI to detect brain injury and close neurodevelopmental surveillance should be considered in this subgroup of infants.

Association of Neonatal Midazolam Exposure With Hippocampal Growth and Working Memory Performance in Children Born Preterm.

BACKGROUND AND OBJECTIVES: Early exposure to analgesics and sedatives is a key concern for later learning disorders in children. The hippocampus, a key region for learning and memory, may be selectively affected by exposure to benzodiazepines that are commonly used for sedation, particularly in the neonatal period. In this prospective cohort study, the long-term association of neonatal midazolam exposure, a widely used benzodiazepine in neonatal intensive care, with school age hippocampal growth was examined. Higher-order cognitive function in preterm born children was assessed in relation to hippocampal volumes. METHODS: Very preterm born children underwent MRI to characterize the hippocampus and its subfields and neuropsychological testing. Generalized linear models were used to determine the predictors of 8-year hippocampal volumes. Children were assessed on the Wechsler Abbreviated Scales of Intelligence, Second Edition, and the Wechsler Intelligence Scales for Children, Fifth Edition (WISC-V). RESULTS: A total of 140 preterm children who were 8 years of age participated, and 25 (18%) were exposed to midazolam as neonates. Reduced hippocampal volumes at age 8 years were associated with neonatal midazolam exposure (B = -400.2, 95% CI -14.37 to -786.03, p = 0.04), adjusting for neonatal clinical care factors. Boys exposed to higher doses of midazolam as neonates had smaller hippocampal volumes (χ2 = 14.4, p = 0.002) compared with nonexposed boys and girls (both, p < 0.03). Analysis of the hippocampal subfields in relation to neonatal midazolam dose revealed that higher doses were associated with smaller volumes of the subiculum (p = 0.008), a hippocampal-cortical relay region implicated in memory processes. Furthermore, smaller school age subiculum volumes predicted significantly lower working memory scores on the WISC-V (B = 0.04, 95% CI 0.01-0.07, p = 0.017). DISCUSSION: Early midazolam exposure and the association with impaired hippocampal growth seem long-lasting and are most apparent in boys. Alterations in subiculum volumes may underlie hippocampus-dependent memory formation processes in preterm born children exposed to midazolam as neonates.

Evaluation of the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing in infantile epilepsy (Gene-STEPS): an international, multicentre, pilot cohort study.

BACKGROUND: Most neonatal and infantile-onset epilepsies have presumed genetic aetiologies, and early genetic diagnoses have the potential to inform clinical management and improve outcomes. We therefore aimed to determine the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing in this population. METHODS: We conducted an international, multicentre, cohort study (Gene-STEPS), which is a pilot study of the International Precision Child Health Partnership (IPCHiP). IPCHiP is a consortium of four paediatric centres with tertiary-level subspecialty services in Australia, Canada, the UK, and the USA. We recruited infants with new-onset epilepsy or complex febrile seizures from IPCHiP centres, who were younger than 12 months at seizure onset. We excluded infants with simple febrile seizures, acute provoked seizures, known acquired cause, or known genetic cause. Blood samples were collected from probands and available biological parents. Clinical data were collected from medical records, treating clinicians, and parents. Trio genome sequencing was done when both parents were available, and duo or singleton genome sequencing was done when one or neither parent was available. Site-specific protocols were used for DNA extraction and library preparation. Rapid genome sequencing and analysis was done at clinically accredited laboratories, and results were returned to families. We analysed summary statistics for cohort demographic and clinical characteristics and the timing, diagnostic yield, and clinical impact of rapid genome sequencing. FINDINGS: Between Sept 1, 2021, and Aug 31, 2022, we enrolled 100 infants with new-onset epilepsy, of whom 41 (41%) were girls and 59 (59%) were boys. Median age of seizure onset was 128 days (IQR 46-192). For 43 (43% [binomial distribution 95% CI 33-53]) of 100 infants, we identified genetic diagnoses, with a median time from seizure onset to rapid genome sequencing result of 37 days (IQR 25-59). Genetic diagnosis was associated with neonatal seizure onset versus infantile seizure onset (14 [74%] of 19 vs 29 [36%] of 81; p=0·0027), referral setting (12 [71%] of 17 for intensive care, 19 [44%] of 43 non-intensive care inpatient, and 12 [28%] of 40 outpatient; p=0·0178), and epilepsy syndrome (13 [87%] of 15 for self-limited epilepsies, 18 [35%] of 51 for developmental and epileptic encephalopathies, 12 [35%] of 34 for other syndromes; p=0·001). Rapid genome sequencing revealed genetic heterogeneity, with 34 unique genes or genomic regions implicated. Genetic diagnoses had immediate clinical utility, informing treatment (24 [56%] of 43), additional evaluation (28 [65%]), prognosis (37 [86%]), and recurrence risk counselling (all cases). INTERPRETATION: Our findings support the feasibility of implementation of rapid genome sequencing in the clinical care of infants with new-onset epilepsy. Longitudinal follow-up is needed to further assess the role of rapid genetic diagnosis in improving clinical, quality-of-life, and economic outcomes. FUNDING: American Academy of Pediatrics, Boston Children's Hospital Children's Rare Disease Cohorts Initiative, Canadian Institutes of Health Research, Epilepsy Canada, Feiga Bresver Academic Foundation, Great Ormond Street Hospital Charity, Medical Research Council, Murdoch Children's Research Institute, National Institute of Child Health and Human Development, National Institute for Health and Care Research Great Ormond Street Hospital Biomedical Research Centre, One8 Foundation, Ontario Brain Institute, Robinson Family Initiative for Transformational Research, The Royal Children's Hospital Foundation, University of Toronto McLaughlin Centre.

Severity and duration of dysglycemia and brain injury among patients with neonatal encephalopathy.

Background: Evidence is needed to inform thresholds for glycemic management in neonatal encephalopathy (NE). We investigated how severity and duration of dysglycemia relate to brain injury after NE. Methods: A prospective cohort of 108 neonates ≥36 weeks gestational age with NE were enrolled between August 2014 and November 2019 at the Hospital for Sick Children, in Toronto, Canada. Participants underwent continuous glucose monitoring for 72 h, MRI at day 4 of life, and follow-up at 18 months. Receiver operating characteristic curves were used to assess the predictive value of glucose measures (minimum and maximum glucose, sequential 1 mmol/L glucose thresholds) during the first 72 h of life (HOL) for each brain injury pattern (basal ganglia, watershed, focal infarct, posterior-predominant). Linear and logistic regression analyses were used to assess the relationship between abnormal glycemia and 18-month outcomes (Bayley-III composite scores, Child Behavior Checklist [CBCL] T-scores, neuromotor score, cerebral palsy [CP], death), adjusting for brain injury severity. Findings: Of 108 neonates enrolled, 102 (94%) had an MRI. Maximum glucose during the first 48 HOL best predicted basal ganglia (AUC = 0.811) and watershed (AUC = 0.858) injury. Minimum glucose was not predictive of brain injury (AUC <0.509). Ninety-one (89%) infants underwent follow-up assessments at 19.0 ± 1.7 months. A glucose threshold of >10.1 mmol/L during the first 48 HOL was associated with 5.8-point higher CBCL Internalizing Composite T-score (P = 0.029), 0.3-point worse neuromotor score (P = 0.035), 8.6-fold higher odds for CP diagnosis (P = 0.014). While the glucose threshold of >10.1 mmol/L during the first 48 HOL was associated with higher odds of the composite outcome of severe disability or death (OR 3.0, 95% CI 1.0-8.4, P = 0.042), it was not associated with the composite outcome of moderate-to-severe disability or death (OR 0.9, 95% CI 0.4-2.2, P = 0.801). All associations with outcome lost significance after adjusting for brain injury severity. Interpretation: Maximum glucose concentration in the first 48 HOL is predictive of brain injury after NE. Further trials are needed to assess if protocols to control maximum glucose concentrations improve outcomes after NE. Funding: Canadian Institutes for Health Research, National Institutes of Health, and SickKids Foundation.

Child Neurology: Cortical Malformations in Preterm Infants: Case From a Prospective Cohort.

Malformations of cortical development (MCD) are a rare group of disorders with heterogeneous clinical, neuroimaging, and genetic features. MCD consist of disruptions in the development of the cerebral cortex secondary to genetic, metabolic, infectious, or vascular etiologies. MCD are typically classified by stage of disrupted cortical development as secondary to abnormal: (1) neuronal proliferation or apoptosis, (2) neuronal migration, or (3) postmigrational cortical development. MCD are typically detected with brain MRI when an infant or child becomes symptomatic, presenting with seizures, developmental delay, or cerebral palsy. With recent advances in neuroimaging, cortical malformations can be detected using ultrasound or MRI during the fetal period or in the neonatal period. Of interest, preterm infants are born at a time when many cortical developmental processes are still occurring. However, there is a paucity of literature describing the neonatal imaging findings, clinical presentation, and evolution over time of cortical malformations in preterm infants. In this study, we present the neuroimaging findings from early life to term-equivalent age and childhood neurodevelopmental outcomes of an infant born very preterm (<32 weeks' postmenstrual age) with MCD detected incidentally on neonatal research brain MRI. These brain MRIs were performed as part of a prospective longitudinal cohort study of 160 very preterm infants; MCD were detected incidentally in 2 infants.

Preterm Neurodevelopmental Trajectories from 18 Months to 4.5 Years.

OBJECTIVE: To assess the longitudinal trajectory of cognitive, language, and motor outcomes from 18 months to 4.5 years of age in children born very preterm. STUDY DESIGN: This was a prospective cohort study of 163 infants born very preterm (born 24-32 weeks of gestation) followed longitudinally and assessed with neurodevelopmental scales and magnetic resonance imaging of the brain. Outcomes at 18 months and 3 years were assessed with the Bayley Scales of Infant and Toddler Development, 3rd Edition, and at 4.5 years with the Wechsler Preschool and Primary Scale of Intelligence-III and the Movement Assessment Battery for Children. Cognitive, language, and motor outcomes were categorized as below-average, average, and above-average, and compared across time. Clinical data were analyzed using ANOVA, χ2 tests, and linear regression. RESULTS: Cognitive and language trajectories were stable from 18 months to 4.5 years for all outcome groups. Motor impairment increased over time, with a greater proportion of children having motor deficits at 4.5 years. Children with below-average cognitive and language outcomes at 4.5 years had more clinical risk factors, greater white matter injury, and lower maternal education. Children with severe motor impairment at 4.5 years were born earlier, had more clinical risk factors, and demonstrated greater white matter injury. CONCLUSIONS: Children born preterm have stable cognitive and language trajectories, while motor impairment increased at 4.5 years. These results highlight the importance of continued developmental surveillance for children born preterm into preschool age.