Mild Hypoxic-ischemic Encephalopathy Group Research Articles

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

ObjectiveTo evaluate associations between neurologic outcomes and early measurements of basal ganglia (BG) and thalamic (Th) perfusion using color Doppler ultrasonography (CDUS) in infants with hypoxic-ischemic encephalopathy (HIE). Study designProspective study of infants with mild (n=18), moderate (n=17), and severe HIE (n=14) and controls (n=17). Infants with moderate-severe HIE received therapeutic hypothermia (TH). CDUS was performed at 24-36h and brain magnetic resonance imaging (MRI) at a median of 10 days. Development was followed through 2.5 to 5 years. The primary outcome was the association between BG and Th perfusion and brain MRI injury. Secondary analyses focused on associations between perfusion measurements and admission neurologic examinations, MRI scores in infants treated with TH, and motor and sensory disability, or death. An exploratory analysis assessed the accuracy of BG and Th perfusion to predict brain MRI injury in infants treated with TH. ResultsIncreased BG and Th perfusion on CDUS was observed in infants with severe MRI scores and those with significant motor and neurosensory disability or death through 2.5 to 5 years (p<0.05). Infants with severe HIE showed increased BG and Th perfusion (p< .005) compared with infants with moderate HIE. No differences were identified between the between the control and mild HIE groups. Th perfusion ≥ 0.237 cm/sec (AUC of 0.824) correctly classified 80% of infants with severe MRI scores. ConclusionEarly dynamic CDUS of the BG and Th is a potential biomarker of severe brain injury in infants with HIE and may be a useful adjunct to currently used assessments.

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

To compare hypoxic-ischemic injury on early cranial ultrasonography (cUS) and post-rewarming brain magnetic resonance imaging (MRI) in newborn infants with hypoxic-ischemic encephalopathy (HIE) and to correlate that neuroimaging with neurodevelopmental outcomes. This was a retrospective cohort study of infants with mild, moderate, and severe HIE treated with therapeutic hypothermia and evaluated with early cUS and postrewarming MRI. Validated scoring systems were used to compare the severity of brain injury on cUS and MRI. Neurodevelopmental outcomes were assessed at 18months of age. Among the 149 included infants, abnormal white matter (WM) and deep gray matter (DGM) hyperechogenicity on cUS in the first 48hours after birth were more common in the severe HIE group than the mild HIE group (81% vs 39% and 50% vs 0%, respectively; P<.001). In infants with a normal cUS, 95% had normal or mildly abnormal brain MRIs. In infants with severely abnormal cUS, none had normal and 83% had severely abnormal brain MRIs. Total abnormality scores on cUS were higher in neonates with near-total brain injury on MRI than in neonates with normal MRI or WM-predominant injury pattern (adjusted P<.001 for both). In the multivariable model, a severely abnormal MRI was the only independent risk factor for adverse outcomes (OR: 19.9, 95% CI: 4.0-98.1; P<.001). The present study shows the complementary utility of cUS in the first 48hours after birth as a predictive tool for the presence of hypoxic-ischemic injury on brain MRI.

Long-chain omega-3 polyunsaturated fatty acids are reduced in neonates with substantial brain injury undergoing therapeutic hypothermia after hypoxic-ischemic encephalopathy.

Hypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal morbidity and mortality. Although therapeutic hypothermia is an effective treatment, substantial chronic neurological impairment often persists. The long-chain omega-3 polyunsaturated fatty acids (PUFAs), docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids, offer therapeutic potential in the post-acute phase. To understand how PUFAs are affected by HIE and therapeutic hypothermia we quantified for the first time the effects of HIE and therapeutic hypothermia on blood PUFA levels and lipid peroxidation. In a cross-sectional approach, blood samples from newborns with moderate to severe HIE, who underwent therapeutic hypothermia (sHIE group) were compared to samples from newborns with mild HIE, who did not receive therapeutic hypothermia, and controls. The sHIE group was stratified into cerebral MRI predictive of good (n = 10), or poor outcomes (n = 10; nine developed cerebral palsy). Cell pellets were analyzed for fatty acid content, and plasma for lipid peroxidation products, thiobarbituric acid reactive substances and 4-hydroxy-2-nonenal. Omega-3 Index (% DHA + EPA) was similar between control and HIE groups; however, with therapeutic hypothermia there were significantly lower levels in poor vs. good prognosis sHIE groups. Estimated Δ-6 desaturase activity was significantly lower in sHIE compared to mild HIE and control groups, and linoleic acid significantly increased in the sHIE group with good prognosis. Reduced long-chain omega-3 PUFAs was associated with poor outcome after HIE and therapeutic hypothermia, potentially due to decreased biosynthesis and tissue incorporation. We speculate a potential role for long-chain omega-3 PUFA interventions in addition to existing treatments to improve neurologic outcomes in sHIE.

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

To investigate the effects of electroencephalography (EEG) power and functional connectivity analysis on cerebral cortex function in neonates with hypoxic-ischemic encephalopathy (HIE), and to identify the neurobiological indicators of neural development in HIE. We recruited 20 mild HIE neonates, 15 moderate HIE neonates, and 30 controls. EEG was performed about 72hr after birth. The power spectral density (PSD) and imaginary part of coherency (ICOH) were analyzed. Gesell developmental schedule (GDS) was used to evaluate the neural development in the mild and moderate HIE groups at 1year of age, and the correlation between the quantitative EEG results and the state of neural development was analyzed. Compared with the controls, FP1, FP2, C3, C4, Fz, Cz, Pz , F3, and P4 of moderate HIE neonates showed that the PSD of theta, alpha and beta bands decreased significantly. In terms of the mean whole-brain PSD, themoderate HIEgroupshowed a significant decrease in all frequency bands. ICOH of the moderate HIE group showed that functional connectivity was significantly less than that in the controls mainly in the delta band, and the functional connectivity of the delta, theta, alpha1, and alpha2 bands was markedly reduced compared with the mild HIE. GDS test at 1year old showed that two infants in the moderate HIE group had suspected neurological delay in gross motor and language. The developmental quotient(DQ) of gross motor, language, and personal-social ability in the moderate HIE group were significantly lower than in the mild HIE group. And there was a significant positive correlation between PSD in each EEG frequency band and GDS score in the moderate HIE group. PSD and ICOH can be used to evaluate brain function. PSD can detect the delayed neurological development in infants with moderate HIE, and can be a neurobiomarker of brain development in HIE.

Term Yenidoğanlarda Hipoksik-İskemik Ensefalopati Şiddetini Öngörmede Kraniyal MRG Bulguları

Objective: The aim of this study is to compare magnetic resonance imaging (MRI) findings with severity of hypoxic-ischemic encephalopathy (HIE) in term neonates. Methods: Sixty-three newborns with HIE in whom cranial MRIs were performed within the first 3 weeks of life between 2016 and 2020 were included in the study. Severity of HIE was graded using Sarnat &amp; Sarnat staging. In statistical analysis, Stage 1 was considered as mild, Stage 2 or 3 as severe HIE. The signal intensities of perirolandic cortex, posterior limb of internal capsule (PLIC), globus pallidus, and cerebrospinal tract on T1- weighted imaging (T1WI), and of perirolandic cortex, PLIC, ventrolateral thalamus, lateral edge of putamen and tegmentum on T2WI, and brain diffusion weighted imaging (DWI) findings were evaluated with consensus by two radiologists blinded to clinical findings. Gestational age, birth weight and MRI signal intensities were compared with HIE groups using t test, and Fisher-Exact test. Results: There were 31 and 32 infants with mild and severe HIE, respectively. Gestational age and birth weight were not different between mild and severe HIE groups. The number of cases with abnormal signals in PLIC and globus pallidus on T1WI, and PLIC on T2WI were significantly higher in severe HIE (p=0.022, p=0.008, and p=0.032, respectively). The presence of signal abnormality in other regions and DWI were not significantly different between HIE groups. Conclusion: Cranial MRI may play a remarkable role in determining pattern and severity of HIE. Signal abnormality in PLIC and globus pallidus may suggest severe HIE in term neonates.

Serum cytokine profiling in neonates with hypoxic ischemic encephalopathy.

The fetal brain is vulnerable to severe and sustained hypoxia during and after birth, which can lead to hypoxic-ischemic encephalopathy (HIE). HIE is characterized by clinical and laboratory evidence of acute or subacute brain injury. The role of cytokines in the pathogenesis of brain injury and their relation to neurological outcomes of asphyxiated neonates are not fully understood. In this study, we investigated cytokine profile related to cerebral palsy (CP) with neonatal hypoxic ischemic encephalopathy (HIE) and HIE severity. Eligible subjects were HIE newborns with a gestational age between 36 and 42 weeks. We included newborns who was born at our NICU and did not admit to NICU as healthy controls. The study comprised 52 newborns, including 13 with mild to severe HIE and 39 healthy control. Serum cytokine profiles were performed using a LUMINEX cytokine kit (R&D Systems). VEGF, MCP-1, IL-15, IL-12p70, IL-12p40, IL-1Ra, IL-2, IL-6, IL-7, IL-8, IL-10, IFN-γ, G-CSF and eotaxin in the HIE patients were significantly increased compared with the healthy neonates. In the subgroup analysis, IL-6 and G-CSF were significantly increased in CP infants (n = 5) compared with non-CP infants (n = 8). Five and eight HIE patients were classified into the mild HIE and moderate-severe HIE groups, respectively. IL-6, 10, 1Ra, and G-CSF in the moderate-severe HIE group were significantly higher than those in the mild HIE group. We demonstrated that higher serum IL-6 and G-CSF at birth in HIE patients were associated with CP and moderate-severe HIE.

Early identification of neonatal mild hypoxic-ischemic encephalopathy by amide proton transfer magnetic resonance imaging: A pilot study

PurposeThis study aimed to evaluate the amide proton transfer (APT) values in neonates with mild hypoxic-ischemic encephalopathy (HIE) using APT imaging. MethodA total of 30 full-term neonates with mild HIE (16 males and 14 females; mean postnatal age 4.2 days, age range 2–7 days) and 12 normal neonates (six males and six females; mean postnatal age 3.3 days, age range 2–5 days) underwent conventional magnetic resonance imaging and APT imaging. APT measurements were performed in multiple regions of interest (ROIs) in the brain. APT values were statistically analyzed to assess for significant differences between the mild HIE and normal neonates in different regions of the brain, and correlation with neonatal gestational age. ResultsIn 30 neonates with mild HIE, 10% (3/30) of the HIE patients had normal conventional MRI. There were significant differences in APT values of the HIE group in bilateral caudate, bilateral thalamus, bilateral centrum semiovale and left globus pallidus/putamen (p < 0.05), and no statistical difference was observed in right globus pallidus/putamen (p = 0.051) and brainstem (p = 0.073) between the two groups. Furthermore, APT values in bilateral caudate, bilateral globus pallidus/putamen, bilateral thalamus, and brainstem regions (p < 0.05) exhibited positive linear correlations with gestational age in the control group, except for bilateral centrum semiovale (right: Pearson’s r = 0.554, p = 0.062; left: Pearson’s r = 0.561, p = 0.058). In the mild HIE groups, no significant correlation with gestational age was found in all regions. ConclusionsAPT imaging is a feasible and useful technique with diagnostic capability for neonatal HIE.

Resting-state network complexity and magnitude changes in neonates with severe hypoxic ischemic encephalopathy.

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.

Raised Plasma Neurofilament Light Protein Levels Are Associated with Abnormal MRI Outcomes in Newborns Undergoing Therapeutic Hypothermia.

Hypoxic-ischemic encephalopathy (HIE) remains an important cause of death and disability in newborns. Mild therapeutic hypothermia (TH) is safe and effective; however, there are no tissue biomarkers available at the bedside to select babies for treatment. The aim of this study was to show that it is feasible to study plasma neurofilament light (NfL) levels from newborns and to evaluate their temporal course. Hypothesis: Raised plasma NFL protein levels from newborns who undergo TH after HIE are associated with abnormal MRI outcomes. Between February 2014 and January 2016, term newborns with HIE treated with TH for 72 h had plasma samples taken at three time points: (i) after the infant had reached target temperature, (ii) prior to commencing rewarming, and (iii) after completing rewarming. Infants with mild HIE who did not receive TH had a single specimen taken. NfL protein was analyzed using an enzyme-linked immunosorbent assay. Twenty-six newborns with moderate-severe HIE treated with TH were studied. Half of these had cerebral MRI predictive of an unfavorable outcome. Plasma NfL levels were significantly higher in the TH group with unfavorable outcome (median age 18 h) compared to levels from both the mild HIE group and TH group with favorable outcome (F = 25.83, p < 0.0001). Newborns who had MRIs predictive of unfavorable outcome had significantly higher NfL levels compared to those with favorable outcomes, at all three time points (mixed models, F = 27.63, p < 0.001). A cutoff NfL level >29 pg/mL at 24 h is predictive of an unfavorable outcome [sensitivity 77%, specificity 69%, positive predictive value (PPV) 67%, negative predictive value (NPV) 72%] with increasing predictive value until after rewarming (sensitivity 92%, specificity 92%, PPV 92%, NPV 86%). Plasma NfL protein levels may be a useful biomarker of unfavorable MRI outcomes in newborns with moderate-severe HIE and may assist in selecting newborns for adjunctive neuroprotective interventions. Larger studies with NfL testing at earlier time points are required.

SBDPs and Tau proteins for diagnosis and hypothermia therapy in neonatal hypoxic ischemic encephalopathy.

The use of spectrin breakdown products (SBDPs) and Tau protein levels for diagnosis and a mild hypothermia therapy for treatment of neonatal hypoxic-ischemic encephalopathy (HIE) was evaluated. One hundred and fifty infants, with HIE within 12 h after birth, participated in the study. There were 30 newborns with mild symptoms, 60 with moderate symptoms, 60 with severe symptoms, and 30 in a control group. Regular therapy was used for the control and the mild HIE groups, and also for 30 cases in the group with moderate symptoms and for 30 in the group with severe symptoms. For the remaining infants, with moderate and severe symptoms, mild hypothermia therapy was used instead. A sandwich ELISA measured plasma concentrations of SBDPs and Tau proteins, at different time-points. For clinical follow-up, the neonatal behavioral neurological assessment (NBNA) assay and the Gesell development scale were performed at different time-points. The levels of SBDP and Tau proteins increased with the exacerbation of HIE, and decreased with the prolongation of therapy with statistically significant differences amongst groups. After treatment, the levels of SBDP and Tau proteins in groups with moderate and severe symptoms treated with mild hypothermia therapy were significantly lower than those of the groups treated with regular therapy. NBNA scores and the developmental quotient (DQ) were both worse with the increase in severity of HIE, however, the scores of groups with moderate and severe symptoms treated with mild hypothermia therapy were significantly better than those of groups treated with regular therapy (P<0.05). A gradual improvement of DQ was seen in the process of therapy in each group (P<0.05). According to a receiver operating characteristic (ROC) curve analysis, at a critical plasma concentration of SBDPs of 1.58 ng/ml, the sensitivity and specificity for HIE diagnosis was 84.6 and 87.5%, respectively. The ROC analysis for Tau protein yielded a sensitivity and specificity of 79.5 and 96.9%, respectively, at a critical plasma concentration of 4.76 pg/ml. Given our results, SBDPs and Tau proteins are very useful for the early diagnosis of HIE. Early application of mild hypothermia therapy for the treatment of HIE can greatly improve the function of neural development. These findings should greatly improve the evaluation and treatment approaches for HIE.

The effects of selective head cooling versus whole-body cooling on some neural and inflammatory biomarkers: a randomized controlled pilot study.

BackgroundTherapeutic hypothermia (TH) has become standard care in newborns with moderate to severe hypoxic ischemic encephalopathy (HIE), and the 2 most commonly used methods are selective head cooling (SHC) and whole body cooling (WBC). This study aimed to determine if the effects of the 2 methods on some neural and inflammatory biomarkers differ.Materials and methodsThis prospective randomized pilot study included newborns delivered after >36 weeks of gestation. SHC or WBC was administered randomly to newborns with moderate to severe HIE that were prescribed TH. The serum interleukin (IL)-1β, IL-6, neuron-specific enolase (NSE), brain-specific creatine kinase (CK-BB), tumor necrosis factor-alpha (TNF-α), and protein S100 levels, the urine S100B level, and the urine lactate/creatinine (L/C) ratio were evaluated 6 and 72 h after birth. The Bayley Scales of Infant and Toddler Development-III was administered at month 12 for assessment of neurodevelopmental findings.ResultsThe SHC group included 14 newborns, the WBC group included 10, the mild HIE group included 7, and the control group included 9. All the biomarker levels in the SHC and WBC groups at 6 and 72 h were similar, and all the changes in the biomarker levels between 6 and 72 h were similar in both groups. The serum IL-6 and protein S100 levels at 6 h in the SHC and WBC groups were significantly higher than in the control group. The urine L/C ratio at 6 h in the SHC and WBC groups was significantly higher than in the mild HIE and control groups. The IL-6 level and L/C ratio at 6 and 72 h in the patients that had died or had disability at month 12 were significantly higher than in the patients without disability at month 12.ConclusionThe effects of SHC and WBC on the biomarkers evaluated did not differ. The urine L/C ratio might be useful for differentiating newborns with moderate and severe HIE from those with mild HIE. Furthermore, the serum IL-6 level and the L/C ratio might be useful for predicting disability and mortality in newborns with HIE.

Semi-quantitative assessment of brain maturation by conventional magnetic resonance imaging in neonates with clinically mild hypoxic-ischemic encephalopathy.

Background:Mild hypoxic-ischemic encephalopathy (HIE) injury is becoming the major type in neonatal brain diseases. The aim of this study was to assess brain maturation in mild HIE neonatal brains using total maturation score (TMS) based on conventional magnetic resonance imaging (MRI).Methods:Totally, 45 neonates with clinically mild HIE and 45 matched control neonates were enrolled. Gestated age, birth weight, age after birth and postmenstrual age at magnetic resonance (MR) scan were homogenous in the two groups. According to MR findings, mild HIE neonates were divided into three subgroups: Pattern I, neonates with normal MR appearance; Pattern II, preterm neonates with abnormal MR appearance; Pattern III, full-term neonates with abnormal MR appearance. TMS and its parameters, progressive myelination (M), cortical infolding (C), involution of germinal matrix tissue (G), and glial cell migration bands (B), were employed to assess brain maturation and compare difference between HIE and control groups.Results:The mean of TMS was significantly lower in mild HIE group than it in the control group (mean ± standard deviation [SD] 11.62 ± 1.53 vs. 12.36 ± 1.26, P < 0.001). In four parameters of TMS scores, the M and C scores were significantly lower in mild HIE group. Of the three patterns of mild HIE, Pattern I (10 cases) showed no significant difference of TMS compared with control neonates, while Pattern II (22 cases), III (13 cases) all had significantly decreased TMS than control neonates (mean ± SD 10.56 ± 0.93 vs. 11.48 ± 0.55, P < 0.05; 12.59 ± 1.28 vs. 13.25 ± 1.29, P < 0.05). It was M, C, and GM scores that significantly decreased in Pattern II, while for Pattern III, only C score significantly decreased.Conclusions:The TMS system, based on conventional MRI, is an effective method to detect delayed brain maturation in clinically mild HIE. The conventional MRI can reveal the different retardations in subtle structures and development processes among the different patterns of mild HIE.

Value of serum MCP-1 and sICAM-1 in neonates with hypoxic-ischemic encephalopathy

Objective To study the levels of serum MCP- 1 and sICAM- 1 in neonates with hypoxicischemic encephalopathy(HIE)and to explore the clinical value of serum MCP- 1 and sICAM- 1 for judgment and prognosis of brain damage in neonates with HIE. Methods The levels of serum MCP- 1 and sICAM-1 in the 1st and 7th day after birth of the 53 cases term infant with HIE(29 cases were mild HIE,15 cases were moderate HIE and 9 cases were severe HIE)were measured by enzyme linked immunosorbent assay(ELISA), and compared with 20 cases of normal newborns. Results The levels of serum MCP- 1 and sICAM- 1 in mild, moderate and severe HIE groups were all significantly higher than those in controls(P< 0.05); With increasing of the degree of brain injury, the levels of serum MCP- 1 and sICAM- 1 increased(P< 0.05); Compared with acute period(the 1st day after birth), the levels of serum MCP- 1 and sICAM- 1 were clearly decreased in recovery stage(the 7th day after birth)in all HIE groups. Conclusion MCP-1 and sICAM-1 may play important roles in the pathogenesis of neonatal HIE and have clinical value in the diagnosis and treatment. Key words: Hypoxia-ischemia encephalopathy; MCP-1; sICAM-1; Brain injury

Value of enhanced T2*-weighted angiography in the intracranial deep vein display in full-term neonates with hypoxic-ischemic encephalopathy

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

Apparent diffusion coefficient in quantitative analysis of brain injury in term neonates with hypoxic-ischemic encephalopathy

Objective Applying diffusion weighted image (DWI) and apparent diffusion coefficient (ADC) to analyze brain injury caused by hypoxic-ischemic encephalopathy (HIE) in term neonates.Methods From June 1,2010 to January 5,2011,thirty-eight full term neonates with HIE were hospitalized in the Second Hospital of Tianjin Medical University.Those with nervous system diseases were excluded.The 38 cases were divided to mild HIE group (n=24) and moderate-to-severe HIE group (n=14).The control group included 10 normal full term neonates without history of asphyxia.All babies were scanned by magnetic resonance imaging (MRI).Spin echo-echo planar imaging sequence was used for DWI images.ADC values of nine regions (frontal lobe gray matter,frontal white matter,parietal gray matter,parietal white matter,corona radiata,caudate nucleus,putamen,posterior limb of the internal capsule and thalamus) were measured.MRI and DWI images were compared.ADC values were compared by analysis of variance and Student-Newman-Keuls test.Results ADC values of the nine indicated regions (frontal lobe gray matter,frontal white matter,parietal gray matter,parietal white matter,corona radiata,caudate nucleus,putamen,posterior limb of the internal capsule and thalamus) were (1.37±0.07),(1.81±0.12),(1.35±0.10),(1.84±0.09),(1.23±0.11),(1.28±0.09),(1.18±0.08),(1.05±0.07) and (1.15±0.08) ×10-3 mm2/s in control group,(1.28±0.11),(1.60±0.15),(1.27±0.09),(1.59±0.20),(1.19±0.15),(1.19±0.13),(1.11±0.09),(0.97±0.11) and (1.06±0.12) ×10-3 mm2/s in mild HIE group,and (1.18±0.14),(1.51±0.22),(1.19±0.09),(1.56±0.19),(1.03±0.16),(1.08±0.07),(1.02±0.07),(0.87±0.09) and (0.96±0.12) × 10-3 mm2/s in moderate-to-severe HIE group.ADC values among the three groups had statistical difference (F=3.89,3.21,4.05,3.30,3.28,3.27,4.12,4.75and 4.72,all P＜0.05).ADC values of frontal lobe gray matter,frontal white matter,parietal gray matter,parietal white matter,putamen,posterior limb of the internal capsule and thalamus in mild HIE group were lower than those in control group (all P＜0.05).All of the ADC values of nine regions in moderate-to-severe HIE group were lower than those in control group (all P＜0.05).ADC value of frontal lobe gray matter,parietal gray matter,corona radiata,caudate nucleus,putamen,posterior limb of the internal capsule and thalamus in moderate-to-severe HIE group were lower than those in mild HIE group (all P＜0.05).Conclusion DWI and ADC values could reflect brain injury caused by HIE,and ADC values can be used to quantitatively analyze the degree of hypoxic-ischemic injury. Key words: Hypoxia-ischemia, brain; Infant, newborn; Diffusion magnetic resonance imaging

Dynamic Changes of Cerebral-Specific Proteins in Full-Term Newborns with Hypoxic–Ischemic Encephalopathy

The aim of this study was to observe the dynamic changes of serum brain-derived neurotrophic factor (BDNF), S-100B, and Tau proteins levels in full-term newborns with hypoxic-ischemic encephalopathy (HIE) and to discuss their significance in brain damage. Serum samples of 28 full-term newborns diagnosed with HIE and 20 controls were obtained in the first 24 h of life. Another serum samples were also taken, respectively, at 3 and 7 days of life in HIE group. The concentrations of BDNF, S-100B, and Tau proteins were measured by the enzyme-linked immunosorbent assay method. Mean concentrations of BDNF, S-100B, and Tau proteins among different time period and in different grades of HIE group were calculated and compared. Compared with the control group, serum BDNF and proteins S-100B levels in HIE group were significantly elevated in 24 h after birth (P < 0.05) and their concentrations were also significantly higher among patients with mod-severe HIE compared to those with mild HIE at 24 h and 7 days after asphyxia (P < 0.05). Regardless of whether mod-severe HIE or mild HIE, there were no significant difference of serum BDNF and proteins S-100B among the three different time periods. There was no difference in Tau protein levels between HIE group and control group, also no difference between mod-severe HIE group and mild HIE group. BDNF and proteins S-100B are up-regulated early in asphyxia neonates with HIE; and the released amount of BDNF and proteins S-100B from nerve center system correlate with the extent of encephalopathy.

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

It is difficult to predict the neurologic outcome of neonates with hypoxic-ischemic encephalopathy (HIE). Our goal was to investigate the prognostic values of magnetic resonance spectroscopy (MRS) in neonatal HIE. During this study, 46 neonates with HIE underwent magnetic resonance imaging (MRI) and proton MRS ((1)HMRS). The sample included 25 cases of mild HIE, 11 cases of moderate HIE, and 10 cases of severe HIE. Nine healthy neonates without asphyxia served as controls. (1)HMRS techniques included single-voxel MRS and 2-D-point-resolved spatially localized spectroscopy (PRESS) multivoxel chemical shift spectroscopy imaging. Then, 31 of 46 neonates with HIE were divided into 3 groups according to their prognosis: dead, abnormal, and normal outcome. Abnormal and normal outcome were defined by follow-up MRI. Metabolic changes were analyzed and compared with HIE grading and prognosis. As a result, the GLx-alpha peak was markedly increased in the moderate and severe HIE groups. The GLx-alpha/Cr ratio in the control, mild, moderate, and severe HIE groups was 0.18, 0.21, 0.64, 1.31, respectively. The Lac/Cr ratio was 0.12, 0.14, 0.19, and 0.26, respectively. A Spearman rank correlation test confirmed that the ratio of GLx-alpha/Cr and Lac/Cr had significant positive correlation with clinical grading of HIE (P < 0.01). The GLx-alpha/Cr ratio in the dead, abnormal, and normal outcome groups was 1.28, 0.82, and 0.25, respectively; the Lac/Cr ratio was 0.34, 0.19, and 0.14, respectively. An anaylsis of variance demonstrated that the differences were significant (both P < 0.01). A Spearman rank correlation test confirmed that the ratio of GLx-alpha/Cr and Lac/Cr had significant negative correlation with prognosis of HIE; GLx-alpha/Cr showed a much stronger correlation than the Lac/Cr ratio (P < 0.01). The formula of the relationship between the poor prognosis of HIE and the ratio of GLx-alpha/Cr in basal ganglia was established by the logistic regression model. In conclusion, (1)HMRS is a useful tool for evaluating the severity and prognosis of HIE. The higher ratio of GLx-alpha/Cr in the basal ganglia and thalamus may predict a poor outcome in neonates with HIE.

Umbilical artery blood S100β protein: a tool for the early identification of neonatal hypoxic-ischemic encephalopathy

Neuroprotective interventions in neonatal hypoxic-ischemic encephalopathy (HIE) require early indicators of brain damage to initiate therapy. In order to find a reliable, rapid, and simple method to identify infants at risk for this disorder, 40 infants with asphyxia were selected as the observation group (HIE group) and 25 normal-term infants as the control group. S100beta protein concentration and gas analysis of the umbilical cord artery blood of all infants were determined. We found that the S100beta protein levels of the HIE group (1.98 microg/L) were higher than those of the control group (1.05 microg/L, p<0.05), and there were significant differences between the mild HIE group (1.72 microg/L) and the moderate or severe HIE groups (3.61 microg/L, p<0.05). An S100beta protein concentration cutoff level of 2.02 microg/L had a sensitivity of 86.7% and a specificity of 88.0% for predicting the development of moderate or severe HIE. The blood gas parameters of umbilical artery blood, such as pH, carbon dioxide tension, and base excess, were significantly different in the HIE group compared to the control group (all p<0.001), but there were no differences between the mild HIE group and the moderate or severe HIE groups. On the basis of clinical manifestations of asphyxiated neonates, detecting the S100beta protein levels in the umbilical artery blood may be of important value in the early diagnosis and grading of HIE.

High Urinary Concentrations of Activin A in Asphyxiated Full-Term Newborns with Moderate or Severe Hypoxic Ischemic Encephalopathy

Hypoxic ischemic encephalopathy (HIE) is a major cause of permanent neurological disabilities in full-term newborns. We measured activin A in urine collected immediately after birth in asphyxiated full-term newborns, and assessed the ability of the measurements to predict the occurrence of perinatal encephalopathy. We studied 30 infants with perinatal asphyxia and 30 healthy term neonates at the same gestational age. We recorded routine laboratory variables, cranial assessments by standard cerebral ultrasound, and the presence or absence of neurological abnormalities during the first 7 days after birth. Urinary activin A concentrations were measured at first urination and 12, 24, 48, and 72 h after birth. Asphyxiated infants were subdivided as follows: group A (n = 18): no or mild HIE with good prognosis and group B (n = 12): moderate or severe HIE with a greater risk of neurological handicap. Activin A concentrations in urine collected at birth (median collection time at first urination <2 h) and at 12, 24, 48, and 72 h from birth were significantly (P <0.0001) higher in asphyxiated newborns with moderate or severe HIE (Group B) than in those with absent of mild HIE (group A) and controls. Concentrations did not differ between group A and controls. Activin A concentrations were >0.08 mug/L at first urination in 10 of 12 patients with moderate or severe HIE but in none of 18 patients with no or mild HIE. Activin A measurements in urine soon after birth may be a promising tool to identify which asphyxiated infants are at risk of neurological sequelae.

Cerebrospinal fluid and serum vascular endothelial growth factor and nitric oxide levels in newborns with hypoxic ischemic encephalopathy

Excitatory amino acids, cytokines and nitric oxide (NO) have been studied in the etiology and pathogenesis of hypoxic ischemic encephalopathy (HIE) of the newborn. Vascular endothelial growth factor (VEGF) is a known mediator of angiogenesis and has been shown to induce vascular proliferation and permeability via NO-mediated mechanism during hypoxia. The objective of this study was to investigate the cerebrospinal fluid and serum VEGF and NO levels in different stages of HIE and the correlation between the two mediators. Cerebrospinal fluid (CSF) and serum samples of 19 newborns with HIE and 13 controls were obtained within the first 24 h of life and kept at −70 °C until the time of measurement. NO levels were determined by Sievers NOA by chemiluminescence method and VEGF levels were measured by the enzyme-linked immunosorbent assay double sandwich method. The NO levels in CSF were higher than the control and mild HIE group in newborns with moderate to severe HIE, and VEGF levels in CSF were higher in the mild HIE group compared to controls but similar in the moderate to severe HIE group compared to mild HIE and control patients. There was no difference between groups with regard to serum NO or VEGF levels, and no correlation was observed between NO and VEGF levels both in CSF and serum samples. Depending on the severity of the hypoxic insult the stimulus for NO production by VEGF may have variable effects on endothelial cells which may give rise to the current results.