Search Results (224)

Hypoxic–ischaemic encephalopathy (HIE), a leading cause of perinatal mortality and neurological impairment, affects 1–8/1000 live births in developed countries. Therapeutic hypothermia (TH), the standard treatment for moderate to severe HIE, reduces brain injury by lowering metabolic demand and inhibiting apoptosis. This case study presents a full-term female newborn delivered via caesarean section due to intrauterine asphyxia, with meconium aspiration syndrome and severe HIE (Apgar 0/0/0/2). Notwithstanding the presence of multiorgan failure and grade II intraventricular haemorrhage, TH was initiated within six hours. The patient received circulatory and respiratory support, sedation, and nitric oxide. Early rehabilitation was initiated immediately. Neurofunctional assessment using the TIMP test revealed initial delays (16–25th percentile) at 11 weeks of age; however, the subsequent two evaluations, conducted approximately every two weeks, indicated that the patient was within normal developmental ranges. A similar outcome was observed in the AIMS assessment conducted at seven months of age, which also yielded normal results. Despite MRI findings post-TH showing hypoxic and haemorrhagic lesions, the patient achieved normal development. This case demonstrates the effectiveness of combining TH with early physiotherapy in mitigating severe consequences of HIE, such as cerebral palsy and epilepsy. Long-term follow-up remains crucial for detecting later deficits, particularly during school age. The outcome of this case underscores the significance of timely intervention and multidisciplinary care. While TH and rehabilitation have been shown to improve prognosis, ongoing monitoring is crucial to ensure optimal neurological development trajectories. Full article

Background: Hypoxic–ischemic encephalopathy (HIE) is a leading cause of severe neurological impairments in childhood. Therapeutic hypothermia (TH) is both safe and effective in neonates born at ≥36 weeks gestation with moderate to severe HIE. We aimed to evaluate short-term outcomes—including brain injury detected on magnetic resonance imaging (MRI)—in infants born at 34–35 weeks of gestation drawing on our clinical experience with neonates under 36 weeks of gestational age (GA). Methods: In this retrospective cohort study, 20 preterm infants with a GA of 34 to 35 weeks and a matched cohort of 80 infants with a GA of ≥36 weeks who were diagnosed with moderate to severe HIE and underwent TH were included. Infants were matched in a 1:4 ratio based on the worst base deficit in blood gas and sex. Maternal and neonatal characteristics, brain MRI findings and short term outcomes were compared. Results: Infants with a GA of 34–35 weeks had a lower birth weight and a higher rate of caesarean delivery (both p < 0.001). Apgar scores, sex, intubation rate in delivery room, blood gas pH, base deficit and lactate were comparable between the groups. Compared to infants born at ≥36 weeks of GA, preterm neonates were more likely to receive inotropes, had a longer time to achieve full enteral feeding, and experienced a longer hospital stay. The mortality rate was 10% in the 34–35 weeks GA group. Neuroimaging revealed injury in 66.7% of infants born at 34–35 weeks of gestation and in 58.8% of those born at ≥36 weeks (p = 0.56). Injury was observed across multiple brain regions, with white matter being the most frequently affected in the 34–35 weeks GA group. Thalamic and cerebellar abnormal signal intensity or diffusion restriction, punctate white matter lesions, and diffusion restriction in the corpus callosum and optic radiations were more frequently detected in infants born at 34–35 weeks of gestation. Conclusions: Our study contributes to the growing body of literature suggesting that TH may be feasible and tolerated in late preterm infants. Larger randomized controlled trials focused on this vulnerable population are necessary to establish clear guidelines regarding the safety and efficacy of TH in late preterm infants. Full article

Pyridoxine-dependent epilepsy (PDE) represents a group of rare developmental and epileptic encephalopathies. The most common PDE is caused by biallelic pathogenic variants in ALDH7A1 (PDE-ALDH7A1; OMIM #266100), which encodes α-aminoadipate semialdehyde (α-AASA) dehydrogenase, a key enzyme in lysine catabolism. Affected individuals present with seizures unresponsive to conventional anticonvulsant medications but responsive to high-dose of pyridoxine (vitamin B6). Adjunctive lysine restriction and arginine supplementation have also shown potential in improving neurodevelopmental outcomes. Given the significant benefit of early intervention, PDE-ALDH7A1 is a strong candidate for newborn screening (NBS). However, traditional biomarkers are biochemically unstable at room temperature (α-AASA and piperideine-6-carboxylate) or lack sufficient specificity (pipecolate), limiting their utility for biomarker-based NBS. The recent identification of two novel and stable biomarkers, 2S,6S-/2S,6R-oxopropylpiperidine-2-carboxylate (2-OPP) and 6-oxo-pipecolate (oxo-PIP), offers renewed potential for biochemical NBS. We evaluated the feasibility of incorporating 2-OPP, oxo-PIP, and pipecolate into routine butylated FIA-MS/MS workflows used for biochemical NBS. A total of 9402 dried blood spots (DBS), including nine confirmed PDE-ALDH7A1 patients and 9393 anonymized controls were analyzed using a single multiplex assay. 2-OPP emerged as the most sensitive biomarker, identifying all PDE-ALDH7A1 patients with 100% sensitivity and a positive predictive value (PPV) of 18.4% using a threshold above the 99.5th percentile. Combining elevated 2-OPP (above the 99.5th percentile) with either pipecolate or oxo-PIP (above the 85.0th percentile) as secondary marker detected within the same multiplex FIA-MS/MS assay further improved the PPVs to 60% and 45%, respectively, while maintaining compatibility with butanol-derivatized method. Notably, increasing the 2-OPP threshold above the 99.89th percentile, in combination with either pipecolate or oxo-PIP above the 85.0th percentile resulted in both 100% sensitivity and 100% PPV. This study supports the strong potential of 2-OPP-based neonatal screening for PDE-ALDH7A1 within existing NBS infrastructures. The ability to multiplex 2-OPP, pipecolate and oxo-PIP within a single assay offers a robust, practical, high-throughput and cost-effective approach. These results support the inclusion of PDE-ALDH7A1 in existing biochemical NBS panels. Further prospective studies in larger cohorts are needed to refine cutoffs and confirm clinical performance. Full article

Preterm infants often require oxygen supplementation, resulting in high risk for bronchopulmonary dysplasia (BPD) and neurodevelopmental deficits. Despite a growing number of studies, there is still little knowledge about brain injury in BPD models. Therefore, we exposed neonatal C57BL/6 mice to 85% oxygen from birth to postnatal day (P) 14. At P28, two weeks after recovery under normoxic conditions, right hemisphere was used for the analysis of mRNA and the left hemisphere for protein expression of neuronal cells, neuroinflammatory and vascularisation markers, analysed by real-time PCR and Western blot, respectively. Hyperoxia led to an altered expression of markers associated with neuronal and oligodendrocyte maturation and neuroinflammation such as Dcx, Nestin, Il-1β, Il-6, NG2, and YM1/2. These changes were accompanied by an increased expression of genes involved in angiogenesis and vascular remodelling, e.g., Vegf-a, Nrp-1, and Icam-1. Together, 14 days of hyperoxia triggered a phenotypic response, resembling signs of encephalopathy of prematurity (EoP). Full article

Background/Objectives: Although there is a critical need for timely, accurate recognition of infants with hypoxic ischemic encephalopathy (HIE) eligible for therapeutic hypothermia (TH), there is little published literature that comprehensively validates strategies to achieve this. For the Mater Mothers’ Hospital, a screening protocol combining use of umbilical cord gases according to obstetric criteria and other evidence of depression at birth with a decision aid (the HIE Trigger Tool (TT)) for at-risk infants was developed. We audited whether the protocol supported appropriate clinical decisions. Methods: Obstetric records were searched from 1 January 2016 to 31 July 2022 for eligible infants. Neonatal records were examined to assess usage, determine outcomes (diagnosis of HIE or other neurological conditions, use of TH, mortality and neurodevelopmental outcomes) and detect any additional HIE cases. Results: Of 64,055 live births ≥35 weeks, 35.4% had cord gases taken. Of 580 eligible infants, the TT was applied to 498 (86.3%), 155 of whom screened positive for HIE (any severity). Of 76 infants with moderate or severe encephalopathy, 69 received TH. The other seven had contraindications to TH (n = 2), late presentations without any depression at birth (>6 h, n = 3) or other causes of their encephalopathy (n = 2). The TT (which per instructions was commenced by one hour of age) was used to identify 61 of the infants with moderate/severe encephalopathy, while 15 were diagnosed before it was applied. No infants who screened negative using the TT presented later with seizures or any other signs of moderate or severe HIE. Conclusions: The protocol including cord gases and the HIE TT is an effective method of screening for acute HIE needing TH. Full article

Prognostication of neurodevelopmental outcomes for neonates with hypoxic–ischemic encephalopathy (HIE) is primarily reliant on structural assessment using conventional brain magnetic resonance imaging in the clinical setting. Diffuse optical tomography (DOT) can provide complementary information on brain function at the bedside, further enhancing prognostic accuracy. The predictive accuracy and generalizability of DOT-based neuroimaging markers are unknown. This study aims to test the feasibility of prospectively recruiting and retaining neonates for 12 months in a larger study that investigates the prognostic utility of DOT-based biomarkers of HIE. The study will recruit 25 neonates with HIE over one year and follow them beyond NICU discharge at 6 and 12 months of age. Study subjects will undergo resting-state DOT measurement within 7 days of life for a 30–45-min period without sedation. A customized neonatal cap with 10 sources and eight detectors per side will be used to quantify cortical functional connectivity and to generate brain networks using MATLAB-based software (version 24.2). The Ages and Stages Questionnaires—3rd edition will be used for standardized developmental assessments at follow-up. This feasibility study will help refine the design and sample-size calculation for an adequately powered larger study that determines the clinical utility of DOT-based neuroimaging in perinatal brain injury. Full article

Background: Neonatal hypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal death and neurodevelopmental disorders, and its pathological mechanisms are closely related to disturbed energy metabolism and lipid remodeling. Exploring the spatial heterogeneity of metabolomics is essential to analyze the pathological process of HIE. Methods: In this study, we established a neonatal mouse hypoxic-ischemic brain damage (HIBD) model by the modified Rice method, and analyzed various metabolic pathways such as the tricarboxylic acid (TCA) cycle, purine metabolism, and lipid metabolism in the ischemic edema area, with contralateral and control brain tissues using matrix-assisted laser desorption mass spectrometry imaging (MALDI-MSI) with a spatial resolution of 50 μm. Results: In the HIBD model, key metabolites of the tricarboxylic acid (TCA) cycle (citrate, succinate, L-glutamate, glucose, aspartate, and glutamine) were significantly enriched in the edematous area compared with the control (fold change: 1.52–2.82), which suggests a blockage of mitochondrial function; ATP/ADP/AMP levels were reduced by 53–73% in the edematous area, and xanthine was abnormally accumulated in the hippocampus of the affected side, suggesting energy depletion and altered purine metabolism; lipid remodeling showed regional specificity: some unsaturated fatty acids, such as docosahexaenoic acid, were abnormally accumulated in the hippocampus. In contrast, pentadecanoic acid levels were reduced across the entire brain in the HIBD model, with a more pronounced decrease in the ipsilateral hippocampus, suggesting impaired membrane stability. Conclusions: The neonatal mouse HIBD model exhibits reprogramming of energy metabolism, characterized by a blockage in the tricarboxylic acid (TCA) cycle and ATP depletion, along with an abnormal spatial distribution of lipids. By targeting xanthine metabolic pathways, restoring mitochondrial function, and intervening in region-specific lipid remodeling, brain energy homeostasis may be improved and neurological damage attenuated. Further studies should validate the clinical feasibility of xanthine and lipid imbalance as diagnostic markers of HIBD and explore the critical time window for metabolic intervention to optimize therapeutic strategies. Full article

Introduction: Hyperbilirubinemia in newborns can lead to kernicterus, a severe form of neonatal encephalopathy caused by bilirubin toxicity. Despite timely interventions such as exchange transfusion, kernicterus can still develop, especially in high-risk infants. MRI is crucial for detecting early and evolving signs of bilirubin-induced brain damage. Case Report: We report a term newborn who developed severe hyperbilirubinemia and kernicterus despite receiving exchange transfusion. The infant presented on day 3 of life with jaundice, hypotonia, and feeding difficulties and had a bilirubin level of 51 mg/dL. After exchange transfusion, bilirubin levels normalized, but neurotoxicity persisted. Initial MRI at one month showed mild T1 hyperintensity in the hippocampi with no changes in the basal ganglia. At two months, T1 hyperintensities in the hippocampi partially resolved. By six months, MRI revealed T2 hyperintensities in the globus pallidus and hippocampal atrophy, consistent with kernicterus. Magnetic resonance spectroscopy (MRS) showed reduced N-acetylaspartate (NAA) levels, indicating neuronal loss. Discussion: MRI is essential in monitoring bilirubin-induced brain injury. In this case, early MRI findings showed mild hippocampal T1 hyperintensity, which resolved partially. At six months, T2 hyperintensities in the globus pallidus confirmed chronic bilirubin encephalopathy. MRS demonstrated a reduction in N-acetylaspartate, indicative of neuronal loss. Susceptibility-Weighted Imaging (SWI) showed no abnormalities, likely due to the myelination process in neonates. Conclusions: This case highlights the importance of repeated MRI in detecting bilirubin-induced brain damage. Early neuroimaging enables timely interventions and improves long-term neurodevelopmental outcomes in infants with severe hyperbilirubinemia. Full article

Introduction: Molybdenum cofactor deficiency (MoCD) is a rare, lethal disorder characterized by early-onset encephalopathy and seizures. In 2021, fosdenopterin (Nulibry^TM) became the first FDA-approved treatment for MoCD type A (MoCD-A). Case Presentation: A G3P2 woman with a prior affected child underwent prenatal diagnosis of MoCD-A at 16 weeks via amniocentesis. Fetal Magnetic Resonance Imaging (MRI) at 22 weeks was normal but showed a mega cisterna magna by 28 weeks. Concerns of ongoing brain damage led to a cesarean section at 32 weeks 6 days estimated gestational age (EGA). Intravenous fosdenopterin was administered within 10 min of birth. Seizures started around 12 h and escalated to status epilepticus by 24 h but resolved by 60 h with treatment. Early MRI demonstrated acute injury without chronic changes. The infant was discharged on day 37 and diagnosed with spastic quadriplegic cerebral palsy at 6 months, with cognition relatively spared. At 24 months, the child remains seizure-free with moderate motor impairment. Conclusions: This case highlights that brain injury in MoCD-A may commence in utero during the second trimester. Early delivery combined with immediate neonatal fosdenopterin treatment controlled seizures and halted progression, but residual injury suggests that prenatal interventions are necessary to optimize outcomes. Full article

Background and Objective: This study aims to investigate the clinical significance and risk factors of retinal hemorrhages (RH) and white-centered retinal hemorrhages (Roth spots, RS) in neonates with hypoxic-ischemic encephalopathy (HIE), as well as their long-term ophthalmologic outcomes. Materials and Methods: Neonates diagnosed with HIE were classified into three stages according to the Sarnat classification. A comprehensive ophthalmologic assessment was performed within the first three days of life and at two years of age. Retinal hemorrhages were staged based on the Egge classification, and the presence of RS was also documented. The clinical characteristics and risk factors associated with RH and RS were systematically recorded. Results: Retinal hemorrhages were identified in 178 eyes (42.3%), and RS were observed in 180 eyes (42.8%). The prevalence of both RH and RS was significantly higher in neonates with Stage 2 and Stage 3 HIE (p < 0.001). The resolution time for both RH and RS was significantly prolonged in neonates with Stage 3 HIE compared to those with lower grades (p < 0.001). Furthermore, the frequency of grade 3 RH increased with advancing HIE stages (p < 0.001). Logistic regression analysis revealed that Stage 2 HIE (OR: 5.41, 95% CI: 1.19–24.54, p = 0.03) and Stage 3 HIE (OR: 27.17, 95% CI: 5.38–137.25, p < 0.001) were significantly associated with RS. Similarly, Stage 2 HIE (OR: 4.54, 95% CI: 1.00–20.68, p = 0.05) and Stage 3 HIE (OR: 40.88, 95% CI: 7.75–215.68, p < 0.001) were significantly associated with RH. At the age of two, strabismus was identified in 34 (18.4%) patients, while refractive errors were detected in 68 (37.4%) patients. Conclusions: The prevalence of RH and RS increases in correlation with the severity of HIE. While these hemorrhages generally resolve spontaneously, the risk of refractive errors and strabismus remains elevated. Full article

In this cohort study, we evaluated the cognitive and learning difficulties of school-age children perinatally infected with Chikungunya virus (CHIKV) on Reunion Island using the Evaluation of Cognitive Functions and Learning in Children (EDA) battery screening test compared to the healthy children cohort used for EDA development. Of the 19 infected children, 11 (57.9%) exhibited subnormal or abnormal scores, of whom 3 were classified as high risk, and 8 were classified as at risk for cognitive and learning difficulties. Children who had encephalopathy were at higher risk for displaying at least one difficulty than non-encephalopathic children (relative risk 2.13; 95% CI 1.05–4.33). The difficulties observed affected verbal functions, non-verbal functions, and learning abilities, such as phonology, lexical evocation and comprehension, graphism, selective visual attention, planning, visual–spatial reasoning, dictation and mathematics, as well as core executive functions, such as inhibitory control, shifting, and working memory. Neurocognitive dysfunctions could be linked to severe brain damage, as evidenced by severe white matter reduction mainly in the frontal lobes and corpus callosum and potentially in all functional networks involved in difficulties. These results should motivate further investigation of intellectual and adaptive functioning to diagnose intellectual deficiency and severe maladaptive behaviour in children perinatally infected with Chikungunya virus. Full article

Hypoxic–Ischemic Encephalopathy (HIE) occurs in patients who experience a decreased flow of blood and oxygen to the brain, with the optimal window for effective treatment being within the first six hours of life. This puts a significant demand on medical professionals to accurately and effectively grade the severity of the HIE present, which is a time-consuming and challenging task. This paper proposes a novel workflow for background EEG grading, implementing a blend of Digital Signal Processing (DSP) and Machine-Learning (ML) techniques. First, the EEG signal is transformed into an amplitude and frequency modulated audio spectrogram, which enhances its relevant signal properties. The difference between EEG Grades 1 and 2 is enhanced. A convolutional neural network is then designed as a regressor to map the input image into an EEG grade, by utilizing an optimized rounding module to leverage the monotonic relationship among the grades. Using a nested cross-validation approach, an accuracy of 89.97% was achieved, in particular improving the AUC of the most challenging grades, Grade 1 and Grade 2, to 0.98 and 0.96. The results of this study show that the proposed representation and workflow increase the potential for background grading of EEG signals, increasing the accuracy of grading background patterns that are most relevant for therapeutic intervention, across large windows of time. Full article

Background/Objectives: Hypoxic–ischemic encephalopathy (HIE), affecting 1.3–1.7/1000 live births, is treated with conventional therapeutic hypothermia (TH) but carries significant mortality and neurological impairment. Here, we compared intravascular cooling with extracorporeal membrane oxygenation (ECMO) and conventional TH in neonates with moderate to severe HIE. Methods: We retrospectively analyzed single-center neonates born in 2000–2022. Neonates with a 10 min Apgar score ≤ 3 or umbilical artery pH ≤ 6.7, along with persistent pulmonary hypertension of the newborn and an oxygenation index of ≥25 to <40, were divided into ECMO (n = 17) and conventional TH (n = 18) groups and administered the Kyoto Scale of Psychological Development at 18 months. Results: Neonatal and maternal characteristics were similar between the groups. A significantly higher proportion of the ECMO group (70.6% vs. 33.3%) achieved a developmental quotient ≥ 70. Conclusions: Intravascular cooling with ECMO may improve the neurodevelopmental outcomes of neonates with HIE, severe acidosis, and low Apgar scores. Full article

Hypothermia (HT) is used clinically for neonatal hypoxic–ischemic encephalopathy (HIE); however, the brain protection is incomplete and selective regional vulnerability and lifelong consequences remain. Refractory damage and impairment with HT cooling/rewarming could result from unchecked or altered persisting cell death and proteinopathy. We tested two hypotheses: (1) HT modifies neurodegeneration type, and (2) intrinsically disordered proteins (IDPs) and encephalopathy cause toxic conformer protein (TCP) proteinopathy neonatally. We studied postmortem human neonatal HIE cases with or without therapeutic HT, neonatal piglets subjected to global hypoxia-ischemia (HI) with and without HT or combinations of HI and quinolinic acid (QA) excitotoxicity surviving for 29–96 h to 14 days, and human oligodendrocytes and neurons exposed to QA for cell models. In human and piglet encephalopathies with normothermia, the neuropathology by hematoxylin and eosin staining was similar; necrotic cell degeneration predominated. With HT, neurodegeneration morphology shifted to apoptosis-necrosis hybrid and apoptotic forms in human HIE, while neurons in HI piglets were unshifting and protected robustly. Oligomers and putative TCPs of α-synuclein (αSyn), nitrated-Syn and aggregated αSyn, misfolded/oxidized superoxide dismutase-1 (SOD1), and prion protein (PrP) were detected with highly specific antibodies by immunohistochemistry, immunofluorescence, and immunoblotting. αSyn and SOD1 TCPs were seen in human HIE brains regardless of HT treatment. αSyn and SOD1 TCPs were detected as early as 29 h after injury in piglets and QA-injured human oligodendrocytes and neurons in culture. Cell immunophenotyping by immunofluorescence showed αSyn detected with antibodies to aggregated/oligomerized protein; nitrated-Syn accumulated in neurons, sometimes appearing as focal dendritic aggregations. Co-localization also showed aberrant αSyn accumulating in presynaptic terminals. Proteinase K-resistant PrP accumulated in ischemic Purkinje cells, and their target regions had PrP-positive neuritic plaque-like pathology. Immunofluorescence revealed misfolded/oxidized SOD1 in neurons, axons, astrocytes, and oligodendrocytes. HT attenuated TCP formation in piglets. We conclude that HT differentially affects brain damage in humans and piglets. HT shifts neuronal cell death to other forms in human while blocking ischemic necrosis in piglet for sustained protection. HI and excitotoxicity also acutely induce formation of TCPs and prion-like proteins from IDPs globally throughout the brain in gray matter and white matter. HT attenuates proteinopathy in piglets but seemingly not in humans. Shifting of cell death type and aberrant toxic protein formation could explain the selective system vulnerability, connectome spreading, and persistent damage seen in neonatal HIE leading to lifelong consequences even after HT treatment. Full article

Preclinical studies have shown that progenitor cells (PCs) are mobilized toward injured tissues to ameliorate damage and contribute to regeneration. The exogenous therapeutic administration of PCs in children affected by neonatal encephalopathy (NE) is a promising, yet underreported, topic. In this prospective study, we investigated whether endogenous circulating progenitor cells (CPCs) are involved in intrinsic regeneration mechanisms following neonatal brain injury. Thirteen full-term infants with moderate/severe NE, eleven with perinatal stress, and twelve controls were enrolled. Blood samples were collected on days 1, 3, 9, 18, and 45, as well as at 8 and 24 months of life, and were analyzed with a focus on Endothelial Progenitor Cells, Haematopoietic Stem Cells, and Very Small Embryonic-Like Stem Cells, in addition to chemotactic factors (erythropoietin, IGF-1, and SDF-1). Correlations between CPCs, chemotactic factors, and brain injury were assessed using serum levels of brain injury biomarkers (S100B and neuron-specific enolase), brain MRIs, and Bayley III developmental scores. Increased brain injury biomarkers were followed by the upregulation of SDF-1 receptor and erythropoietin and, finally, by elevated CPCs. These findings suggest a potential endogenous regenerative effort, primarily observed in the moderate encephalopathy group, but this is suppressed in cases of severe brain injury. Mimicking and enhancing endogenous regeneration pathways in cases of failure—regarding cell type and timeframe—could provide a novel therapeutic model. Full article