Retrospective study on neonatal seizures in a tertiary center of northern Italy after ILAE classification: Incidence, seizure type, EEG and etiology.

OBJECTIVE: We aimed to evaluate epidemiology, seizure type, EEG, and etiology of neonatal seizures (NS) in a tertiary neonatal intensive care unit. METHODS: Data on infants with a neurophysiological confirmation of NS were collected between 2009 and 2022. Seizure types and epileptic syndromes were classified by the ILAE classification and EEG by the Italian Neonatal Seizure Collaborative Network (INNESCO) score. RESULTS: Out of 91,253 neonates, 145 presented with NS; 69.7 % were born at term and 30.3 % were preterm infants. The incidence of NS in neonates born at our center was 1.2 per 1,000 live newborns (96/80697 neonates) while in the entire neonatal population admitted to our center it was 1.6 per 1,000 live births, increasing with lower preterm age. Compared to previous studies, we found a lower proportion of hypoxic-ischemic encephalopathy (HIE) (23.4 %) and a higher rate of genetic contribution (26.2 %). The infection rate was higher in preterm (31.8 %) than in full term (9.9 %) infants. Electrographic seizures were associated with acute provoked seizures (35.9 %), preterm age (52.3 %), and HIE (52.9 %). Vascular etiology was associated with focal clonic seizures (56.8 %). Non-structural neonatal genetic epilepsy was associated with sequential seizures (68.2 %), particularly KCNQ2 and SCN2A epilepsy. Background EEG was abnormal in all HIE, infections (85.7 %) and metabolic NS (83.3 %). In genetic epilepsy, background EEG depended on the epileptic syndrome: normal in 80 % of self-limited neonatal epilepsy and abnormal in 77.8 % of developmental and epileptic encephalopathy. Electroclinical seizures were associated with focal onset, while electrographic seizures correlated with a multifocal onset. CONCLUSIONS: A low incidence of HIE and a high incidence of genetic etiology were observed in our cohort of NS. Seizure type and EEG features are fundamental to address etiology.

Neonatal Encephalopathy is a Complex Phenotype Representing Reproductive and Pregnancy Exposome Effects on the Maternal-Placental-Fetal Triad.

Reproductive, pregnancy, and placental exposomes influence the fetal neural exposome through toxic stressor interplay, impairing the maternal-placental-fetal (MPF) triad. Neonatal encephalopathy represents different clinical presentations based on complex time-dependent etiopathogenetic mechanisms including hypoxia-ischemia that challenge diagnosis and prognosis. Reproductive, pregnancy, and placental exposomes impair the fetal neural exposome through toxic stressor interplay within the MPF triad. Long intervals often separate disease onset from phenotype. Interdisciplinary fetal-neonatal neurology training, practice, and research closes this knowledge gap. Maintaining reproductive health preserves MPF triad health with life-course benefits.

Causes and Terminology in Neonatal Encephalopathy: What is in a Name? Neonatal Encephalopathy, Hypoxic-ischemic Encephalopathy or Perinatal Asphyxia.

Neurologic depression in term/near-term neonates (neonatal encephalopathy, NE) is uncommon with modern obstetric care. Asphyxial birth, with or without co-factors, accounts for a minority of NE, while maldevelopment (congenital malformations, growth aberrations, genetic, metabolic and placental abnormalities) plays an enlarging role in identifying etiologic subgroups of NE. The terms NE and hypoxic-ischemic encephalopathy (HIE) have not been employed uniformly, hampering research and clinical care. The authors propose the term NE as an early working-diagnosis, to be supplemented by a diagnosis of NE due to HIE or to other factors, as a final diagnosis once workup is complete.

Reverse Therapy: Impact of Hyperthermia and Rewarming on Newborn Outcomes.

Therapeutic hypothermia is now well established to improve neurodevelopmental outcomes after hypoxic-ischemic encephalopathy (HIE). Although the overall principles of treatment are now well established, many smaller questions are unclear. The potential impact of reversal of hypothermia therapy and the effect of high temperatures on recovery of the neurovascular unit after therapeutic hypothermia for HIE has received relatively little attention. This article will address the effects of hypoxia-ischemia and rewarming and increased temperatures on the neurovascular unit in preclinical and clinical models.

Long-Term Outcomes Following Hypoxic Ischemic Encephalopathy.

Hypoxic ischemic encephalopathy (HIE) is the most common cause of neonatal encephalopathy and results in significant morbidity and mortality. Long-term outcomes of the condition encompass impairments across all developmental domains. While therapeutic hypothermia (TH) has improved outcomes for term and late preterm infants with moderate to severe HIE, trials are ongoing to investigate the use of TH for infants with mild or preterm HIE. There is no evidence that adjuvant therapies in combination with TH improve long-term outcomes. Numerous trials of various adjuvant therapies are underway in the quest to further improve outcomes for infants with HIE.

Communicating with Parents About Therapeutic Hypothermia and Hypoxic Ischemic Encephalopathy: Integrating a Palliative Care Approach into Practice.

Parents of newborns with hypoxic ischemic encephalopathy (HIE) can face communication challenges in the neonatal intensive care unit. Both specialty palliative care and primary palliative care trained clinicians can assist parents as they navigate traumatic experiences and uncertain prognoses. Using evidence-based frameworks, the authors provide samples of how to communicate with parents and promote parent well-being across the care trajectory. The authors demonstrate how to involve parents in a shared decision-making process and give special consideration to the complexities of hospital discharge and the transition home. Sustained investment to guide the development of effective communication skills is crucial to support families of infants with HIE.

A New Horizon for Understanding the Comparative Effectiveness for Cooling Prospectively Infants with Mild Encephalopathy.

The authors summarize the methodology for a new pragmatic comparative effectiveness research investigation, Cooling Prospectively Infants with Mild Encephalopathy (COOLPRIME), which uses sites' existing mild hypoxic-ischemic encephalopathy (HIE) treatment preference (hypothermia or normothermia) to assess hypothermia effectiveness and safety. COOLPRIME's primary aim is to determine the safety and effectiveness of hypothermia compared to normothermia in mild HIE. Engagement of Families and Community Affected by Hypoxic-Ischemic Encephalopathy strongly favored Effectiveness over Efficacy Trials leading to COOL PRIME design.

Key Inflammatory Biomarkers in Perinatal Asphyxia: A Comprehensive Review.

This article summarizes the current evidence regarding inflammatory biomarkers (placental and postnatal) and provides a comprehensive understanding of their roles: (1) diagnostic accuracy to predict the severity of hypoxic-ischemia encephalopathy (HIE), (2) value in assessing treatment responses, and (3) prediction of both short- and long-term neurodevelopmental outcomes. In the early critical stages of perinatal asphyxia, inflammatory biomarkers may guide clinical decision-making. Additional research is required to increase our understanding of the optimal utility of biomarkers to predict the severity, evolution, and developmental outcomes after exposure to HIE.

Pipeline to Neonatal Clinical Transformation: The Importance of Preclinical Data.

Historically, neonatal neuroscience boasted a robust and successful preclinical pipeline for therapeutic interventions, in particular for the treatment of hypoxic-ischemic encephalopathy (HIE). However, since the successful translation of therapeutic hypothermia (TH), several high-profile failures of promising adjunctive therapies, in addition to the lack of benefit of TH in lower resource settings, have brought to light critical issues in that same pipeline. Using recent data from clinical trials of erythropoietin as an example, the authors highlight several key challenges facing preclinical neonatal neuroscience for HIE therapeutic development and propose key areas where model development and collaboration across the field in general can ensure ongoing success in treatment development for HIE worldwide.

Ethical and Legal Perspectives on the Treatment of Hypoxic Ischemic Encephalopathy in the Newborn.

Hypoxic ischemic encephalopathy (HIE) in neonates can cause severe, life-long functional impairments or death. Treatment of these neonates can involve ethically challenging questions about if, when, and how it may be appropriate to limit life-sustaining medical therapy. Further, parents whose infants suffer severe neurologic damage may seek recourse in the form of a medical malpractice lawsuit. This study uses several hypothetical cases to highlight important ethical and legal considerations in the care of infants with HIE.

Improving the future of clinical trials and translation of mesenchymal stromal cell therapies for neonatal disorders.

Despite recent advances in neonatal intensive care medicine, neonatal disorders such as (bronchopulmonary dysplasia [BPD], intraventricular hemorrhage [IVH], and hypoxic ischemic encephalopathy [HIE]) remain major causes of death and morbidity in survivors, with few effective treatments being available. Recent preclinical studies have demonstrated the pleiotropic host injury-responsive paracrine protective effects of cell therapy especially with mesenchymal stromal cells (MSCs) against BPD, IVH, and HIE. These findings suggest that MSCs therapy might emerge as a novel therapeutic modality for these currently devastating neonatal disorders with complex multifactorial etiologies. Although early-phase clinical trials suggest their safety and feasibility, their clinical therapeutic benefits have not yet been proven. Therefore, based on currently available preclinical research and clinical trial data, we focus on critical issues that need to be addressed for future successful clinical trials and eventual clinical translation such as selecting the right patient and optimal cell type, route, dose, and timing of MSCs therapy for neonatal disorders such as BPD, HIE, and IVH.

A case report of spastic diplegic cerebral palsy in a late preterm child with hypoplastic left heart syndrome.

Background: Congenital heart disease (CHD) is the most common birth defect, affecting 1% of children who are born in the United States each year. Children with hypoplastic left heart syndrome, a type of critical CHD, are at high risk for neurodevelopmental disabilities, which are conditions that can affect motor, language, and cognitive development. In children with critical CHD, the severity and prevalence of their motor delays is most pronounced in infancy. Case Description: We present a case of a former late preterm male with hypoplastic left heart syndrome and history of hypoxic ischemic encephalopathy, who was diagnosed with spastic diplegic cerebral palsy in the setting of periventricular leukomalacia. Like many children with critical CHD, this child had gross motor delays and tone abnormalities in infancy. However, unlike many children with CHD, he continued to have neurologic differences that prompted additional evaluation through a Cardiac Neurodevelopmental Program. He was diagnosed with spastic diplegic cerebral palsy based upon clinical history and physical examination. Ancillary testing showed periventricular leukomalacia on brain magnetic resonance imaging (MRI); this finding was consistent with his clinical diagnosis. Conclusions: This is an interesting case report of spastic diplegic cerebral palsy in a late preterm infant with critical CHD. When making a diagnosis of cerebral palsy, it is important to consider the etiology of the motor impairment. Selective vulnerability may have played a factor in this child's condition. The most vulnerable part of the neonatal brain is the periventricular white matter; cerebral hypoxia can lead to periventricular leukomalacia. Children with CHD have brain dysmaturity beginning in-utero. Thus, it is possible that this child's brain dysmaturity may have increased his susceptibility to periventricular leukomalacia. Because most children with CHD have gross motor delays in infancy, it may be challenging to make a definitive diagnosis of cerebral palsy in an infant with critical CHD. Children with cerebral palsy have early motor delays that persist throughout life. It is the identification of persistent motor impairments through repeat evaluations that enabled this child's cerebral palsy diagnosis. This illustrates the importance of developmental surveillance in children with critical CHD.

Prevalence of Pulmonary Hypertension During Therapeutic Hypothermia for Hypoxic Ischemic Encephalopathy and Evaluation of Short-Term Outcomes.

Infants with perinatal asphyxia and moderate-to-severe hypoxic ischemic encephalopathy (HIE) are currently treated with therapeutic hypothermia (TH) as part of a brain protective strategy. However, perinatal asphyxia is a risk factor for development of persistent pulmonary hypertension (PPHN). As such, the aim of this study was to quantify the risk of PPHN in infants undergoing TH and assess short-term outcomes in infants developing PPHN. All N = 59 infants undergoing TH for moderate-to-severe HIE over a period of 3 years (January 2020-December 2022) at a single center were included. PPHN was diagnosed in N = 10 (17%), with this deemed to have been exacerbated by TH in n = 6 (10%). Only 50% (5/10) with PPHN required inhaled nitric oxide, and none of the infants received extracorporeal membrane oxygenation. PPHN was not found to be significantly associated with short-term outcomes, including the extent of HIE on brain magnetic resonance imagings, in-hospital mortality or requirement for nasogastric feeding at discharge. In conclusion, TH appears to be a safe and effective treatment for moderate-to-severe HIE with or without PPHN.

Neocortical cholinergic pathology after neonatal brain injury is increased by Alzheimer's disease-related genes in mice.

Hypoxic-ischemic encephalopathy (HIE) in neonates causes mortality and neurologic morbidity, including poor cognition with a complex neuropathology. Injury to the cholinergic basal forebrain and its rich innervation of cerebral cortex may also drive cognitive pathology. It is uncertain whether genes associated with adult cognition-related neurodegeneration worsen outcomes after neonatal HIE. We hypothesized that neocortical damage caused by neonatal HI in mice is ushered by persistent cholinergic innervation and interneuron (IN) pathology that correlates with cognitive outcome and is exacerbated by genes linked to Alzheimer's disease. We subjected non-transgenic (nTg) C57Bl6 mice and mice transgenically (Tg) expressing human mutant amyloid precursor protein (APP-Swedish variant) and mutant presenilin (PS1-ΔE9) to the Rice-Vannucci HI model on postnatal day 10 (P10). nTg and Tg mice with sham procedure were controls. Visual discrimination (VD) was tested for cognition. Cortical and hippocampal cholinergic axonal and IN pathology and Aß plaques, identified by immunohistochemistry for choline acetyltransferase (ChAT) and 6E10 antibody respectively, were counted at P210. Simple ChAT+ axonal swellings were present in all sham and HI groups; Tg mice had more than their nTg counterparts, but HI did not affect the number of axonal swellings in APP/PS1 Tg mice. In contrast, complex ChAT+ neuritic clusters (NC) occurred only in Tg mice; HI increased that burden. The abundance of ChAT+ clusters in specific regions correlated with decreased VD. The frequency of attritional ChAT+ INs in the entorhinal cortex (EC) was increased in Tg shams relative to their nTg counterparts, but HI obviated this difference. Cholinergic IN pathology in EC correlated with NC number. The Aß deposition in APP/PS1 Tg mice was not exacerbated by HI, nor did it correlate with other metrics. Adult APP/PS1 Tg mice have significant cortical cholinergic axon and EC ChAT+ IN pathologies; some pathology was exacerbated by neonatal HI and correlated with VD. Mechanisms of neonatal HI induced cognitive deficits and cortical neuropathology may be modulated by genetic risk, perhaps accounting for some of the variability in outcomes.

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OBJECTIVES: To investigate the efficacy of therapeutic hypothermia on mild neonatal hypoxic-ischemic encephalopathy (HIE). METHODS: A prospective study was performed on 153 neonates with mild HIE who were born from September 2019 to September 2023. These neonates were randomly divided into two groups: therapeutic hypothermia (n=77) and non-therapeutic hypothermia group (n=76). The short-term clinical efficacy of the two groups were compared. Barkovich scoring system was used to analyze the severity of brain injury shown on magnetic resonance imaging (MRI) between the two groups. RESULTS: There were no significant differences in gestational age, gender, birth weight, mode of birth, and Apgar score between the therapeutic hypothermia and non-therapeutic hypothermia groups (P>0.05). There were no significant differences in the incidence rates of sepsis, arrhythmia, persistent pulmonary hypertension and pulmonary hemorrhage and the duration of mechanical ventilation within the first 72 hours after birth between the two groups. The therapeutic hypothermia group had longer prothrombin time within the first 72 hours after birth and a longer hospital stay (P<0.05). Compared with the non-therapeutic hypothermia group, the therapeutic hypothermia group had lower incidence rates of MRI abnormalities (30% vs 57%), moderate to severe brain injury on MRI (5% vs 28%), and watershed injury (27% vs 51%) (P<0.05), as well as lower medium watershed injury score (0 vs 1) (P<0.05). CONCLUSIONS: Therapeutic hypothermia can reduce the incidence rates of MRI abnormalities and watershed injury, without obvious adverse effects, in neonates with mild HIE, suggesting that therapeutic hypothermia may be beneficial in neuroprotection in these neonates.

Combined use of the Montreal Cognitive Assessment and Symbol Digit Modalities Test improves neurocognitive screening accuracy after cardiac arrest: A validation sub-study of the TTM2 trial.

AIM: To assess the merit of clinical assessment tools in a neurocognitive screening following out-of-hospital cardiac arrest (OHCA). METHODS: The neurocognitive screening that was evaluated included the performance-based Montreal Cognitive Assessment (MoCA) and Symbol Digit Modalities Test (SDMT), the patient-reported Two Simple Questions (TSQ) and the observer-reported Informant Questionnaire on Cognitive Decline in the Elderly-Cardiac Arrest (IQCODE-CA). These instruments were administered at 6-months in the Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trial. We used a comprehensive neuropsychological test battery from a TTM2 trial sub-study as a gold standard to evaluate the sensitivity and specificity of the neurocognitive screening. RESULTS: In our cohort of 108 OHCA survivors (median age = 62, 88% male), the most favourable cut-off scores were: MoCA < 26; SDMT z ≤ -1; IQCODE-CA ≥ 3.04. The MoCA (sensitivity 0.64, specificity 0.85) and SDMT (sensitivity 0.59, specificity 0.83) had a higher classification accuracy than the TSQ (sensitivity 0.28, specificity 0.74) and IQCODE-CA (sensitivity 0.42, specificity 0.60). When using the cut-points for MoCA or SDMT in combination to identify neurocognitive impairment, sensitivity improved (0.81, specificity 0.74), area under the curve = 0.77, 95% CI [0.69, 0.85]. The most common unidentified impairments were within the episodic memory and executive functions domains, with fewer false negative cases on the MoCA or SDMT combined. CONCLUSION: The MoCA and SDMT have acceptable diagnostic accuracy for screening for neurocognitive impairment in an OHCA population, and when used in combination the sensitivity improves. Patient and observer-reports correspond poorly with neurocognitive performance. CLINICALTRIALS: gov Identifier: NCT03543371.

Histone modifications in hypoxic ischemic encephalopathy: Implications for therapeutic interventions.

Hypoxic-ischemic encephalopathy (HIE) is a brain injury induced by many causes of cerebral tissue ischemia and hypoxia. Although HIE may occur at many ages, its impact on the neonatal brain is greater because it occurs during the formative stage. Recent research suggests that histone modifications may occur in the human brain in response to acute stress events, resulting in transcriptional changes and HIE development. Because there are no safe and effective therapies for HIE, researchers have focused on HIE treatments that target histone modifications. In this review, four main histone modifications are explored, histone methylation, acetylation, phosphorylation, and crotonylation, as well as their relevance to HIE. The efficacy of histone deacetylase inhibitors in the treatment of HIE is also explored. In conclusion, targeting histone modifications may be a novel strategy for elucidating the mechanism of HIE, as well as a novel approach to HIE treatment.

2,3-Diphosphoglyceric Acid Alleviating Hypoxic-Ischemic Brain Damage through p38 MAPK Modulation.

Neonatal hypoxic-ischemic encephalopathy (HIE) is a critical condition characterized by significant brain damage due to insufficient blood flow and oxygen delivery at birth, leading to high rates of neonatal mortality and long-term neurological deficits worldwide. 2,3-Diphosphoglyceric acid (2,3-DPG), a small molecule metabolite prevalent in erythrocytes, plays an important role in regulating oxygen delivery, but its potential neuroprotective role in hypoxic-ischemic brain damage (HIBD) has yet to be fully elucidated. Our research reveals that the administration of 2,3-DPG effectively reduces neuron damage caused by hypoxia-ischemia (HI) both in vitro and in vivo. We observed a notable decrease in HI-induced neuronal cell apoptosis, attributed to the downregulation of Bax and cleaved-caspase 3, alongside an upregulation of Bcl-2 expression. Furthermore, 2,3-DPG significantly alleviates oxidative stress and mitochondrial damage induced by oxygen-glucose deprivation/reperfusion (OGD/R). The administration of 2,3-DPG in rats subjected to HIBD resulted in a marked reduction in brain edema and infarct volume, achieved through the suppression of neuronal apoptosis and neuroinflammation. Using RNA-seq analysis, we validated that 2,3-DPG offers protection against neuronal apoptosis under HI conditions by modulating the p38 MAPK pathway. These insights indicated that 2,3-DPG might act as a promising novel therapeutic candidate for HIE.

Circulating MicroRNAs as a biomarker signature of perinatal asphyxia.

AIM: This study aimed to explore whether microRNAs (miRNAs) could serve as biomarkers of perinatal asphyxia and whether they were correlated with severity of brain magnetic resonance imaging. METHODS: We prospectively enrolled 26 full-term newborns, including 10 with perinatal asphyxia and 16 healthy controls. Plasma samples were collected at 0-6 h and 7 days of age. Encephalopathy was classified according to modified Sarnat staging. Magnetic resonance imaging was performed in surviving infants within 30 days of birth, and a score was established. We used next-generation sequencing to explore differentially expressed miRNAs, which were then further validated using quantitative reverse transcription real-time polymerase chain reaction (RT-PCR). RESULTS: A significantly lower expression of miR-486-5p was found at 0-6 h of age in the asphyxiated newborns compared with the healthy controls (p = 0.005). The area under the receiver operating characteristic curve (AUC) of miR-486-5p at 0-6 h of age to differentiate the perinatal asphyxia group from the healthy control group was 0.831, and the AUC to differentiate newborns eligible for therapeutic hypothermia from others was 0.782. In addition, a lower expression of miR-486-5p at 7 days of age was noted in the asphyxiated newborns with adverse outcomes compared to those with normal outcomes. CONCLUSION: MiR-486-5p may be a biomarker of perinatal asphyxia in newborns, and further research is warranted to clarify its role.

Hypothermia for Hypoxic-ischemic Encephalopathy: Second-generation Trials to Address Gaps in Knowledge.

Multiple randomized controlled trials of hypothermia for moderate or severe neonatal hypoxic-ischemic encephalopathy (HIE) have uniformly demonstrated a reduction in death or disability at early childhood evaluation. These initial trials along with other smaller studies established hypothermia as a standard of care in the neonatal community for moderate or severe HIE. The results of the initial trials have identified gaps in knowledge. This article describes 3 randomized controlled trials of hypothermia (second-generation trials) to address refinement of hypothermia therapy (longer and/or deeper cooling), late initiation of hypothermia (after 6 hours following birth), and use of hypothermia in preterm newborns.