Cause Of Neonatal Encephalopathy Research Articles

Neuromodulation using transcranial focused ultrasonography in neonates with perinatal hypoxic-ischemic encephalopathy

Perinatal hypoxic-ischemic encephalopathy (HIE) is the most common cause of neonatal encephalopathy, accounting for over half of all cases and the consequences of HIE can be devastating, making it one of the most severe perinatal complications. Therapeutic hypothermia has been shown to offer neuroprotection by reducing metabolic demand and slowing the cascade of injury processes. However, despite its benefits, therapeutic hypothermia has only modestly improved neurodevelopmental outcomes, indicating a major need for additional therapeutic approaches. Low-intensity transcranial ultrasound stimulation (TUS) is an emerging non-invasive brain stimulation technique for focally modulating specific brain regions that has recently drawn attention for its potential to modulate brain activity and promote neuroplasticity. The capacity of TUS to induce neuroplasticity through specific sonication parameters has been demonstrated in adult patients. Leveraging TUS to enhance functional connectivity and inhibit GABAergic systems within the injured thalami holds promise for inducing neuroplasticity in neonates with HIE. We hypothesize that enhancing thalamocortical functional connectivity and reducing local GABA levels through the use of TUS could potentially improve neurodevelopmental outcomes in neonates with HIE who have sustained thalamic injury and aim to test this hypothesis. Testing of the hypothesis will be conducted with a comprehensive assessment of safety and feasibility in neonates through a Phase I study, followed by further clinical studies to evaluate efficacy.

Ultrasound Diagnosis and Near-Infrared Spectroscopy in the Study of Encephalopathy in Neonates Born under Asphyxia: Narrative Review.

Brain injury resulting from adverse events during pregnancy and delivery is the leading cause of neonatal morbidity and disability. Surviving neonates often suffer long-term motor, sensory, and cognitive impairments. Birth asphyxia is among the most common causes of neonatal encephalopathy. The integration of ultrasound, including Doppler ultrasound, and near-infrared spectroscopy (NIRS) offers a promising approach to understanding the pathology and diagnosis of encephalopathy in this special patient population. Ultrasound diagnosis can be very helpful for the assessment of structural abnormalities associated with neonatal encephalopathy such as alterations in brain structures (intraventricular hemorrhage, infarcts, hydrocephalus, white matter injury) and evaluation of morphologic changes. Doppler sonography is the most valuable method as it provides information about blood flow patterns and outcome prediction. NIRS provides valuable insight into the functional aspects of brain activity by measuring tissue oxygenation and blood flow. The combination of ultrasonography and NIRS may produce complementary information on structural and functional aspects of the brain. This review summarizes the current state of research, discusses advantages and limitations, and explores future directions to improve applicability and efficacy.

Interleukin-33 improves the neurogenesis of neural stem cells in perinatal brain after hypoxia–ischemia

Perinatal hypoxia–ischemia (HI) insult is an important cause of neonatal encephalopathy, and the effective therapeutic approaches are currently limited. Interleukin (IL)-33 acts as a member of the IL-1 superfamily and has been shown to be neuroprotective following experimental neonatal HI and adult stroke. Here, we explore the effect of IL-33 and its specific receptor ST2 axis on endogenous neurogenesis in neonatal brain after HI. ST2 was found on the surface of NSCs, and the expression of ST2 was further enhanced after HI challenge. Delivery of IL-33 obviously repopulated the size of NSC pool, whereas ST2 deficiency worsened the neurogenesis of NSCs in neonatal brain post HI insult. Further in vivo and in vitro studies showed IL-33 regulates the survival, proliferation and differentiation of NSCs through ST2 signaling pathways. Intriguingly, IL-33 facilitated translocation of Nrf2 from the cytoplasm to the nucleus, which is involved in neural differentiation of NSCs. These data demonstrate a critical role of IL-33/ST2 axis in regulation of endogenous neurogenesis of NSCs via activation of the Nrf2 signaling, which provide a new insight into the effect of IL-33 in neonatal brain following HI injury.

Early MR brain findings in a neonate with molybdenum cofactor deficiency

Molybdenum cofactor deficiency (MoCD) is an inborn error of metabolism which presents with neonatal encephalopathy, seizures, and a turbulent postnatal course. It is an under-recognized cause of neonatal encephalopathy as it mimics hypoxic ischemic encephalopathy (HIE) on imaging. We present the case of an affected male neonate of a twin pregnancy whose magnetic resonance imaging in the early neonatal period showed restricted diffusion in lobar distribution with areas of cystic gliosis and mild tortuosity of the intracranial vessels. There are only a few case reports to the best of our knowledge which describe magnetic resonance (MR) findings of MoCD on diffusion-weighted images, none of which mentions unilateral changes or vessel tortuosity. MoCD should be considered in children with MR findings mimicking HIE in the absence of a history of perinatal hypoxia. This is important as the disorder has a poorer prognosis and the parents need appropriate prenatal counseling.

Evaluation of the Prevalence of Punctate White Matter Lesions in a Healthy Volunteer Neonatal Population.

Hypoxic-ischemic injury is the most common cause of neonatal encephalopathy. T1-weighted punctate white matter lesions have been described in hypoxic-ischemic injury. We have reviewed a healthy volunteer neonatal population to assess the prevalence of punctate white matter lesions in neonates with no clinical signs of hypoxic-ischemic injury. Fifty-two subjects were scanned on a neonatal-specific 3T MR imaging scanner. Twelve patients were excluded due to the lack of T1-weighted imaging, leaving a total of 40 patients (35 term, 5 preterm) assessed in the study. One had a solitary T1-punctate white matter lesion. We concluded that solitary punctate white matter lesions have a low prevalence in healthy neonates.

Role of MRI in the prognosis of hypoxic–ischemic encephalopathy

BackgroundNeonatal encephalopathy is a heterogeneous syndrome characterized by signs of central nervous system dysfunction in newborn infants. The main cause of neonatal encephalopathy can be broadly divided into perinatal asphyxia [hypoxic–ischemic encephalopathy (HIE)], perinatal stroke, metabolic encephalopathy from inborn errors of metabolism, congenital neonatal central nervous system infections, and severe birth trauma.ObjectivesTo highlight the predictive value of MRI as a safe and superior neuroimaging technique in cases of HIE.Patients and methodsThis progressive study was conducted on 30 neonates with HIE referred to the Radiology Department at Menoufia University Hospitals for advanced magnetic resonance techniques assessment during the period from July 2019 to December 2020. The study received the approval of Ethics Committee of Faculty of Medicine, Menoufia University. A written informed consent was taken from the parents or caregivers and written informed consent was obtained from them.ResultsApparent diffusion coefficient (ADC) value was significantly increased with hypertonia (1.75 ± 1.21), hypotonia (1.52 ± 1.51), and MRI than flaccid (0.86 ± 0.67). There was no statistically significant relation between ADC value with time of birth, causes of admission, Apgar score, time of birth at 5 min, Tendon reflex, seizures, periventricular leukomalacia, and intraventricular hemorrhage.ConclusionMRI findings were significantly related with diffusion-weighted (DW) and ADC value. MRI findings indicated that periventricular leukomalacia and basal ganglia ischemia were significantly related with DW. Moreover, it was noted that MRI is a very efficient tool in evaluating morphometric HIE. It's noninvasiveness and no exposure to ionizing radiation is an added advantage. However, experience and understanding of the principles are essential for accurate diagnosis. Also, DW and ADC values may add value to routine MRI examination. However, there is limitation in our study as regards the small number of cases, lack of clinical data, and long-term follow-up of cases.

Distinctive Neuroimaging Pattern in Term Newborns With Neonatal Placental Encephalopathy: A Case Series

BackgroundIdentifying antepartum versus intrapartum timing and the cause of neonatal encephalopathy (NE) often remains elusive owing to our limited understanding of the underlying pathophysiological processes and lack of appropriate biomarkers. ObjectivesThis retrospective observational study describes a case series of term newborns with NE who displayed a recognizable magnetic resonance imaging pattern of immediately postnatal brain abnormalities that rapidly evolved toward cavitation. Our aim is to (1) report this neuroimaging pattern, (2) look for placental determinants, and (3) depict the outcome. Design/MethodsThis is a unicentric retrospective case series reporting the clinical, radiological, and laboratory findings of NE associated with a distinctive neuroimaging pattern, that is, immediately postnatal extensive corticosubcortical T2 hyperintensities, followed by rapid corticosubcortical cavitation that does not match the neuroimaging picture of intrapartum hypoxic-ischemic encephalopathy (HIE). ResultsSeven term newborns presented bilateral corticosubcortical hyperintensities that were detected on T2 between day of life (DOL) 1-4, which rapidly evolved toward cystic encephalomalacia, that is, between DOL9 and DOL12. All these newborns presented with moderate/severe NE. The outcome was either neonatal death or quadriplegic cerebral palsy and epilepsy. None of the reported patients fulfilled the criteria of a high likelihood of acute intrapartum hypoxic-ischemic or quadriplegic cerebral palsy. All these newborns were exposed to chronic and/or acute placental inflammation and/or hypoxic-ischemic. ConclusionsTo further define the antepartum causes of NE, early neuroimaging and a placental examination are recommended. Brain T2 hyperintense injuries before DOL4 followed by rapid cavitation before DOL12 might be biomarkers of NE from an antepartum/placental origin.

Cognitive outcomes in late childhood and adolescence of neonatal hypoxic-ischemic encephalopathy.

Hypoxic-ischemic encephalopathy (HIE) is the most common cause of neonatal encephalopathy with a global incidence of approximately 1 to 8 per 1,000 live births. Neonatal encephalopathy can cause neurodevelopmental and cognitive impairments in survivors of hypoxic-ischemic insults with and without functional motor deficits. Normal neurodevelopmental outcomes in early childhood do not preclude cognitive and behavioral difficulties in late childhood and adolescence because cognitive functions are not yet fully developed at this early age. Therapeutic hypothermia has been shown to significantly reduced death and severe disabilities in term newborns with HIE. However, children treated with hypothermia therapy remain at risk for cognitive impairments and follow-up is necessary throughout late childhood and adolescence. Novel adjunctive neuroprotective therapies combined with therapeutic hypothermia may enhance the survival and neurodevelopmental outcomes of infants with HIE. The extent and severity of brain injury on magnetic resonance imaging might predict neurodevelopmental outcomes and lead to targeted interven tions in children with a history of neonatal encephalopathy. We provide a summary of the long-term cognitive outcomes in late childhood and adolescence in children with a history of HIE and the association between pattern of brain injury and neurodevelopmental outcomes.

The role of MRI in evaluating vascular causes of nonhypoxic–ischemic neonatal encephalopathy

Background Neonatal encephalopathy (NE) is a clinical syndrome characterized by abnormal neurobehavioral status of the newborn. Aim This study was conducted to evaluate the role of MRI in identifying vascular causes of NE. Patients and methods The study was conducted on 50 full-term neonates admitted to the neonatal ICU at Alexandria University Children’s Hospital with clinical picture suggestive of encephalopathy. MRI examinations were performed on a 1.5-T General Electric (GE) machine. Results In the current study, the causes of non-hypoxic–ischemic encephalopathy NE were categorized into six groups, each group displayed specific MRI features. P value was calculated, and the results revealed that MRI was successful in reaching the final diagnosis with P value of 0.045, confidence interval 95%, and RRF=1.385. Conclusion Those with vascular insults had 1.39 times the rate of reaching a final diagnosis compared with those with nonvascular insults.

Genotype and phenotype analysis of neonates with neonatal encephalopathy complicated with perinatal hypoxic event

Objective: To explore the underlying genetic causes of neonatal encephalopathy complicated with perinatal asphyxia. Methods: From the neonates recruited to the Neonatal Genome Project of Children's Hospital of Fudan University between January 2016 and January 2019, 113 neonates with neonatal encephalopathy and acute peripartum or intrapartum event or Apgar score ≤7 were enrolled in this study. The clinical data, laboratory results, the findings of electroencephalograph and magnetic resonance imaging or head ultrasound, and the genetic information were retrospectively analyzed. Results: Of the 133 neonates with neonatal encephalopathy and acute peripartum or intrapartum event or Apgar score ≤7 scores, 77 (57.9%) were males, 56 (42.1%) were female, 56 (42.1%) were delivered via cesarean section, and 77(57.9%) were born by vaginal delivery. Among these cases, 68 (51.1%) were diagnosed of hypoxic ischemic encephalopathy, 25 (18.8%) had intracranial hemorrhage, 20 (15%) were related to genetic diseases, and 5 (3.8%) had sepsis without central nervous infection. A total of 20 cases with positive results by next-generation sequencing test were identified, including 19 cases with pathogenic variations and 1 case with variation of uncertain significance. These 20 cases included 4 cases with congenital myopathy (2 cases of MTM1 gene pathogenic variants, 1 case of ACTA1 and 1 case of RYR1 gene pathogenic variants), 4 cases with genetic syndrome (2 cases of CHD7 gene pathogenic variants, 1 case of PTN11 gene pathogenic variant, and 1 case of NSDHL gene pathogenic variant), 3 cases with metabolic disorders (1 case of OTC gene pathogenic variant, 1 case of MTHFR gene pathogenic variant, and 1 case of ALDH7A1 gene pathogenic variant), 2 cases with epileptic encephalopathy (1 case of KCNT1 and 1 case of PACS2 gene pathogenic variants), 1 case with congenital central hypoventilation syndrome (PHOX2B gene pathogenic variant) and 6 cases with copy-number pathogenic variations. Among these 20 cases, 8(40.0%) neonates were presented with persistent hypotonia, 7(35.0%) neonates with seizures, and 5(25.0%) neonates with congenital malformation. Genetic counseling and further follow-up were performed or suggested for these 20 cases; 4 neonates were deceased, 10 neonates underwent palliative care, and 6 neonates were improved after supportive care and their further follow-up plan were performed in clinics. Conclusions: Genetic diseases are not rare in neonates with neonatal encephalopathy complicated with perinatal hypoxia event. The common causes in these neonates include congenital myopathy, metabolic disorders, genetic syndrome, and epilepsy encephalopathy.

Neonatal Encephalopathy: Beyond Hypoxic-Ischemic Encephalopathy

Neonatal encephalopathy is a clinical syndrome of neurologic dysfunction that encompasses a broad spectrum of symptoms and severity, from mild irritability and feeding difficulties to coma and seizures. It is vital for providers to understand that the term "neonatal encephalopathy" is simply a description of the neonate's neurologic status that is agnostic to the underlying etiology. Unfortunately, hypoxic-ischemic encephalopathy (HIE) has become common vernacular to describe any neonate with encephalopathy, but this can be misleading. The term should not be used unless there is evidence of perinatal asphyxia as the primary cause of encephalopathy. HIE is a common cause of neonatal encephalopathy; the differential diagnosis also includes conditions with infectious, vascular, epileptic, genetic/congenital, metabolic, and toxic causes. Because neonatal encephalopathy is estimated to affect 2 to 6 per 1,000 term births, of which HIE accounts for approximately 1.5 per 1,000 term births, (1)(2)(3)(4)(5)(6) neonatologists and child neurologists should familiarize themselves with the evaluation, diagnosis, and treatment of the diverse causes of neonatal encephalopathy. This review begins by discussing HIE, but also helps practitioners extend the differential to consider the broad array of other causes of neonatal encephalopathy, emphasizing the epidemiology, neurologic presentations, diagnostics, imaging findings, and therapeutic strategies for each potential category.

Perinatal Brain Injury and Inflammation: Lessons from Experimental Murine Models.

Perinatal brain injury or neonatal encephalopathy (NE) is a state of disturbed neurological function in neonates, caused by a number of different aetiologies. The most prominent cause of NE is hypoxic ischaemic encephalopathy, which can often induce seizures. NE and neonatal seizures are both associated with poor neurological outcomes, resulting in conditions such as cerebral palsy, epilepsy, autism, schizophrenia and intellectual disability. The current treatment strategies for NE and neonatal seizures have suboptimal success in effectively treating neonates. Therapeutic hypothermia is currently used to treat NE and has been shown to reduce morbidity and has neuroprotective effects. However, its success varies between developed and developing countries, most likely as a result of lack of sufficient resources. The first-line pharmacological treatment for NE is phenobarbital, followed by phenytoin, fosphenytoin and lidocaine as second-line treatments. While these drugs are mostly effective at halting seizure activity, they are associated with long-lasting adverse neurological effects on development. Over the last years, inflammation has been recognized as a trigger of NE and seizures, and evidence has indicated that this inflammation plays a role in the long-term neuronal damage experienced by survivors. Researchers are therefore investigating the possible neuroprotective effects that could be achieved by using anti-inflammatory drugs in the treatment of NE. In this review we will highlight the current knowledge of the inflammatory response after perinatal brain injury and what we can learn from animal models.

Clinical features and underlying genetic causes in neonatal encephalopathy: A large cohort study.

This study aimed to investigate the potential genetic causes of neonatal encephalopathy (NE) in a large cohort of Chinese patients. We included 366 neonates with encephalopathy. Whole exome sequencing was performed to assess the potential molecular defects. In this study, 43 patients (11.7%) were identified with pathogenic or likely pathogenic variants and 10 patients (2.7%) carried variants with unknown significance. Compared with patients without genetic findings (28.9%), patients with genetic findings (96.2%) displayed a significant higher incidence of seizure (P = .0009); however, a lower frequency of abnormal magnetic resonance imaging (MRI) results (P < .0001). Epileptic encephalopathy related genes account for nearly half (46.4%) of all genetic defects of NE with seizures. Follow-up results revealed genetic diagnosis, seizure and severe abnormal electroencephalograph results were significantly associated with high risk of developmental delay (P < .05). This study increases the understanding of genetic contribution to NE. Our findings suggest that the full-term NE patients with seizure, the greater the possibility of genetic diseases. However, for newborns especially the preterm babies with abnormal MRI findings, there is smaller possibility of genetic diseases. NE caused from genetic diseases have poor prognosis, and intensive intervention and follow-up is necessary for these newborns.

The epidemiology of FIRS in term and late preterm births

The definition of FIRS requires systemic inflammation and elevated levels of IL-6 in fetal plasma. That definition does not specify how systemic inflammation is to be recognized, and perinatal measurement of IL-6 is not a standard procedure. FIRS has not been examined in a population-based study that included post-neonatal outcome so its incidence and natural history are not known. The overlap, and similarities and differences, of FIRS as compared with other causes of neonatal encephalopathy, and how these relate to findings in the placenta, have not been jointly examined in a generalizable sample. FIRS has chiefly been discussed in the obstetric literature because of the need for decisions about management of delivery and antibiotic use. If the term “FIRS” is to be employed in other contexts, consensus should be sought as to which clinical, placental, and laboratory findings are most appropriate for identification of perinatal inflammatory processes, infectious or sterile.

Evaluation for the etiology of neonatal encephalopathy and the diagnosis of FIRS

A common disorder managed in the neonatal intensive care unit (NICU) is neonatal encephalopathy (NE). There are multiple causes of NE, including hypoxic-ischemic encephalopathy (HIE) and the fetal inflammatory response syndrome (FIRS). It is important to ascertain the specific cause of NE in an affected child, as it may affect the clinical management and will assist in prognostication. This paper discusses the background of inflammatory damage to the fetal brain, the history of FIRS as a clinical diagnosis, the characteristics of infants with FIRS, and methods to evaluate the etiology of NE.

Hypoxic-ischaemic encephalopathy: Identifying newborns who will benefit from therapeutic hypothermia in developing countries

Hypoxic-ischaemic encephalopathy (HIE) is only one of the many causes of neonatal encephalopathy, with no definitive test to make the diagnosis and very little available in terms of neuroprotective strategies, except for the use of therapeutic hypothermia (TH). TH improves survival and neurodevelopmental outcome at 18 months of age in neonates with moderate or severe encephalopathy. Based on this evidence, the International Liaison Committee on Resuscitation has recommended TH as standard of care since 2010. Low-cost methods of administering TH in low- and middle-income countries are effective as long as intensive care facilities are available, and provided that a TH guideline based on published international trials is in place. A local guideline, taking into consideration the care capable at different hospital levels, would be valuable in a developing country with resource constraints and increasing litigation.

Prospective cohort study for identification of underlying genetic causes in neonatal encephalopathy using whole-exome sequencing.

PurposeNeonatal encephalopathy, which is characterized by a decreased level of consciousness, occurs in 1-7/1,000 live-term births. In more than half of term newborns, there is no identifiable etiological factor. To identify underlying genetic defects, we applied whole-exome sequencing (WES) in term newborns with neonatal encephalopathy as a prospective cohort study.MethodsTerm newborns with neonatal encephalopathy and no history of perinatal asphyxia were included. WES was performed using patient and both parents' DNA.ResultsNineteen patients fulfilling inclusion criteria were enrolled. Five patients were excluded owing to withdrawal of consent, no parental DNA samples, or a genetic diagnosis prior to WES. Fourteen patients underwent WES. We confirmed a genetic diagnosis in five patients (36%): epileptic encephalopathy associated with autosomal dominant de novo variants in SCN2A (p.Met1545Val), KCNQ2 (p.Asp212Tyr), and GNAO1 (p.Gly40Arg); lipoic acid synthetase deficiency due to compound heterozygous variants in LIAS (p.Ala253Pro and p.His236Gln); and encephalopathy associated with an X-linked variant in CUL4B (p.Asn211Ser).ConclusionWES is helpful at arriving genetic diagnoses in neonatal encephalopathy and/or seizures and brain damage. It will increase our understanding and probably enable us to develop targeted neuroprotective treatment strategies.

Management and investigation of neonatal encephalopathy: 2017 update

This review discusses an approach to determining the cause of neonatal encephalopathy, as well as current evidence on resuscitation and subsequent management of hypoxic-ischaemic encephalopathy (HIE). Encephalopathy in neonates can...

A Qualitative Study of Physician Perspectives on Prognostication in Neonatal Hypoxic Ischemic Encephalopathy.

Hypoxic ischemic encephalopathy is the most frequent cause of neonatal encephalopathy and yields a great degree of morbidity and mortality. From an ethical and clinical standpoint, neurological prognosis is fundamental in the care of neonates with hypoxic ischemic encephalopathy. This qualitative study explores physician perspectives about neurological prognosis in neonatal hypoxic ischemic encephalopathy. This study aimed, through semistructured interviews with neonatologists and pediatric neurologists, to understand the practice of prognostication. Qualitative thematic content analysis was used for data analysis. The authors report 2 main findings: (1) neurological prognosis remains fundamental to quality-of-life predictions and considerations of best interest, and (2) magnetic resonance imaging is presented to parents with a greater degree of certainty than actually exists. Further research is needed to explore both the parental perspective and, prospectively, the impact of different clinical approaches and styles to prognostication for neonatal hypoxic ischemic encephalopathy.

Behavioral benefits of maternal swimming are counteracted by neonatal hypoxia-ischemia in the offspring

Hypoxia-ischemia (HI) represents one of the most common causes of neonatal encephalopathy. The central nervous system injury comprises several mechanisms, including inflammatory, excitotoxicity, and redox homeostasis unbalance leading to cell death and cognitive impairment. Exercise during pregnancy is a potential therapeutic tool due to benefits offered to mother and fetus. Swimming during pregnancy elicits a strong metabolic programming in the offspring’s brain, evidenced by increased antioxidant enzymes, mitochondrial biogenesis, and neurogenesis. This article aims to evaluate whether the benefits of maternal exercise are able to prevent behavioral brain injury caused by neonatal HI. Female adult Wistar rats swam before and during pregnancy (30min/day, 5 days/week, 4 weeks). At 7th day after birth, the offspring was submitted to HI protocol and, in adulthood (60th day), it performed the behavioral tests. It was observed an increase in motor activity in the open field test in HI-rats, which was not prevented by maternal exercise. The rats subjected to maternal swimming presented an improved long-term memory in the object recognition task, which was totally reversed by neonatal HI encephalopathy. BDNF brain levels were not altered; suggesting that HI or maternal exercise effects were BDNF-independent. In summary, our data suggest a beneficial long-term effect of maternal swimming, despite not being robust enough to protect from HI injury.