Hypoxic-ischemic Encephalopathy Group Research Articles

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.

The clinical research of serum glial fibrillary acidic protein combined with craniocerebral MRI in neonatal hypoxic-ischemic encephalopathy

Objective To explore the relationship between serum glial fibrillary acidic protein (GFAP) level and neonatal hypoxic-ischemic encephalopathy (HIE), and to verify whether GFAP combined with craniocerebral magnetic resonance imaging (MRI) can more accurately evaluate the prognosis of HIE. Methods We selected HIE children who hospitalized in the department of neonatology, the affiliated hospital of Inner Mongolia Medical University from January 2017 to December 2017, and full-term newborns without brain injury who were hospitalized in the same period. Serum samples were taken for GFAP detection on the 1st, 3rd, 7th day after birth of HIE and the 3rd day after birth of full-term newborns without brain injury. All the subjects completed craniocerebral MRI examination and followed up. At the same time, the correlation between GFAP level and the severity of brain MRI was evaluated. Results ⑴ The level of serum GFAP in HIE group on the 3rd day after birth [(5.54±1.30)ng/ml] was significantly higher than that in control group [(3.38±0.31)ng/ml] (P 0.05); there was significant difference between sequelae group [(6.93±1.29)ng/ml] and non-sequelae group [(4.91±0.77)ng/ml] on the 7th day (P 0.05), and there were significant differences on day 7 (P<0.05). Conclusions It is speculated that the increase of serum GFAP level in HIE newborns is related to the severity and prognosis of the disease, and is positively related to the results of craniocerebral MRI examination.Detecting the changes of serum GFAP in HIE newborns is helpful to determine the severity of the disease and evaluate the prognosis of the children. Combining GFAP with craniocerebral MRI may improve the accuracy of the judgment. Key words: Glial fibrillary acidic protein; Magnetic resonance imaging; Hypoxia-ischemia, brain; Infant, newborn, diseases

Antenatal and intrapartum risk factors for neonatal hypoxic ischemic encephalopathy

To identify antenatal and intrapartum risk factors for neonatal hypoxic ischemic encephalopathy (HIE). A single center, retrospective cohort study was conducted for 25,494 singleton births ≥36 weeks' gestation born between 2009 and 2016. Univariate and multivariate analyses were performed to identify risk factors for HIE. Thirty-seven infants met HIE inclusion criteria. Independent antenatal risk factors included primigravida, previous fetal death/stillbirth, antidepressant use, illicit drug use, Rh sensitization, and adjusted gestational weight gain >13.6 kg. Independent intrapartum risk factors identified were placental abruption, ruptured uterus, moderate-to-heavy meconium stained amniotic fluid, and delivery by cesarean-section. An intrapartum risk factor was present in 70.3% of the HIE group compared with 29.6% of the non-HIE group. Intrapartum period risk factors appear to be important for the development of HIE. Gestational weight gain may serve as an important modifiable factor to reduce the risk of HIE.

Oropharyngeal Dysphagia in Breastfeeding Neonates with Hypoxic-Ischemic Encephalopathy on Therapeutic Hypothermia.

Purpose: To identify symptoms of oropharyngeal dysphagia (OPD) in breastfeeding neonates with hypoxic-ischemic encephalopathy (HIE) on therapeutic hypothermia (TH). Early identification of feeding problems in neonates with HIE by speech-language therapists (SLTs) may prevent secondary complications of OPD such as aspiration pneumonia and death. Materials and Methods: Twenty-eight full-term neonates with HIE (mean chronological age = 4.5 days) and 30 healthy term controls were prospectively recruited for this case-control study. Participants with HIE (mild [n = 15], moderate [n = 11], severe [n = 2]), diagnosed by pediatricians, received whole-body TH. Feeding was clinically evaluated by an SLT using the Preterm Infant Breastfeeding Behavior Scale. Results: Twenty-five neonates (89.2%) had at least one symptom of OPD. Falling asleep during feeding, noticeable oral secretions, coughing, and flaring nostrils were symptoms of OPD most frequently identified. The HIE group displayed limited arousal during breastfeeding and had less obvious rooting, shallower latching onto the breast, and more single sucks in comparison to term newborns. The HIE group had significantly more closed eyes and minimal movement during breastfeeding, while controls showed the quiet-alert state ideal for breastfeeding. Conclusions: OPD was identified in the majority of infants with HIE. Underlying the appearance of an inactive neonate with HIE may be OPD that could be overlooked if not investigated. Interprofessional collaboration between SLTs, pediatricians and nurses to determine feeding-readiness is imperative. SLTs may assist in decision-making to improve safety of breastfeeding in this population. This study contributes to the small body of research on early breastfeeding of neonates with 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.

Application of a 3D pseudocontinuous arterial spin-labeled perfusion MRI scan combined with a postlabeling delay value in the diagnosis of neonatal hypoxic-ischemic encephalopathy.

BackgroundCurrently, there are many studies on the application of the 3D pseudocontinuous arterial spin-labeled (3D-pcASL) perfusion MRI technique for adult brain examinations, but few studies exist on the application of the technique for child brain examinations.PurposeTo explore the application of a 3D-pcASL perfusion MRI scan combined with postlabeling delay (PLD) for assessing neonatal hypoxic-ischemic encephalopathy (HIE).Materials and methodsTwo-hundred neonates diagnosed with neonatal HIE were equally divided into five groups (40/group): 0- to <24-hour-old HIE group, 1- to <3-day-old HIE group, 3- to <7-day-old HIE group, 7- to <15-day-old HIE group and 15- to 28-day-old HIE group; 200 healthy neonates were equivalently divided. All 10 groups received a conventional and a 3D-pcASL perfusion MRI scan. For groups <3 days old, PLD values for the 3D-pcASL cerebral perfusion MRI scan were preset at 1025 ms; in all other groups, PLD values were preset at 1525 ms. CBF values for the 3D-pcASL cerebral perfusion MRI were compared between the HIE and corresponding control groups to determine the distinguishing characteristics of CBF values in HIE neonates.ResultsOn the 3D-pcASL cerebral perfusion MRI scan, in the 1- to <3-day-old groups, HIE neonate CBF values were higher than those of controls in all brain regions (excluding the frontal lobe); in the 0- to <24-hour-old and 3- to <7-day-old groups, HIE neonate CBF values were lower than those of corresponding controls in all brain regions; in the 7- to <15-day-old and 15- to 28-day-old groups, there were no significant differences in the CBF values between groups in any brain regions.ConclusionsThe 3D-pcASL perfusion MRI scan combined with a PLD can assist in the early diagnosis of neonatal HIE, as this method more comprehensively reflects the HIE pathological process.

Patterns of neurobehavioral functioning in school-aged survivors of neonatal jaundice and hypoxic-ischemic encephalopathy in Kilifi, Kenya: A cross-sectional study

Background: Studies in high-income countries have reported that school-aged children who survive neonatal jaundice (NNJ) and hypoxic-ischemic encephalopathy (HIE) develop long-term neurocognitive problems. However, less is known about the patterns of functioning in school-aged survivors of NNJ and HIE in sub-Saharan Africa. This study examined patterns of functioning in school-aged children who survived NNJ and HIE in Kilifi, Kenya. Methods: This is a cross-sectional study that included 107 survivors of NNJ/HIE (64 with NNJ, 43 with HIE), aged 6-12 years, admitted to Kilifi County Hospital on the Kenyan Coast. The Gross Motor Function Classification System (GMFCS), Adapted Communication Profile, Raven’s Coloured Progressive Matrices (RCPM) and an epilepsy screening tool were used to assess gross motor function, communication function, intellectual functioning, and epilepsy, respectively. Results: Most of the survivors of NNJ (95.2%) and HIE (95.3%) had no impairments in gross motor functioning. A small percentage of the children in the NNJ and HIE groups had profound problems in their communication (4.7% and 4.7%); expressive communication function (4.7% and 4.7%); social functions (3.1% and 2.3%); receptive communication (4.7% and 2.3%); and communicative effectiveness (4.7% and 2.3%). Cognitive impairment was reported in 10.9% and 11.9% for NNJ and HIE survivors, respectively. Active epilepsy was detected in 1.6% of survivors of NNJ and 2.3% of survivors of HIE. All children had normal hearing and visual functioning except one participant who presented with mild visual acuity problems. Conclusions: Most school-aged children who survive with NNJ and HIE have normal motor and communication function; however, one in ten are likely to present with lowered intellectual functioning compared to the normative sample.

Circulating blood cellular glucose transporters – Surrogate biomarkers for neonatal hypoxic-ischemic encephalopathy assessed by novel scoring systems

ObjectiveWe examined Red Blood Cell (RBC) Glucose Transporter isoform 1 (GLUT1) and White Blood Cell (WBC) Glucose Transporter isoform 3 (GLUT3) protein concentrations to assess their potential as surrogate biomarkers for the presence of hypoxic-ischemic encephalopathy (HIE) and response to therapeutic hypothermia (TH), with respect to the neurodevelopmental prognosis. Study designA prospective feasibility study of 10 infants with HIE and 8 age-matched control subjects was undertaken. Following parental consent, blood samples were obtained at baseline before institution of TH (<6 h of life), during TH, at rewarming and post-TH in the HIE group with a baseline sample from the control group. GLUT1 and GLUT3 were measured by Enzyme-linked immunosorbent assay (ELISA) with brain biomarkers, Neuron-Specific Enolase (NSE) and Glial Fibrillary Acidic Protein (GFAP). Novel “HIE-high risk” and “Neurological” scores were developed to help identify HIE and to assess severity and prognosis, respectively. ResultsRBC GLUT1 concentrations were increased at the baseline pre-TH time point in HIE versus control subjects (p = .006), normalizing after TH (p = .05). An association between GLUT1 and NSE concentrations (which was reflective of the HIE-high risk and the Neuro-scores) in controls and HIE pre-TH was seen (R2 = 0.36, p = .008), with GLUT1 demonstrating 90% sensitivity and 88% specificity for presence of HIE identified by Sarnat Staging. WBC GLUT3 concentrations were low and no different in HIE versus control, and GFAP concentrations trended higher during re-warming (p = .11) and post-TH (p = .16). We demonstrated a significant difference between HIE and controls for both the “HIE-high risk” and the “Neurological” Scores. The latter score revealing the severity of clinical neurological illness correlated with the corresponding RBC GLUT1 (R2 value = 0.39; p = .006). ConclusionCirculating RBC GLUT1 concentrations with NSE demonstrate a significant potential in reflecting the severity of HIE pre-TH and gauging effectiveness of TH. In contrast, the low neonatal WBC GLUT3 concentrations make discerning differences between degrees of HIE as well as assessing effectiveness of TH difficult. The HIE-high risk and Neurological scores may extend the “Sarnat staging” towards assessing severity and neuro-developmental prognosis of HIE.

Study on serum Tau protein level and neurodevelopmental outcome of placental abruption with neonatal hypoxic-ischemic encephalopathy

Objective: The aim of this study was to explore differences in serum Tau protein levels and neurodevelopmental prognoses of placental abruption or umbilical cord around neck with hypoxic-ischemic encephalopathy (HIE).Methods: Forty neonates with moderate/severe HIE divided into placental abruption with HIE group (placental abruption with hypoxic-ischemic encephalopathy (PA-HIE) group) (n = 18) and umbilical cord around the neck with HIE group (umbilical cord around the neck with hypoxic-ischemic encephalopathy (UCAN-HIE) group) (n = 22). Healthy term newborns comprised the control group (n = 35). Serum Tau protein levels were measured using an enzyme-linked immunosorbent assay 24 hours (3.50 hours [1.00–24.00]) after birth. Neurodevelopment outcomes were assessed based on the Gesell Developmental Scale at 9 months of age.Results: Serum Tau protein levels were significantly higher in 40 cases (1013 pg/ml [538.04–1190.42]) than in the control group (106.41 pg/ml [64.55–154.71], p = .0001). Serum Tau protein levels in the PA-HIE group (1024.46 pg/ml [657.88–1190.42]) were significantly higher than those in the UCAN-HIE group (892.78 pg/ml [538.04–1179.50], p = .0149). The development quotient score in the PA-HIE group (67.0 [47.0–90.0]) was significantly lower than that in the UCAN-HIE group (81.5 [52.6–100.0]) (p = .0028). The component ratio of neurodevelopmental retardation in the PA-HIE group (44.45%) was significantly higher than that in the UCAN-HIE group (22.73%) (X2 = 13.3138, p = .0013).Conclusions: Compared with the UCAN-HIE group, the serum Tau protein level and the component ratio of neurodevelopmental retardation were significantly higher in the PA-HIE group.

Validation of Raised Cord Blood Interleukin-16 in Perinatal Asphyxia and Neonatal Hypoxic-Ischaemic Encephalopathy in the BiHiVE2 Cohort

The role of inflammation is an important factor in the progression of hypoxic-ischaemic encephalopathy (HIE). We have previously shown that interleukin-16 (IL-16) is increased in infants with moderate and severe HIE and relates to poor neurodevelopmental outcomes. We aimed to validate IL-16 as a cord blood-based biomarker for HIE and to examine its relationship to long-term outcomes. The study sample consisted of 105 full-term infants who experienced perinatal asphyxia (PA) (with and without an encephalopathy) along with healthy, gestational age-matched newborn controls. Umbilical cord blood serum was processed and biobanked at delivery. Infants were assigned a modified Sarnat score at 24 h. Analysis of IL-16 cytokine cord blood levels was performed using the sandwich-based enzyme-linked immunosorbent assay (ELISA) technique. Cord blood-based IL-16 was increased in infants with PA and HIE relative to controls (p = 0.025). IL-16 was also increased in the HIE group relative to controls (p = 0.042). There was no significant difference in IL-16 across grades of HIE or in those with abnormal outcomes at 2 years of age. This study validates findings that cord blood-based IL-16 levels are increased in infants with PA, including those who go on to develop HIE.

Identification of a panel of cytokines in neonates with hypoxic ischemic encephalopathy treated with hypothermia

PurposeInflammation is a crucial but understudied mechanism of neuronal injury after hypoxia-ischemia. The aim was to identify a panel of cytokines involved in brain injury in neonates with hypoxic ischemic encephalopathy (HIE). MethodsTen newborns with HIE undergoing to therapeutic hypothermia (TH, HIE Group) and 8 healthy newborns (CTRL Group) were enrolled. For the HIE group, 5 samples were collected: between 0 and 6 h of life (time 1), 12 h (time 2), 24 h (time 3), 48 h (time 4) and 96 h of life (time 5). For the CTRL group, one sample was collected. A panel of 48 inflammatory cytokines was determined in all samples. Data were analyzed using multivariate statistical analysis (Principal component analysis, PCA) Results17 cytokines, among 48 analyzed, were found to be significantly different, initially, between the CTRL and HIE groups: 12 with reported pro-inflammatory effects and 5 with reported anti-inflammatory effects. In the HIE group cytokines showed a decreasing trend during the TH and at the end of treatment comparable to the CTRL group. IL-18 did demonstrate a slight increase at time 3 during HT but decreased steadily at sampling times, 4 and 5. ConclusionsOur data demonstrates that many pathways of the inflammatory cascade are activated following hypoxic-ischemic injury. This information will increase our understanding of changes in cytokines over time in neonates with HIE undergoing TH.

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.

Splanchnic hemodynamics as a predictor of feeding tolerance in preterm neonates

Background: The superior mesenteric artery (SMA) supplies the greatest volume of blood to the small intestine. The use of Doppler ultrasound to measure SMA blood flow velocity (BFV) is increasingly used to investigate intestinal hemodynamics in neonates. Aim: The aim of this study was designed to correlate Doppler indices of splanchnic perfusion and vascular resistance to early tolerance of feeding and development of necrotizing enterocolitis in preterm (PT) infants. Setting and Design: This study was conducted at the Neonatal Intensive Care Unit, Ain Shams University Hospital, Cairo Governorate, Egypt. Subjects and Methods: Complete Prenatal, natal, and postnatal history were taken; blood culture and complete blood count, C-reactive protein with titer, and assessment of BFA in SMA at day (D) 1 and D7 of life, including peak systolic velocity (PSV), end diastolic velocity (EDV), resistance index (RI), and pulsatility index (PI), were done upon enrollment of 65 neonates who subdivided into either PT groups, hypoxic-ischemic encephalopathy group, or full-term group. Results: There was a significant difference between the three groups regarding PSV, EDV, and RI before and after feeding. As for the qualitative data of the Doppler indices of SMA, there was a statistically significant difference between the three groups as regards the PI in D1 (P = 0.022), PSV in D7 (P = 0.018), and EDV in D7 (P = 0.040); however, there was no significant difference between the three groups as regard PSV in D1, EDV in D1, RI in D1 and D7, and PI in D7. Conclusion: Doppler hemodynamic studies of SMA in PT infants showed that change in RI parameter in response to small enteral feeds proved to have a highly significant difference with the dependent variable (feeding tolerance) which might be a good tool for the clinician in predicting early tolerance to enteral feeding.

Untargeted metabolomic analysis and pathway discovery in perinatal asphyxia and hypoxic-ischaemic encephalopathy

Elucidating metabolic effects of hypoxic-ischaemic encephalopathy (HIE) may reveal early biomarkers of injury and new treatment targets. This study uses untargeted metabolomics to examine early metabolic alterations in a carefully defined neonatal population. Infants with perinatal asphyxia who were resuscitated at birth and recovered (PA group), those who developed HIE (HIE group) and healthy controls were all recruited at birth. Metabolomic analysis of cord blood was performed using direct infusion FT-ICR mass spectrometry. For each reproducibly detected metabolic feature, mean fold differences were calculated HIE vs. controls (ΔHIE) and PA vs. controls (ΔPA). Putative metabolite annotations were assigned and pathway analysis was performed. Twenty-nine putatively annotated metabolic features were significantly different in ΔPA after false discovery correction (q < 0.05), with eight of these also significantly altered in ΔHIE. Altered putative metabolites included; melatonin, leucine, kynurenine and 3-hydroxydodecanoic acid which differentiated between infant groups (ΔPA and ΔHIE); and D-erythrose-phosphate, acetone, 3-oxotetradecanoic acid and methylglutarylcarnitine which differentiated across severity grades of HIE. Pathway analysis revealed ΔHIE was associated with a 50% and 75% perturbation of tryptophan and pyrimidine metabolism, respectively. We have identified perturbed metabolic pathways and potential biomarkers specific to PA and HIE, which measured at birth, may help direct treatment.

Early detection of neonatal hypoxic-ischemic white matter injury: an MR diffusion tensor imaging study.

The purpose of this study was to compare diffusion tensor metrics in normal age-matched neonates with survivors of hypoxic–ischemic encephalopathy (HIE) and extracorporeal membrane oxygenation (ECMO). Thirty-five normal, 27 HIE, and 13 ECMO infants underwent MRI at 3 T. Neurodevelopmental assessments were performed. Fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD) of the inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, anterior commissure, genu corpus callosum and splenium of the corpus callosum, anterior and posterior limb of the internal capsule, superior longitudinal fasciculus, and the centrum semiovale were analyzed with tract-based spatial statistics modified for use in neonates. Linear regression analysis was performed, and 95% confidence intervals were created for age effects on the tensor metrics with the control patients. Two-sample t-test was done to determine whether there was a difference in the tensor metrics between the normal and patient cohort. There was a statistically significant age effect on the FA and RD in the selected regions of the brain (F<0.05) and a group difference in the FA and RD between the normal and the HIE group (P<0.05). The group difference in the FA and RD between the normal and ECMO groups was seen in the anterior commissure, genu corpus callosum, right inferior longitudinal fasciculus, fronto-occipital fasciculus, centrum semiovale, and superior longitudinal fasciculus (P<0.05). Patients who were outside the 95% confidence intervals of the FA, AD, and RD overlapped with those with abnormalities clinically and on the conventional MRI. In conclusion, diffusion tensor imaging can play a significant role in detecting infants with early indications of hypoxic–ischemic brain injury.

Effects of hypothermia therapy on coagulopathy in neonates with hypoxic-ischemic encephalopathy of diffe-rent degrees

Objective To study the effects of hypothermia therapy on coagulopathy in neonates with hypoxic-ischemic encephalopathy(HIE) of different degrees. Methods Twenty-five newborns with HIE were divided into 2 groups (moderate HIE group and severe HIE group) by amplitude integrated electroencephalogram(aEEG). The platelet (PLT) count, activated partial thromboplastin time (APTT), prothrombin time(PT), thrombin time(TT), fibrinogen (Fbg) and international normalized ratio (INR) were measured before hypothermia therapy and those after 24 hours, 48 hours, 72 hours after hypothermia therapy were collected.The hematological parameters of 2 groups were analyzed by repeated measurement analysis of variance. Results The APTT(t=2.239, P 0.05)showed no statistically significant difference between 2 groups after hypothermia therapy.The differences in INR(F=12.470, P 0.05) between 2 groups.The differences in PLT(F=32.420, P 0.05). But the degree of brain injury and time had interactive effects in PT(F=3.374, P 0.05). Conclusion The coagulopathy function is worse in neonates with severe HIE in hypothermia therapy which may aggravate the hemorrhage risk.And the effect of hypothermia on neonates with moderate HIE is less evident.So hierarchical intervention on coagulopathy in neonates with HIE during hypothermia should be adopted to relieve the hemorrhage risk. Key words: Hypothermia; Hypoxic-ischemic encephalopathy; Coagulopathy; Amplitude integrated electroencephalogram

Long-Term Dosing of Intrathecal Baclofen in the Treatment of Spasticity After Acquired Brain Injury

BackgroundIntrathecal baclofen (ITB) often is used to treat severe spasticity of cerebral origin. Although literature exists regarding the efficacy of ITB, there has been minimal investigation related to dosing in the adult-acquired brain injury population, particularly at long-term duration. ObjectiveTo investigate long-term dosing of ITB in adult patients with spasticity of cerebral origin due traumatic brain injury (TBI), stroke, and hypoxic-ischemic encephalopathy (HIE). DesignRetrospective cohort study. SettingAn academic outpatient rehabilitation clinic. PatientsForty-two adult patients with spasticity secondary to TBI, stroke, or HIE treated with ITB for greater than 3 years. MethodsMedical records and device manufacturer records of included patients were reviewed to obtain demographic data, dosing information, dates of pump and catheter placements, and revisions. Main Outcome MeasureAverage daily ITB doses and mean change in ITB dose over 1, 2, and 3 years. Goal of ITB treatment (active function versus comfort/care/positioning) also was compared. ResultsOf 42 total patients, spasticity was attributed to either TBI (n = 19), stroke (n = 11), or HIE (n = 12). The mean (standard deviation) age was 35.21 (10.17), 56.7 (13.1), and 35.1 (12.4) years for the TBI, stroke, and HIE groups, respectively (P < .001). There was a significant difference in the goal of therapy with “improving functional independence,” accounting for 27.8%, 72.8%, and 0% in the TBI, stroke, and HIE groups, respectively (P = .002). The mean duration of ITB therapy was 8.5 (5.0), 7.8 (3.4), and 9.1 (4.6) years in the TBI, stroke, and HIE groups, respectively (P = .79). The mean daily ITB dose was 596.9 (322.8) μg/d, 513.2 (405.7) μg/d, and 705.2 (271.7) μg/d for the TBI, stroke, and HIE groups, respectively (P = .39). In the subset of the cohort with ITB therapy for more than 5 years, the mean percent change in daily ITB dose between time of chart review and 1, 2, and 3 years previously was 7.3% (13.6), 12.7% (16), and 24.7% (50.3), respectively. A complex dosing pattern was used more frequently in those with stroke (36.4%) compared with the TBI and HIE (9.7%) groups (P = .04). ConclusionDespite the long-term use of ITB therapy in this cohort, the mean daily dose of ITB continued to require adjustments. There was no significant difference in the mean daily dose between patients with a diagnosis of TBI, stroke, or HIE. A complex dosing pattern was used more frequently in patients with stroke. Level of EvidenceIII

Predictive Value of Neurodevelopmental Outcome and Serum Tau Protein Level in Neonates with Hypoxic Ischemic Encephalopathy.

Tau protein is s specific protein expressed by neurons in the central nervous system. Elevated serum Tau protein is associated with many diseases of the central nervous system. The serum Tau protein level in neonates with hypoxic ischemic encephalopathy (HIE) is still poorly understood. Forty-one human neonates with HIE and thirty-five healthy neonates (control group) within 24 hours after birth were studied. Tau protein in serum was detected by enzyme-linked immunosorbent assay. Neurological outcome was assessed at 9 months of age according to the Gesell developmental scale. Tau protein in serum was significantly higher in the HIE group than in the control group (p < 0.01), in neonates with severe HIE than neonates with moderate HIE (p < 0.01), and in infants with neurodevelopmental retardation compared with those with normal neurodevelopment (p < 0.01). The result of this study showed an obvious negative correlation between the serum Tau protein level and development quotients of neonates with HIE (rs = -0.6172, p < 0.01). Receiver operator characteristic curve analysis showed that Tau protein (cutoff value 933.04 pg/mL) was a predictor of neurodevelopmental retardation outcome (AUC value = 0.860 (95% CI: 0.736 - 0.983, p < 0.01), sensitivity 100%, specificity 70.8%). Serum Tau protein level within 24 hours after birth can be used as a marker for the early diagnosis of neonatal HIE and predicting neurodevelopmental outcomes.

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.

Hypoxic-Ischemic Encephalopathy-Associated Liver Fatty Degeneration and the Effects of Therapeutic Hypothermia in Newborn Piglets

Background: Although liver can be injured under the hypoxic-ischemic encephalopathy (HIE) condition, there is currently no histopathological evidence. Therapeutic hypothermia is used to protect the brain; however, the therapeutic potential for concomitant liver injury is unknown. Objectives: This study aimed to histopathologically prove HIE-associated liver injury and to investigate the influence of therapeutic hypothermia in a newborn piglet HIE model. Methods: Eighteen newborn piglets were divided into 3 groups: control (n = 4), HIE (n = 8), and therapeutic hypothermia (n = 6) groups. The hypoxic insult was induced by decreasing the fraction of inspiratory oxygen from 21 to 2-4% over 40 min while monitoring cerebral blood volume and cerebral hemoglobin oxygen saturation. For therapeutic hypothermia, whole-body cooling at 33-34°C was administered for 24 h after the hypoxic insult. We hematologically and histopathologically investigated the liver injury in all groups. Results: Alanine transaminase and lactate dehydrogenase levels in the HIE group were significantly elevated compared with those in the control group. Micro-lipid droplet accumulation in the periportal zone, but not in the perivenous zone, was significantly greater in the HIE group than in the control group and significantly smaller in the therapeutic hypothermia group than in the HIE group. Conclusions: We demonstrated that micro-lipid droplet accumulation in the cytoplasm of hepatocytes in the periportal zone occurs under the HIE condition and that this accumulation is suppressed by therapeutic hypothermia.