Perinatal Hypoxic-ischemic Encephalopathy Research Articles

Longitudinal Analysis of Sleep-Wake States in Neonatal Rats Subjected to Hypoxia-Ischemia.

ObjectiveSleep is necessary for brain maturation in infants. Perinatal hypoxic-ischemic encephalopathy (HIE) is a major cause of chronic neurological disease in infants. Although the developmental changes of electroencephalogram (EEG) in human newborns have been described, little is known about the EEG normal maturation characteristics in rodents and the changes in sleep-awake states caused by hypoxia-ischemia (HI). This study aimed to investigate the pathological response of sleep-wake states in neonatal rats with HIE.MethodsWe constructed HIE and sham models on postnatal day (P) 3 rats and continuously monitored them using electroencephalography and electromyography for up to P12. The distribution of sleep-wake states was analyzed to estimate the effects of HIE.ResultsCompared with the sham group, the HI group showed lower rapid eye movement (REM) sleep percentage, but wake percentage and frequency was higher during P4-P12. The frequency of REM and non-rapid eye movement (NREM) sleep increased and the duration of REM and NREM sleep decreased after HI induction. However, it gradually returned to the normal level with an increase in daytime.ConclusionHI damage alters the sleep-wake patterns during early neural development. The findings provide a comprehensive assessment of serial sleep-wake state recordings in neonatal rats from P4-P12.

MicroRNA Expression Profiles as Diagnostic and Prognostic Biomarkers of Perinatal Asphyxia and Hypoxic-Ischaemic Encephalopathy

Introduction: Perinatal asphyxia is a leading cause of neonatal death. Up to one-third of asphyxiated neonates suffer from hypoxic-ischaemic encephalopathy (HIE) with substantial long-term morbidity. Currently available diagnostic and prognostic tools bear limitations, and additional reliable biomarkers are needed for all stages of clinical management. A novel tool in neuroscientific research is micro-ribonucleic acid (miRNA) profiling. The aim of the present study was to determine miRNA expression profiles of healthy and asphyxiated neonates with and without HIE and to assess their potential as diagnostic and prognostic biomarkers. Methods: We prospectively enrolled 49 neonates with a gestational age of ≥36 weeks, 15 of which fulfilled the diagnostic criteria of perinatal asphyxia and 34 served as healthy controls. Dried blood spots were collected from umbilical cord blood (UCB) and from venous blood upon admission to neonatal intensive care unit (NICU) and at 48 h of life. Samples were analysed by means of FirePlex™ technology (Abcam, Cambridge, MA, USA). Results: In the UCB, miRNA expression levels of hsa-mir-124-3p, hsa-mir-1285-5p, and hsa-mir-331-5p were significantly lower in asphyxiated neonates compared to healthy controls. Asphyxiated neonates requiring therapeutic hypothermia had significantly increased expression of hsa-miR-30e-5p and significantly decreased expression of hsa-miR-142-3p, hsa-miR-338-3p, hsa-miR-34b-3p, hsa-miR-497-5p, and hsa-miR-98-5p at the time of admission to the NICU. At 48 h, infants suffering from moderate/severe HIE with a poor long-term neurodevelopmental outcome showed a significant increase in hsa-mir-145-5p. Discussion/Conclusion: MiRNA profiling shows promise as a biomarker for perinatal asphyxia, hypothermia-requiring HIE, and poor neurodevelopmental outcome. Confirmatory studies are called for.

Neurophysiological recordings improve the accuracy of the evaluation of the outcome in perinatal hypoxic ischemic encephalopathy.

Our objective was to evaluate the potential additional value of electroencephalogram (EEG) and evoked potentials in neonates with hypoxic-ischemic encephalopathy to predict their disability at 1 and 2 years old. 30 full-term infants after perinatal asphyxia who underwent therapeutic hypothermia were evaluated at 1 year and 2 years for disability using International Classification of Functioning, Disability and Health classification. Scores for EEG, sensory evoked potentials and brainstem auditory evoked potentials were evaluated after withdrawal of therapeutic hypothermia that lasted 72h. A regression approach was investigated to build models allowing to distinguish neonates according to their disability at 1 and 2 years. Two models were built, the first by considering the clinical data and EEG before and after therapeutic hypothermia and the second by incorporating evoked potentials recording. Adding EEG and evoked potentials data after rewarming improved dramatically the accuracy of the model considering outcome at 1 and 2 years. We propose to record systematically EEG and evoked potentials following rewarming to predict the outcome of neonates with hypoxic ischemic encephalopathy. Combination of altered evoked potentials with no improvement of EEG after rewarming appeared to be a robust criterion for a poor outcome.

The value of ultrasonography in predicting outcomes at an early school age among individuals with perinatal hypoxic-ischemic encephalopathy

Neurosonography (NSG) is a readily available non-invasive radiological examination technique that assesses brain damage in neonates who experienced perinatal hypoxia. The aim of the study was to determine the relationship between hypoxic-ischemic (HI) brain injuries in full-term neonates detected during ultrasonography and mental and neuromotor development outcomes at an early school age. We evaluated 8–9-year-old children (n = 32) who had experienced hypoxia at birth with mild to moderate hypoxic-ischemic encephalopathy (HIE) and hadn’t undergone therapeutic hypothermia. The control group consisted of 8–9-year-old children (n = 16) who were born healthy. During the first five days of life, the newborns underwent cerebral ultrasonography. The HIE stage was evaluated according to the Sarnat and Sarnat scale. Neuromotor and neurological outcomes were assessed using the Gross Motor Function Classification System, the Health Utilities Index (HUI) questionnaire, the Wechsler Intelligence Scale for Children WISC-III, and structured neurological examination. In the case of moderate brain edema and/or thalamus and/or basal ganglion injuries along with cerebellum and brainstem (E/T/BG/C/B) injuries compared to other injuries, the following abnormalities were statistically significantly more common: hearing disorders (100%, p = 0.03), cerebellar dysfunction (60%, p = 0.02), epilepsy (60%, p = 0.01), a lower Working Memory Index (median, 82.0, p = 0.015). In case of moderate brain swelling (edema) and thalamus and/or basal ganglion (E/T/BG) injuries, the sensitivity and specificity of the ultrasound examination when predicting epilepsy, hearing disorders, lower full IQ, and the Perceptual Organization Index were 100%. Neurosonography helps predict the outcomes of mental and neuromotor development at an early school age in full-term neonates who experienced perinatal asphyxia/hypoxia. Moderate hypoxic-ischemic brain changes detected during ultrasonography were statistically significantly associated with hearing disorders, cerebellar dysfunction, epilepsy, and a lower Working Memory Index in children at an early school age.

Hydrogen Attenuated Inflammation Response and Oxidative in Hypoxic Ischemic Encephalopathy via Nrf2 Mediated the Inhibition of NLRP3 and NF-κB

Hypoxia and ischemia cause neonatal encephalopathy and brain injury and can further result in cerebral palsy, cognitive impairment, growth restriction, and epilepsy. Induction of neuroprotection is a crucial therapeutic strategy for the treatment of perinatal hypoxic–ischaemic encephalopathy (HIE). Hydrogen has neuroprotective effects against brain-related diseases. Inflammation and oxidative stress are the two main pathophysiological mechanisms in neonatal hypoxic–ischaemic injury. Nuclear factor erythroid 2-related factor 2 (Nrf2) is an endogenous redox-sensitive transcription factor that participates in the antioxidant defence system through its effects on inflammation and oxidative stress. Herein, the research focuses on the mechanisms by which Nrf2 participates in the protection of hydrogen against HIE. The model of HIE was established by ligation of the right carotid artery and hypoxia in wild-type (WT) and Nrf2−/− mice. First, Nrf2 pathway activity was detected after hypoxia–ischaemia (HI) followed or not by hydrogen treatment. Brain injury, apoptosis, the inflammatory response, oxidative stress injury, and learning and memory function were assayed. We found that HI induced Nrf2 expression and signalling activation. Hydrogen alleviated the infarction volume, brain water content, neurological scores, apoptosis and long-term learning and memory functions after HI in WT mice but not in Nrf2−/− mice. Moreover, the oxidative products reactive oxygen species (ROS) and malondialdehyde (MDA) and the cytokines tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6) and High mobility group box 1 (HMGB1) were reduced and the antioxidant enzymes Superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT) were upregulated by hydrogen treatment after HI in WT mice, but not in Nrf2−/− mice. In addition, the absence of Nrf2 abolished the suppressive effect of hydrogen on the expression of Nacht, Lrr, and Pyd domains-containing protein 3 (NLRP3) pathway members and p65 NF-κB after HI. Taken together, our findings showed that hydrogen alleviated cellular injury and apoptosis, neurobehavioural deficits, the inflammatory response and oxidative stress via the Nrf2-mediated NLRP3 and NF-κB pathways.

Integrated 2D Doppler indices of uteroplacental and fetal blood flow in diagnosis of intrauterine hypoxia

Relevance . Intrauterine hypoxia associated with placental disorders is a significant factor of ante-, intra- and postnatal fetal and newborn death. Despite clinical examination of pregnant women using ultrasound and cardiotocography, cases of intrauterine hypoxia often remain undetected prenatally. Clinical manifestation of placental disorders and intrauterine hypoxia are associated with pathological changes of blood flow resistance in the uterine, placental and fetal vessels. A combined Doppler assessment of blood flow in the uterine, placental and fetal vessels could improve detection of intrauterine hypoxia. The aim of the study was to assess the prognostic significance of integrated 2D Doppler indices of uteroplacental and fetal blood flow for the detection of fetal hypoxia in the 3rd trimester and to predict unfavorable perinatal outcomes. Materials and Methods. The outcomes of pregnancy of 48 women with fetal hypoxia delivered at 29 - 40 gestational weeks (study group), and 21 women who gave birth to healthy full-term infants (control group) were retrospectively analyzed. On the eve of delivery all women had 2D Doppler assessment of the uterine arteries, umbilical arteries, and fetal middle cerebral artery with an assessment of the cerebro-placental ratio, umbilical-cerebral ratio and cerebro-placental-uterine ratio. Results and Discussion . Analysis of the obtained values of cerebro-placental-uterine ratio, cerebro-placental ratio and umbilical-cerebral ratio showed the benefit from use of integrated 2D Doppler indices in the diagnosis of fetal hypoxia at 29 - 40 gestations weeks and in predicting complications in newborns. The high sensitivity of the cerebro-placental-uterine ratio (90.5%) makes it possible to effectively use this index for the diagnosis of intrauterine hypoxia. Conclusion. Pathological cerebro-placental-uterine ratio 2.44 is a clinically significant 2D Doppler criterion that predicts a high risk of asphyxia, respiratory distress syndrome, hypotrophy, and perinatal hypoxic-ischemic encephalopathy. Lower values of the cerebro-placental ratio and umbilical-cerebral ratio sensitivity (77.1% and 81.3%, respectively) limit their use for the diagnosis of fetal hypoxia as compared with cerebro-placental-uterine ratio.

Speech development in children of preschool age with arthrogryposis multiplex congenital with upper limb deformities

BACKGROUND: The difficulties or gross disturbance in motor development, which are diagnosed in children at an early age, are one of the prognostic markers of further problems in their speech development.
 AIM: This study aimed to determine the speech development of children with arthrogryposis multiplex congenita with upper limb deformities.
 MATERIALS AND METHODS: Speech examination was conducted in 21 children with arthrogryposis multiplex congenita preschool age (average age: 5.16 1.49 years) from 2020 to 2021. Patients were divided into 2 groups: group 1 (10 people) with children of younger and middle preschool age (average age 3.81 0.63 years) and group 2 (11 people) with children of older and preparatory preschool age (average age 6.39 0.78 years). The speech examination results were exposed to statistical analysis.
 RESULTS: The majority of children with arthrogryposis multiplex congenita had speech pathology (90.5%), whereas general speech underdevelopment dominated over speech development delay (78.9% and 21.1%, respectively). A high frequency of perinatal hypoxic-ischemic encephalopathy in children with arthrogryposis multiplex congenita (80.9%), a complicated perinatal anamnesis (57.1%), and a delay in early motor or speech development (100% and 52.4%, respectively) links with speech disorder development in the future. Patients with arthrogryposis have a large percentage of congenital pathology of the articulatory apparatus structure (57.1%). Of the children, 76.2% were with a total form of arthrogryposis multiplex congenita, whereas 23.8% with an isolated upper extremity lesion. No statistically significant differences were determined in the form of speech pathology between patients with various forms of arthrogryposis multiplex congenita. Children of the first age group had speech disorders in 90% of cases, whereas 90.9% in group 2. Based on the form of speech pathology, patients with general speech underdevelopment and speech development delay were determined in group 1 (55.6% and 44.4%, respectively), whereas children with general speech underdevelopment in group 2 (100%). In the clinical form of speech pathology, dysarthria prevailed in children of both age groups (80%).
 CONCLUSIONS: Children with arthrogryposis multiplex congenita with upper limb deformities have a high incidence of speech disorders. Early speech examination and speech therapy eliminated all detected disturbances.

The role of urine metabolomics among newborn infants with hypoxic ishaemic encephalopathy: a literature review

Background: Perinatal asphyxia (PA) which may result in hypoxic ischaemic encephalopathy (HIE) affects four million neonates worldwide and accounts for the death of one million of affected babies. The science of metabolomics has become an area of growing interest in neonatal research, with a potential role in identifying useful biomarkers that can accurately predict injury severity in perinatal asphyxia and HIE. The aim of this review is to look at the evidence of the usefulness of urine metabolomics in predicting outcome in PA/HIE. Methods: The key words used in the advanced search ‘urine metabolomics’ AND ‘perinatal asphyxia’ OR ‘hypoxic ischaemic encephalopathy’, yielded 13 articles. Results: Of the selected thirteen studies, 38% (n = 5) were human studies, 31% (n= 4) were animal studies and 31% (n = 4) were review articles. The studies confirmed the involvement of known pathways in the development of PA/HIE, primarily the Krebs cycle evidenced by accumulation of TCA cycle intermediates (citrate, α-ketoglutarate, succinate) and anaerobic pathways indicated by increased lactate. Other pathways involved include amino acid and carbohydrate pathways. Conclusion: Metabolomic studies so far are promising in highlighting potential biomarker profiles in PA/HIE. Further research is necessary to further clarify the role of identified metabolites in predicting outcome and prognosis in neonates affected by PA/HIE.

Assessing Creatine Supplementation for Neuroprotection against Perinatal Hypoxic-Ischaemic Encephalopathy: A Systematic Review of Perinatal and Adult Pre-Clinical Studies.

There is an important unmet need to develop interventions that improve outcomes of hypoxic-ischaemic encephalopathy (HIE). Creatine has emerged as a promising neuroprotective agent. Our objective was to systematically evaluate the preclinical animal studies that used creatine for perinatal neuroprotection, and to identify knowledge gaps that need to be addressed before creatine can be considered for pragmatic clinical trials for HIE. Methods: We reviewed preclinical studies up to 20 September 2021 using PubMed, EMBASE and OVID MEDLINE databases. The SYRCLE risk of bias assessment tool was utilized. Results: Seventeen studies were identified. Dietary creatine was the most common administration route. Cerebral creatine loading was age-dependent with near term/term-equivalent studies reporting higher increases in creatine/phosphocreatine compared to adolescent-adult equivalent studies. Most studies did not control for sex, study long-term histological and functional outcomes, or test creatine post-HI. None of the perinatal studies that suggested benefit directly controlled core body temperature (a known confounder) and many did not clearly state controlling for potential study bias. Conclusion: Creatine is a promising neuroprotective intervention for HIE. However, this systematic review reveals key knowledge gaps and improvements to preclinical studies that must be addressed before creatine can be trailed for neuroprotection of the human fetus/neonate.

Classical complement pathway inhibition reduces brain damage in a hypoxic ischemic encephalopathy animal model.

Perinatal hypoxic ischemic encephalopathy (HIE) remains a major contributor of infant death and long-term disability worldwide. The role played by the complement system in this ischemia-reperfusion injury remains poorly understood. In order to better understand the role of complement activation and other modifiable mechanisms of injury in HIE, we tested the dual-targeting anti-inflammatory peptide, RLS-0071 in an animal model of HIE. Using the well-established HIE rat pup model we measured the effects of RLS-0071 during the acute stages of the brain injury and on long-term neurocognitive outcomes. Rat pups subject to hypoxia-ischemia insult received one of 4 interventions including normothermia, hypothermia and RLS-0071 with and without hypothermia. We measured histopathological effects, brain C1q levels and neuroimaging at day 1 and 21 after the injury. A subset of animals was followed into adolescence and evaluated for neurocognitive function. On histological evaluation, RLS-0071 showed neuronal protection in combination with hypothermia (P = 0.048) in addition to reducing C1q levels in the brain at 1hr (P = 0.01) and at 8 hr in combination with hypothermia (P = 0.005). MRI neuroimaging demonstrated that RLS-0071 in combination with hypothermia reduced lesion volume at 24 hours (P<0.05) as well as decreased T2 signal at day 21 in combination with hypothermia (P<0.01). RLS-0071 alone or in combination with hypothermia improved both short-term and long-term memory. These findings suggest that modulation by RLS-0071 can potentially decrease brain damage resulting from HIE.

Modern Physical Rehabilitation Technologies for Children with Perinatal Lesions of the Central Nervous System

The subject of this publication is the medical rehabilitation of children with perinatal lesions of the central nervous system. Currently, the main methodological principles of stage-by-stage medical rehabilitation of newborns, mainly children with the consequencesof perinatal damage to the nervous system, have been determined. Special attention should be paid to the issue of minimal use of medicines in children with perinatal pathology, in this regard, an importanttask is the development and scientific justification of new non-drug technologies of medical rehabilitation, especially in childrenunder 1 year. Medical rehabilitation sets itself the following tasks: stimulation of blood circulation in the brain tissues, improvement of muscle toneby affecting the central nervous system and the peripheral nervous system, activation of neuromuscular transmission processes andimprovement of psychomotor development of a child with perinatal pathology of the central nervous system. Medical rehabilitationof children with perinatal lesions of the central nervous system begins at the earliest possible time and is carried out by specialists ofa multidisciplinary rehabilitation team based on an individual medical rehabilitation program. Aim. To study the results of research conducted by Russian and foreign authors on the issues of physical rehabilitation of children withperinatal damage to the central nervous system and to conduct an analysis of the effectiveness of the proposed technologies. Material and methods. The literature review for this article was conducted from the elibrary, PubMed, Cochrane Library databaseswith a search depth of 10 years. The selection of publications was carried out using keywords: non-drug technologies, perinatal damageto the central nervous system; perinatal hypoxic-ischemic encephalopathy, kinesotherapy, neurodevelopmental therapy, massage,thin finger training method, dry immersion, fitball gymnastics, V. Voit therapy; Bobat therapy. Conclusion. Currently, a wide range of non-drug technologies of medical rehabilitation of children with the consequences of perinataldamage to the central nervous system is used such as therapeutic gymnastics, massage, kinesiotherapy with a neuroreflex locomotionaccording to Vojta’s method, Bobath-therapy, massage, etc. The analysis of publications has shown that kinesotherapy and massagein in the complex of rehabilitation measures for children with perinatal lesions allows to increase the effectiveness of rehabilitationmeasures, reduce the severity of motor disorders, and can help reduce the frequency of formation of cerebral palsy.

Neuron-specific enolase in cerebrospinal fluid as a biomarker of brain damage in infants with hypoxic-ischemic encephalopathy.

Neuron-specific enolase in cerebrospinal fluid as a biomarker of brain damage in infants with hypoxic-ischemic encephalopathy.

Repetitive sleep starts: An important differential diagnosis of infantile spasms

ObjectiveRepetitive sleep starts (RSS) are clusters of nonepileptic, spasm-like movements occurring during sleep onset. However, their characteristics have yet to be defined. We conducted a clinicoelectroencephalographic study of children with RSS to clarify their detailed characteristics. MethodsTo differentiate starts from epileptic spasms, we recruited children with brief “crescendo–decrescendo” muscle contractions that simultaneously involved the limbs and trunk without electroencephalogram changes, and that fulfilled the following criteria: (1) repeated occurrence (five or more) and (2) manifestation during sleep stage N1–N2. A total of nine children met these criteria. Their clinical information and video-electroencephalogram data were analyzed retrospectively. ResultsThe background conditions observed at onset of RSS were perinatal hypoxic–ischemic encephalopathy (n = 4), West syndrome of unknown etiology (n = 1), and traumatic brain injury (n = 1). The age at onset of RSS, the number of starts in a given RSS cluster, the interval between starts, and the duration of surface electromyogram activity were between 3 and 46 months, 5 and 547, <1 and 60 s, and 0.3 and 5.4 s, respectively. None of the median value of these parameters differed between children with and without corticospinal tract injury. During the median follow-up period of 33 months, RSS disappeared spontaneously in five. ConclusionThis is the largest case series of RSS clarifying their clinicoelectroencephalographic characteristics reported to date. To avoid unnecessary antiepileptic therapies, clinicians should be aware of RSS and distinguish it from other disorders involving involuntary movements or seizures, especially epileptic spasms.

Structural Changes in the Cortico-Ponto-Cerebellar Axis at Birth are Associated with Abnormal Neurological Outcomes in Childhood.

White matter lesions in hypoxic-ischemic encephalopathy (HIE) are considered to be the important substrate of frequent neurological consequences in preterm infants. The aim of the study was to analyze volumes and tractographic parameters of the cortico-ponto-cerebellar axis to assess alterations in the periventricular fiber system and crossroads, corticopontine and corticospinal pathways and prospective transsynaptic changes of the cerebellum.Term infants (control), premature infants without (normotypic) and with perinatal HIE (HIE) underwent brain magnetic resonance imaging at term-equivalent age (TEA) and at 2 years. Cerebrum, cerebellum, brainstem divisions and ventrodorsal compartments volumetric analysis were performed, as well as fractional anisotropy (FA) and apparent diffusion coefficient (ADC) of corticopontine, corticospinal pathways and middle cerebellar peduncles. Amiel-Tison scale at TEA and the Hempel test at 2 years were assessed.Cerebellum, brainstem and its compartments volumes were decreased in normotypic and HIE groups at TEA, while at 2 years volumes were significantly reduced in the HIE group, accompanied by decreased volume and FA and increased ADC of corticopontine and corticospinal pathways. Negative association of the brainstem, cerebellum, mesencephalon, pons, corticopontine volumes and corticospinal pathway FA at TEA with the neurological score at 2 years. Cerebellum and pons volumes presented as potential prognostic indicators of neurological outcomes.Our findings agree that these pathways, as a part of the periventricular fiber system and crossroads, exhibit lesion-induced reaction and vulnerability in HIE. Structural differences between normotypic and HIE group at the 2 years suggest a different developmental structural plasticity.

Non-Tumorigenic Pluripotent Reparative Muse Cells Provide a New Therapeutic Approach for Neurologic Diseases.

Muse cells are non-tumorigenic endogenous reparative pluripotent cells with high therapeutic potential. They are identified as cells positive for the pluripotent surface marker SSEA-3 in the bone marrow, peripheral blood, and connective tissue. Muse cells also express other pluripotent stem cell markers, are able to differentiate into cells representative of all three germ layers, self-renew from a single cell, and are stress tolerant. They express receptors for sphingosine-1-phosphate (S1P), which is actively produced by damaged cells, allowing circulating cells to selectively home to damaged tissue. Muse cells spontaneously differentiate on-site into multiple tissue-constituent cells with few errors and replace damaged/apoptotic cells with functional cells, thereby contributing to tissue repair. Intravenous injection of exogenous Muse cells to increase the number of circulating Muse cells enhances their reparative activity. Muse cells also have a specific immunomodulatory system, represented by HLA-G expression, allowing them to be directly administered without HLA-matching or immunosuppressant treatment. Owing to these unique characteristics, clinical trials using intravenously administered donor-Muse cells have been conducted for myocardial infarction, stroke, epidermolysis bullosa, spinal cord injury, perinatal hypoxic ischemic encephalopathy, and amyotrophic lateral sclerosis. Muse cells have the potential to break through the limitations of current cell therapies for neurologic diseases, including amyotrophic lateral sclerosis. Muse cells provide a new therapeutic strategy that requires no HLA-matching or immunosuppressant treatment for administering donor-derived cells, no gene introduction or differentiation induction for cell preparation, and no surgery for delivering the cells to patients.

Mitochondrial Dysfunction and Permeability Transition in Neonatal Brain and Lung Injuries

This review discusses the potential mechanistic role of abnormally elevated mitochondrial proton leak and mitochondrial bioenergetic dysfunction in the pathogenesis of neonatal brain and lung injuries associated with premature birth. Providing supporting evidence, we hypothesized that mitochondrial dysfunction contributes to postnatal alveolar developmental arrest in bronchopulmonary dysplasia (BPD) and cerebral myelination failure in diffuse white matter injury (WMI). This review also analyzes data on mitochondrial dysfunction triggered by activation of mitochondrial permeability transition pore(s) (mPTP) during the evolution of perinatal hypoxic-ischemic encephalopathy. While the still cryptic molecular identity of mPTP continues to be a subject for extensive basic science research efforts, the translational significance of mitochondrial proton leak received less scientific attention, especially in diseases of the developing organs. This review is focused on the potential mechanistic relevance of mPTP and mitochondrial dysfunction to neonatal diseases driven by developmental failure of organ maturation or by acute ischemia-reperfusion insult during development.

Safety and Efficacy of Sildenafil Citrate to Reduce Operative Birth for Intrapartum Fetal Compromise at Term: A Phase 2 Randomized Controlled Trial

(Am J Obstet Gynecol. 2020;222:401–414) Intrapartum fetal compromise, or fetal distress, is a major cause of perinatal death and hypoxic-ischemic encephalopathy in low- to middle-income countries, and causes 1 in 5 cases of cerebral palsy in high-income countries. The only proven interventions for intrapartum fetal compromise are emergency cesarean delivery or emergency delivery by instrumental vaginal birth, both of which carry significant risks. Sildenafil citrate increases fetal and uteroplacental blood flow and is an effective treatment for adult and newborn pulmonary hypertension. This study evaluated the efficacy and safety of sildenafil citrate in reducing the rate of emergency cesarean delivery or instrumental vaginal birth for intrapartum fetal distress.

Neuromonitoring in Neonatal-Onset Epileptic Encephalopathies.

Considering the wide spectrum of etiologies of neonatal-onset epileptic encephalopathies (EE) and their unfavorable consequences for neurodevelopmental prognoses, neuromonitoring at-risk neonates is increasingly important. EEG is highly sensitive for early identification of electrographic seizures and abnormal background activity. Amplitude-integrated EEG (aEEG) is recommended as a useful bedside monitoring method but as a complementary tool because of methodical limitations. It is of special significance in monitoring neonates with acute symptomatic as well as structural, metabolic and genetic neonatal-onset EE, being at high risk of electrographic-only and prolonged seizures. EEG/aEEG monitoring is established as an adjunctive tool to confirm perinatal hypoxic-ischemic encephalopathy (HIE). In neonates with HIE undergoing therapeutic hypothermia, burst suppression pattern is associated with good outcomes in about 40% of the patients. The prognostic specificity of EEG/aEEG is lower compared to cMRI. As infants with HIE may develop seizures after cessation of hypothermia, recording for at least 24 h after the last seizure is recommended. Progress in the identification of genetic etiology of neonatal EE constantly increases. However, presently, no specific EEG changes indicative of a genetic variant have been characterized, except for individual variants associated with typical EEG patterns (e.g., KCNQ2, KCNT1). Long-term monitoring studies are necessary to define and classify electro-clinical patterns of neonatal-onset EE.

Evaluation of perinatal hypoxic encephalopathy with advanced MR sequences

Perinatal hypoxic ischemic encephalopathy (HIE) among important causes of neurological morbidity and mortality in full-term neonates. Identifying ischemic injury clinically usually is difficult in the immediate postnatal period, nonspecific clinical features are present and consid-erations regarding initiation of active life preserving therapies are needed. MR imaging is the most sensitive and specific imaging tech-nique available for the assessment of perinatal birth asphyxia related brain injury in term-born neonates. This study investigates the utility of MR spectroscopy peak ratios, ADC values along with conventional MRI. To compare the association of encephalopathy following hypoxia in term neonates with proton MRS ratios and ADC values. Conventional MRI (T1 and T2) along with DWI followed by MR Spectroscopy was done in 25 term neonates with clinical and neurological features of en-cephalopathy following perinatal asphyxia. MRS peak ratios, DWI with ADC values and conventional MRI findings were compared with each grade of HIE. Among 25 patients suspected cases of hypoxic enceph-alopathy, 15 patients had early positive conventional MR findings, 16 patients had late positive conventional MR findings, 19 patients had positive DWI, and 22 patients had positive MRS with high lac-tate/choline and lactate/NAA ratio. Higher association was found be-tween spectroscopy findings and hypoxic ischemic injury compared to MR imaging and ADC. The combination of MRS, DWI with ADC values and conventional MRI may assist in localizing and predicting the severi-ty of ischemic injury in HIE patients.

Novel Concepts for the Role of Chloride Cotransporters in Refractory Seizures.

Epilepsy is associated with a multitude of acquired or genetic neurological disorders characterized by a predisposition to spontaneous recurrent seizures. An estimated 15 million patients worldwide have ongoing seizures despite optimal management and are classified as having refractory epilepsy. Early-life seizures like those caused by perinatal hypoxic ischemic encephalopathy (HIE) remain a clinical challenge because although transient, they are difficult to treat and associated with poor neurological outcomes. Pediatric epilepsy syndromes are consistently associated with intellectual disability and neurocognitive comorbidities. HIE and arterial ischemic stroke are the most common causes of seizures in term neonates and account for 7.5-20% of neonatal seizures. Standard first-line treatments such as phenobarbital (PB) and phenytoin fail to curb seizures in ~50% of neonates. In the long-term, HIE can result in hippocampal sclerosis and temporal lobe epilepsy (TLE), which is the most common adult epilepsy, ~30% of which is associated with refractory seizures. For patients with refractory TLE seizures, a viable option is the surgical resection of the epileptic foci. Novel insights gained from investigating the developmental role of Cl- cotransporter function have helped to elucidate some of the mechanisms underlying the emergence of refractory seizures in both HIE and TLE. KCC2 as the chief Cl- extruder in neurons is critical for enabling strong hyperpolarizing synaptic inhibition in the brain and has been implicated in the pathophysiology underlying both conditions. More recently, KCC2 function has become a novel therapeutic target to combat refractory seizures.