Association between Early Basal Ganglia and Thalami Perfusion Assessed by Color Doppler Ultrasonography and Brain Injury in Infants with Hypoxic-Ischemic Encephalopathy: A Prospective Cohort Study

Therapeutic Hypothermia in Neonatal Hypoxic Ischemic Encephalopathy: Electrographic Seizures and Magnetic Resonance Imaging Evidence of Injury

Therapeutic hypothermia is the standard-of-care treatment for infants diagnosed with moderate-to-severe hypoxic-ischemic encephalopathy (HIE). MRI for assessing brain injury is usually performed after hypothermia because of logistical challenges in bringing acutely sick infants receiving hypothermia from the neonatal intensive care unit (NICU) to the MRI suite. Perhaps examining and comparing early cerebral oxygen metabolism disturbances to those after rewarming will lead to a better understanding of the mechanisms of brain injury in HIE and the effects of therapeutic hypothermia. The objectives were to assess the feasibility of performing a novel T2-relaxation under spin tagging (TRUST) MRI technique to measure venous oxygen saturation very early in the time course of treatment, 18-24h after the initiation of therapeutic hypothermia, to provide a framework to measure neonatal cerebral oxygen metabolism noninvasively, and to compare parameters between early and post-hypothermia MRIs. Early (18-24h after initiating hypothermia) MRIs were performed during hypothermia treatment in nine infants with HIE (six with moderate and three with severe HIE). Six infants subsequently had an MRI after hypothermia. Mean values of cerebral blood flow, oxygen extraction fraction, and cerebral metabolic rate of oxygen from MRIs during hypothermia were compared between infants with moderate and severe HIE; and in those with moderate HIE, we compared cerebral oxygen metabolism parameters between MRIs performed during and after hypothermia. During the initial hypothermia MRI at 23.5±5.2h after birth, infants with severe HIE had lower oxygen extraction fraction (P=0.04) and cerebral metabolic rate of oxygen (P=0.03) and a trend toward lower cerebral blood flow (P=0.33) compared to infants with moderate HIE. In infants with moderate HIE, cerebral blood flow decreased and oxygen extraction fraction increased between MRIs during and after hypothermia (although not significantly); cerebral metabolic rate of oxygen (P=0.93) was not different. Early MRIs were technically feasible while maintaining hypothermic goal temperatures in infants with HIE. Cerebral oxygen metabolism early during hypothermia is more disturbed in severe HIE. In infants with moderate HIE, cerebral blood flow decreased and oxygen extraction fraction increased between early and post-hypothermia scans. A comparison of cerebral oxygen metabolism parameters between early and post-hypothermia MRIs might improve our understanding of the evolution of HIE and the benefits of hypothermia. This approach could guide the use of adjunctive neuroprotective strategies in affected infants.

Objective To explore the value of enhanced T2*-weighted angiography(ESWAN) sequence in displaying the intracranial deep vein distension in full-term neonates with hypoxic-ischemic encephalopathy(HIE). Methods Thirty-two confirmed cases of full-term neonates confirmed with HIE and 10 cases of normal full-term neonates received the brain magnetic resonance imaging(MRI) ESWAN sequence scanning.The display rate of intracra-nial deep vein in normal group and HIE group with mild, moderate and severe degree was evaluated.The differences in intracranial deep vein display rate between the normal group and the HIE group or within different degrees of HIE patients were compared respectively to observe the relationships between intracranial ischemic lesion and deep vein conditions.The role of ESWAN sequence in the diagnosis of HIE was evaluated. Results The display rate of intracranial deep vein in normal group was 26.2%(21/80 cases); the display rate of intracranial deep vein in mild, moderate and severe HIE groups were 59.8%(67/112 cases), 92.3%(96/104 cases) and 95.0%(38/40 cases), respectively.The differences of intracranial deep vein display rate between normal group and mild HIE group were statistically significant(P 0.05). The distribution of intracranial deep vein distension and ischemic lesion in HIE group was consistent. Conclusions ESWAN sequence can clearly show the relationship between intracranial venous distension and ischemic lesion, which has diagnostic value in judging the location and extent of HIE.It can indicate the severity of HIE by displaying secondary distension of intracranial vein. Key words: Hypoxic-ischemic encephalopathy; Enhanced T2*-weighted angiography; Deep vein; Neonate

Therapeutic hypothermia reduces risk of death and disability in infants with moderate to severe hypoxic ischemic encephalopathy (HIE). Randomized clinical trials of therapeutic hypothermia to date have not included infants with mild HIE because of a perceived good prognosis. To test the hypothesis that children with mild HIE have worse neurodevelopmental outcomes than their healthy peers. Analysis of pooled data from 4 prospective cohort studies in Cork, Ireland, and Stockholm, Sweden, between January 2007 and August 2015. The dates of data analysis were September 2017 to June 2019. Follow-up was performed at age 18 to 42 months. In this multicenter cohort study, all children were born or treated at the tertiary centers of Cork University Maternity Hospital, Cork, Ireland, or Karolinska University Hospital, Stockholm, Sweden. In all, 690 children were eligible for this study. At discharge, all children were categorized into the following 5 groups using a modified Sarnat score: healthy controls, perinatal asphyxia (PA) without HIE, mild HIE, moderate HIE, and severe HIE. Cognitive, language, and motor development were assessed with the Bayley Scales of Infant and Toddler Development, Third Edition (BSITD-III). The BSITD-III scores are standardized to a mean (SD) of 100 (15), with lower scores indicating risk of developmental delay. Of the 690 children eligible for this study, 2-year follow-up data were available in 471 (mean [SD] age at follow-up, 25.6 [5.7] months; 54.8% male), including 152 controls, 185 children with PA without HIE, and 134 children with HIE, of whom 14 had died. Infants with mild HIE (n = 55) had lower cognitive composite scores compared with controls, with a mean (SD) of 97.6 (11.9) vs 103.6 (14.6); the crude mean difference was -6.0 (95% CI, -9.9 to -2.1), and the adjusted mean difference was -5.2 (95% CI, -9.1 to -1.3). There was no significant difference in the mean cognitive composite scores between untreated children (n = 47) with mild HIE and surviving children with moderate HIE (n = 53) treated with therapeutic hypothermia, with a crude mean difference for mild vs moderate of -2.2 (95% CI, -8.1 to 3.7). This study's findings suggest that, at age 2 years, the cognitive composite scores of children with a history of mild HIE may be lower than those of a contemporaneous control group and may not be significantly different from those of survivors of moderate HIE treated with therapeutic hypothermia.

Neonatal hypoxic ischemic encephalopathy (HIE) is one of the most common causes of neonatal morbidity and mortality worldwide. It has an overall mortality rate ranging from 15% to 25%, with up to 50% of survivors developing long-term neurological disabilities. Therapeutic hypothermia (TH) has been the only effective treatment for moderate to severe HIE in neonates ≥35 weeks of gestation. Infants with mild HIE previously had been excluded from studies, but a recent study reported approximately 16% developed a disability at 18 to 22 months of age. Despite treatment, up to 29% of neonates with HIE still develop adverse outcomes. To decrease the prevalence of neonatal HIE, prevention is key and a better understanding of associated maternal, perinatal, and neonatal risk factors is needed. The aim of this study was to assess trends of HIE prevalence and use of TH, mortality, and clinical neonatal outcomes. This was a cross-sectional analysis using National Inpatient Sample data sets from 2010 to 2018. Included were newborn infants diagnosed with HIE or asphyxia, who were ≥35 weeks of gestation and had a birth weight ≥2500 g. Excluded were those with congenital heart disease, congenital central nervous system anomalies, congenital lung anomalies, congenital abdominal wall defects, gastroschisis or omphalocele, multiple congenital anomalies, common syndromes, and chromosomal disorders. Of the 32,180,617 infants included in the analysis, 31,249,100 were term infants (>35 weeks). The prevalence of all degrees of HIE for term infants was approximately 0.1%. There was a modest increase from 0.093% during the years 2010 and 2012 up to 0.097% during 2016 and 2018. Approximately 21% of cases were managed with TH. More infants with moderate HIE received TH than those with severe HIE (29.9% vs 19.9%; P < 0.01). Fewer infants with mild or unspecified HIE received TH than those with severe HIE (17.7% and 17.3%, respectively; P < 0.01). From 2010 to 2018, the use of TH increased overall and within each grade of HIE (P < 0.01). The mortality rate was higher in term infants with all degrees of asphyxia than the general population (10.8% vs 0.06%; P < 0.01). Over time, the mortality rate in term infants decreased from 12.3% in 2010 to 8.3% in 2018 (P < 0.01). The analysis included 931,517 were late preterm infants (35–36 weeks of gestation). The combined prevalence for all grades of HIE was 0.23% and did not change significantly over the years. Approximately 21% of late preterm infants were managed with TH. More infants with moderate HIE received TH than those with severe HIE (26.9% vs 20.1%). Fewer infants with mild HIE received TH (13.2%), and no significant difference was observed in infants with unspecified HIE compared with those with severe HIE (18.7% vs 20.1%). The use of TH increased has increased in late preterm infants over the years. The strongest factors associated with HIE were placental infarction or insufficiency, placental abruption, and cord prolapse. Female infant sex, maternal Hispanic ethnicity, and maternal Asian race were associated with lower risk of HIE. In conclusion, HIE prevalence remained essentially the same at 1 per 1000 live births. Use of TH increased, and mortality decreased over time. The strongest factors associated with HIE were placental factors.

Resting-state functional magnetic resonance imaging has revealed disrupted brain network connectivity in adults and teenagers with cerebral palsy. However, the specific brain networks implicated in neonatal cases remain poorly understood. In this study, we recruited 14 term-born infants with mild hypoxic ischemic encephalopathy and 14 term-born infants with severe hypoxic ischemic encephalopathy from Changzhou Children's Hospital, China. Resting-state functional magnetic resonance imaging data showed efficient small-world organization in whole-brain networks in both the mild and severe hypoxic ischemic encephalopathy groups. However, compared with the mild hypoxic ischemic encephalopathy group, the severe hypoxic ischemic encephalopathy group exhibited decreased local efficiency and a low clustering coefficient. The distribution of hub regions in the functional networks had fewer nodes in the severe hypoxic ischemic encephalopathy group compared with the mild hypoxic ischemic encephalopathy group. Moreover, nodal efficiency was reduced in the left rolandic operculum, left supramarginal gyrus, bilateral superior temporal gyrus, and right middle temporal gyrus. These results suggest that the topological structure of the resting state functional network in children with severe hypoxic ischemic encephalopathy is clearly distinct from that in children with mild hypoxic ischemic encephalopathy, and may be associated with impaired language, motion, and cognition. These data indicate that it may be possible to make early predictions regarding brain development in children with severe hypoxic ischemic encephalopathy, enabling early interventions targeting brain function. This study was approved by the Regional Ethics Review Boards of the Changzhou Children's Hospital (approval No. 2013-001) on January 31, 2013. Informed consent was obtained from the family members of the children. The trial was registered with the Chinese Clinical Trial Registry (registration number: ChiCTR1800016409) and the protocol version is 1.0.

AimNeonatal Hypoxic Ischemic Encephalopathy (HIE) diagnosis and prognosis are established through clinical evidence, laboratory, imaging, and electrophysiological assessment of the nervous system. Netrin-1 (NT-1) was the first axon guidance molecule...

Hypoxic ischaemic encephalopathy (HIE) is a common cause of neonatal death and severe neurological deficit in children, contributing to medico-legal litigation. To describe the neurodevelopmental outcomes of infants with moderate and severe HIE at Chris Hani Baragwanath Academic Hospital and the proportions with neurodevelopmental impairment (NDI) and complications. To explore the effect of HIE severity and therapeutic hypothermia (TH) on neurodevelopmental outcome. A retrospective, descriptive study at the Neonatal Neurodevelopmental Clinic included 239 infants with moderate and severe HIE, between 2015 and 2020. Neurodevelopmental outcomes were assessed by using the Griffiths Mental Developmental Scales at 1 year. General Quotient (GQ) scores defined NDI. Clinical and investigation criteria determined those with neurological complications. Of the 239 infants, 211 (88.3%) and 28 (11.7%) had moderate HIE and severe HIE, respectively. Cerebral palsy (CP) was diagnosed in 9.2% and NDI in 17.1%. Severe HIE infants had significantly higher rates of NDI and CP, 50% (14) and 21.4% (6) respectively, as compared to those of moderate HIE infants, who had 12.7% (27) NDI and 7.6% (16) CP; 152(72%) moderate and 14 (50%) severe HIE infants received TH. Those who received TH were less likely to have NDI (p = 0.005), CP (p = 0.002), epilepsy and visual impairment. Developmental scores at 1 year of age were in the average range for the cohort, with equivalent profiles across domains. Those with severe HIE had the worst outcomes. Therapeutic hypothermia was associated with decreased CP and NDI in both groups. This report supports the use of TH as a neuroprotective strategy in stage 2 and 3 HIE, highlighting the need for neurodevelopmental assessments at 2 years and beyond to determine longer-term outcomes and subtle deficits.

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

Clinical significance of electroencephalography power spectrum density and functional connection analysis in neonates with hypoxic-ischemic encephalopathy.

Proton magnetic resonance spectroscopy in neonates with hypoxic-ischemic injury and its prognostic value

Hypoxic-ischemic encephalopathy (HIE) remains a significant cause of mortality and neurodevelopmental impairment despite treatment with therapeutic hypothermia. Magnetic resonance H1-spectroscopy measures concentrations of cerebral metabolites to detect derangements in aerobic metabolism. We assessed MR spectroscopy in neonates with HIE within 18-24h of initiating therapeutic hypothermia and at 5-6 days post therapeutic hypothermia. Eleven neonates with HIE underwent MR spectroscopy of the basal ganglia and white matter. We compared metabolite concentrations during therapeutic hypothermia and post-therapeutic hypothermia and between moderate and severe HIE. During therapeutic hypothermia, neonates with severe HIE had decreased basal ganglia N-acetylaspartate (NAA; 0.62±0.08 vs. 0.72±0.05; P=0.02), NAA + N-acetylaspartylglutamate (NAAG; 0.66±0.11 vs. 0.77±0.06; P=0.05), glycerophosphorylcholine + phosphatidylcholine (GPC+PCh; 0.28±0.05 vs. 0.38±0.06; P=0.02) and decreased white matter GPC+PCh (0.35±0.13 vs. 0.48±0.04; P=0.02) compared to neonates with moderate HIE. For all subjects, basal ganglia NAA decreased (-0.08±0.07; P=0.01), whereas white matter GPC+PCh increased (0.03±0.04; P=0.04) from therapeutic hypothermia MRI to post-therapeutic-hypothermia MRI. All metabolite values are expressed in mmol/L. Decreased NAA and GPC+PCh were associated with greater HIE severity and could distinguish neonates who might benefit most from targeted additional neuroprotective therapies.

Brain Temperature in Neonates with Hypoxic-Ischemic Encephalopathy during Therapeutic Hypothermia

Early diagnosis and outcome prediction of neonatal hypoxic-ischemic encephalopathy with color Doppler ultrasound.

More than half of all infants with neonatal hypoxic ischemic encephalopathy (HIE) are graded as mild and do not meet current criteria for therapeutic hypothermia. These infants are often not enrolled in follow-up, and hence our knowledge of their long-term outcome is sparse. We wished to compare 5-year outcomes in a group of infants with mild, moderate, and severe HIE, graded with both early EEG and clinical assessment, none of whom were treated with therapeutic hypothermia. Term infants with HIE and a healthy comparison group were recruited at birth. Both groups had early continuous EEG recordings. Cognitive and motor outcome was assessed at 5 years. Outcome was available in 53 infants with HIE and 30 infants in the comparison group at 5 years. Infants with mild HIE at birth (n = 22) had significantly lower full-scale IQ, verbal IQ, and performance IQ than comparison infants (n = 30) at 5 years (P = .001, .001, and 0.004, respectively). No difference in cognitive measures was seen between infants with mild and moderate grades HIE. Intact survival at 5 years varied across EEG grade HIE at 6 hours after birth; 75% in mild, 46% in moderate, 43% in major abnormalities, and 0% with inactive EEGs, compared with 97% in the comparison group. Survivors of mild HIE, graded clinically or by early EEG, have higher rates of disability than their peers and have cognitive outcomes similar to that of children with moderate encephalopathy in an uncooled HIE cohort.