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1.  Early clinical signs in neonates with hypoxic ischemic encephalopathy predict an abnormal amplitude-integrated electroencephalogram at age 6 hours 
BMC Pediatrics  2013;13:52.
An early clinical score predicting an abnormal amplitude-integrated electroencephalogram (aEEG) or moderate-severe hypoxic ischemic encephalopathy (HIE) may allow rapid triage of infants for therapeutic hypothermia. We aimed to determine if early clinical examination could predict either an abnormal aEEG at age 6 hours or moderate-severe HIE presenting within 72 hours of birth.
Sixty infants ≥ 36 weeks gestational age were prospectively enrolled following suspected intrapartum hypoxia and signs of encephalopathy. Infants who were moribund, had congenital conditions that could contribute to the encephalopathy or had severe cardio-respiratory instability were excluded. Predictive values of the Thompson HIE score, modified Sarnat encephalopathy grade (MSEG) and specific individual signs at age 3–5 hours were calculated.
All of the 60 infants recruited had at least one abnormal primitive reflex. Visible seizures and hypotonia at 3–5 hours were strongly associated with an abnormal 6-hour aEEG (specificity 88% and 92%, respectively), but both had a low sensitivity (47% and 33%, respectively). Overall, 52% of the infants without hypotonia at 3–5 hours had an abnormal 6-hour aEEG. Twelve of the 29 infants (41%) without decreased level of consciousness at 3–5 hours had an abnormal 6-hour aEEG (sensitivity 67%; specificity 71%). A Thompson score ≥ 7 and moderate-severe MSEG at 3–5 hours, both predicted an abnormal 6-hour aEEG (sensitivity 100 vs. 97% and specificity 67 vs. 71% respectively). Both assessments predicted moderate-severe encephalopathy within 72 hours after birth (sensitivity 90%, vs. 88%, specificity 92% vs. 100%). The 6-hour aEEG predicted moderate-severe encephalopathy within 72 hours (sensitivity 75%, specificity 100%) but with lower sensitivity (p = 0.0156) than the Thompson score (sensitivity 90%, specificity 92%). However, all infants with a normal 3- and 6-hour aEEG with moderate-severe encephalopathy within 72 hours who were not cooled had a normal 24-hour aEEG.
The encephalopathy assessment described by the Thompson score at age 3–5 hours is a sensitive predictor of either an abnormal 6-hour aEEG or moderate-severe encephalopathy presenting within 72 hours after birth. An early Thompson score may be useful to assist with triage and selection of infants for therapeutic hypothermia.
PMCID: PMC3635928  PMID: 23574923
Asphyxia; Neonate; Hypoxic ischemic encephalopathy; Electroencephalogram; aEEG; Prognostic
2.  Value of amplitude-integrated electroencephalograph in early diagnosis and prognosis prediction of neonatal hypoxic-ischemic encephalopathy 
To investigate value of amplitude-integrated electroencephalograph (aEEG) in early diagnosis and prediction of long-term prognosis of neonatal hypoxic-ischemic encephalopathy (HIE), 120 HIE Children were randomly assigned into aEEG group and control group (n = 60 per group). Children in each group were sub-divided into mild, moderate and severe HIE groups (n = 20 per group). 1, 3, 14 and 28 days after birth, aEEG was performed in aEEG group; 3, 14 and 28 days after birth, neonatal behavioral neurological assessment (NBNA) was done in both groups. Children who discharged were followed up at adjusted gestational age of 12 months with Denver Developmental Screening Test (DDST) and prognosis evaluation. Results: aEEG manifestation was positively related to clinical severityb of HIE (r = 0.843, P < 0.01). On day 3 and 14, NBNA score was comparable between two groups (P > 0.05), but significant difference in NBNA score was noted on day 28 (P < 0.05). On day 3, 14 and 28, aEEG manifestation was positively associated with prognosis at adjusted gestational age of 12 months (r = 0.832, 0.857, 0.778, 0.743, P < 0.01). In aEEG group, disability rate was 13.8%, which was significantly lower than that in control group (23.2%); cure rate in aEEG group (60%) was significantly higher than that in control group (40%). Moreover, long-term prognosis was also dramatically different between aEEG group and control group (χ2 = 4.107, P < 0.05). Conclusion: aEEG manifestation is significantly associated with clinical severity of HIE and may be helpful for early diagnosis of HIE. aEEG may be used to predict long term prognosis of HIE children.
PMCID: PMC4057868  PMID: 24955189
Amplitude-integrated electroencephalograph; neonatal hypoxic-ischemic encephalopathy; early diagnosis; prognosis
3.  Limited short-term prognostic utility of cerebral NIRS during neonatal therapeutic hypothermia 
Neurology  2013;81(3):249-255.
We evaluated the utility of amplitude-integrated EEG (aEEG) and regional oxygen saturation (rSO2) measured using near-infrared spectroscopy (NIRS) for short-term outcome prediction in neonates with hypoxic ischemic encephalopathy (HIE) treated with therapeutic hypothermia.
Neonates with HIE were monitored with dual-channel aEEG, bilateral cerebral NIRS, and systemic NIRS throughout cooling and rewarming. The short-term outcome measure was a composite of neurologic examination and brain MRI scores at 7 to 10 days. Multiple regression models were developed to assess NIRS and aEEG recorded during the 6 hours before rewarming and the 6-hour rewarming period as predictors of short-term outcome.
Twenty-one infants, mean gestational age 38.8 ± 1.6 weeks, median 10-minute Apgar score 4 (range 0–8), and mean initial pH 6.92 ± 0.19, were enrolled. Before rewarming, the most parsimonious model included 4 parameters (adjusted R2 = 0.59; p = 0.006): lower values of systemic rSO2 variability (p = 0.004), aEEG bandwidth variability (p = 0.019), and mean aEEG upper margin (p = 0.006), combined with higher mean aEEG bandwidth (worse discontinuity; p = 0.013), predicted worse short-term outcome. During rewarming, lower systemic rSO2 variability (p = 0.007) and depressed aEEG lower margin (p = 0.034) were associated with worse outcome (model-adjusted R2 = 0.49; p = 0.005). Cerebral NIRS data did not contribute to either model.
During day 3 of cooling and during rewarming, loss of physiologic variability (by systemic NIRS) and invariant, discontinuous aEEG patterns predict poor short-term outcome in neonates with HIE. These parameters, but not cerebral NIRS, may be useful to identify infants suitable for studies of adjuvant neuroprotective therapies or modification of the duration of cooling and/or rewarming.
PMCID: PMC3770165  PMID: 23771483
4.  Predictive value of the amplitude integrated EEG in infants with hypoxic ischaemic encephalopathy: data from a randomised trial of therapeutic hypothermia 
The amplitude integrated EEG (aEEG) is reputed to be one of the best predictors of neurological outcome following hypoxic ischaemic encephalopathy in term newborns and was used to select infants into trials of neuroprotection with hypothermia, but its predictive value and the effect of moderate hypothermia on the aEEG have not previously been examined in a randomised study. The positive predictive value (PPV) of the aEEG recorded within 6 h of birth for death or disability at 18 months of age was determined in 314 infants born after 35 weeks gestation who were randomised to receive standard care with or without cooling for 72 h. The aEEG was classified according to voltage and by pattern. The PPV of a severely abnormal aEEG assessed by the voltage and pattern methods was 0.63 and 0.59 respectively in non-cooled infants and 0.55 and 0.51 in cooled infants (p>0.05). Although the differences in PPV between cooled and non-cooled groups were not significant, they are consistent with observational studies showing a lower PPV in infants treated with hypothermia, probably due to a neuroprotective effect of cooling.
PMCID: PMC3888630  PMID: 23800393
Neonatology; Neurodisability; Evidence Based Medicine
5.  Prevalence and etiology of false normal aEEG recordings in neonatal hypoxic-ischaemic encephalopathy 
BMC Pediatrics  2013;13:194.
Amplitude-integrated electroencephalography (aEEG) is a useful tool to determine the severity of neonatal hypoxic-ischemic encephalopathy (HIE). Our aim was to assess the prevalence and study the origin of false normal aEEG recordings based on 85 aEEG recordings registered before six hours of age.
Raw EEG recordings were reevaluated retrospectively with Fourier analysis to identify and describe the frequency patterns of the raw EEG signal, in cases with inconsistent aEEG recordings and clinical symptoms. Power spectral density curves, power (P) and median frequency (MF) were determined using the raw EEG. In 7 patients non-depolarizing muscle relaxant (NDMR) exposure was found. The EEG sections were analyzed and compared before and after NDMR administration.
The reevaluation found that the aEEG was truly normal in 4 neonates. In 3 neonates, high voltage electrocardiographic (ECG) artifacts were found with flat trace on raw EEG. High frequency component (HFC) was found as a cause of normal appearing aEEG in 10 neonates. HFC disappeared while P and MF decreased significantly upon NDMR administration in each observed case.
Occurrence of false normal aEEG background pattern is relatively high in neonates with HIE and hypothermia. High frequency EEG artifacts suggestive of shivering were found to be the most common cause of false normal aEEG in hypothermic neonates while high voltage ECG artifacts are less common.
PMCID: PMC4222766  PMID: 24268061
Perinatal asphyxia; Muscular artifact; Fourier analysis; EEG noise; aEEG
6.  The use of amplitude-integrated electroencephalography combined with continuous conventional electroencephalography during therapeutic hypothermia for an infant with postnatal cardiac arrest 
SpringerPlus  2014;3:373.
Amplitude-integrated electroencephalography (aEEG) has been employed in therapeutic hypothermia (TH) trials of neonates after perinatal hypoxic-ischemic encephalopathy (HIE). We present a case report involving the use of aEEG during TH with continuous conventional electroencephalography (cEEG) for an infant who experienced postnatal intraoperative cardiac arrest.
Case description
A five-month-old infant developed cardiac arrest during operation. Return of spontaneous circulation was achieved after one hour of cardiopulmonary resuscitation. Therapeutic hypothermia was applied with neuromuscular blockades. During the TH, the brain function and seizures were monitored with aEEG, which can also display continuous cEEG. Intermittent and discrete seizures were detected on aEEG and confirmed with raw cEEG during the TH and rewarming periods. Several kinds of antiepileptic drugs (AEDs) were administered to manage seizures according to the findings of aEEG with cEEG. Seizures were controlled by the treatments, and she showed no clinical seizures after TH and AED discontinuation.
Discussion and evaluation, conclusions
This case indicated the possibility that the use of aEEG with continuous cEEG for a postnatal infant after cardiac arrest was feasible to detect and assess seizures and the effects of antiepileptic therapy while undergoing TH.
PMCID: PMC4117861  PMID: 25089256
Amplitude-integrated electroencephalography; Continuous conventional electroencephalography; Therapeutic hypothermia; Cardiac arrest; Hypoxic ischemic encephalopathy; Seizures
7.  Recovery of amplitude integrated electroencephalographic background patterns within 24 hours of perinatal asphyxia 
Objective: To assess the time course of recovery of severely abnormal initial amplitude integrated electroencephalographic (aEEG) patterns (flat trace (FT), continuous low voltage (CLV), or burst suppression (BS)) in full term asphyxiated neonates, in relation to other neurophysiological and neuroimaging findings and neurodevelopmental outcome.
Methods: A total of 190 aEEGs of full term infants were reviewed. The neonates were admitted within 6 hours of birth to the neonatal intensive care unit because of perinatal asphyxia, and aEEG recording was started immediately. In all, 160 infants were included; 65 of these had an initial FT or CLV pattern and 25 an initial BS pattern. Neurodevelopmental outcome was assessed using a full neurological examination and the Griffiths' mental developmental scale.
Results: In the FT/CLV group, the background pattern recovered to continuous normal voltage within 24 hours in six of the 65 infants (9%). All six infants survived the neonatal period; one had a severe disability, and five were normal at follow up. In the BS group, the background pattern improved to normal voltage in 12 of the 25 infants (48%) within 24 hours. Of these infants, one died, five survived with moderate to severe disability, two with mild disability, and four were normal. The patients who did not recover within 24 hours either died in the neonatal period or survived with a severe disability.
Conclusion: In this study there was a small group of infants who presented with a severely abnormal aEEG background pattern within six hours of birth, but who achieved recovery to a continuous normal background pattern within the first 24 hours. Sixty one percent of these infants survived without, or with a mild, disability.
PMCID: PMC1721875  PMID: 15846017
8.  Predictive value of early continuous amplitude integrated EEG recordings on outcome after severe birth asphyxia in full term infants. 
The background pattern in single channel amplitude integrated EEG recordings (aEEG) was recorded in 47 infants within the first six hours after birth to see if this could predict outcome after birth asphyxia. The aEEG background pattern during the first six hours of life was continuous and of normal voltage in 26 infants. All these infants survived; 25 were healthy, one had delayed psychomotor development. A continuous but extremely low voltage pattern was present in two infants, both of whom survived with severe handicap. Five infants had flat (mainly isoelectric) tracings during the first six hours of life; four died in the neonatal period, and one survived with severe neurological handicap. Burst-suppression pattern was identified in 14 infants, of whom five died, six survived with severe handicap, and three were healthy at follow up. The type of background pattern recorded within the first six postnatal hours in the aEEG tracings predicted outcome correctly in 43 of 47 (91.5%) infants. Use of aEEG monitoring can predict outcome, with a high degree of accuracy, after birth asphyxia, within the first six hours after birth. The predictive value of a suppression-burst pattern was, however, somewhat lower than the other background patterns. The aEEG seems to be a feasible technique for identifying infants at high risk of subsequent brain damage who might benefit from interventionist treatment after asphyxia.
PMCID: PMC2528413  PMID: 7743282
9.  Evolution of Encephalopathy during Whole Body Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy 
The Journal of Pediatrics  2011;160(4):567-572.e3.
To examine the predictive ability of stage of hypoxic-ischemic encephalopathy (HIE) for death or moderate/severe disability at 18 months among neonates undergoing hypothermia.
Study design
Stage of encephalopathy was evaluated at <6 hr of age, during study intervention and at discharge among 204 participants in the NICHD Neonatal Research Network Trial of whole body hypothermia for HIE. HIE was examined as a predictor of outcome by regression models.
Moderate and severe HIE occurred at <6 hrs of age among 68% and 32% of 101 hypothermia group infants and 60% and 40% of 103 control group infants, respectively. At 24 and 48 hrs of study intervention, infants in the hypothermia group had less severe HIE than infants in the control group. Persistence of severe HIE at 72 hrs increased the risk of death or disability after controlling for treatment group. The discharge exam improved the predictive value of stage of HIE at < 6hrs for death/disability.
On serial neurological examinations, improvement in stage of HIE was associated with cooling. Persistence of severe HIE at 72 hours and an abnormal neurological exam at discharge was associated with a greater risk of death or disability.
PMCID: PMC3299861  PMID: 22050871
Neurological examinations; neonates; clinical biomarker; death; disability
10.  Therapeutic Hypothermia for Neonatal Encephalopathy 
Opinion statement
Neonatal Hypoxic-ischemic encephalopathy in full term infants has been associated with a high risk for morbidity and mortality. The patho-physiology of brain injury following hypoxia-ischemia, noted in preclinical models, is a cascade of events resulting from excitotoxic and oxidative injury culminating in cell death. Hypothermia has been noted to be protective by inhibiting various events in the cascade of injury. Major randomized clinical trials in neonatal HIE have demonstrated reduction in death and disability and continued safety and efficacy of neuroprotection in childhood. There is now clinical and imaging evidence for hypothermia as neuroprotection. Hypothermia should be offered to term infants with either severe acidosis at birth or resuscitation needing continued ventilation and evidence of either moderate or severe encephalopathy within 6 hours of birth. The target temperature should be 33° to 34 °C and duration of cooling should be 72 hours, as per the published trials. Rewarming should be slow, at 0.5 °C per hour. Infants should have serial neurological examinations during and at the end of cooling and at discharge. Multiorgan function should be supported and hypocarbia should be avoided during ventilator therapy. If available, the amplitude integrated EEG should be obtained prior to cooling and following rewarming. All infants should have magnetic resonance brain imaging studies within 1 to 2 weeks of age. Information from the neurological examination, aEEG and MRI studies will be helpful in discussing prognosis with parents. All infants should be followed for a minimum of 18 months to evaluate growth parameters and neurodevelopment al outcome.
PMCID: PMC3519960  PMID: 23007949
Therapeutic hypothermia; Neonatal encephalopathy; Term infants; Neonatal hypoxic-ischemic encephalopathy; Pathophysiology; Neurodevelopmental outcome; Neuroprotection; Head cooling; Whole body cooling; Randomized controlled trials; Knowledge gaps; Adjuvant therapies; Treatment
11.  Early single-channel aEEG/EEG predicts outcome in very preterm infants 
To characterize early amplitude-integrated electroencephalogram (aEEG) and single-channel EEG (aEEG/EEG) in very preterm (VPT) infants for prediction of long-term outcome.
Forty-nine infants with median (range) gestational age of 25 (22–30) weeks.
Amplitude-integrated electroencephalogram/EEG recorded during the first 72 h and analysed over 0–12, 12–24, 24–48 and 48–72 h, for background pattern, sleep–wake cycling, seizures, interburst intervals (IBI) and interburst percentage (IB%). In total, 2614 h of single-channel EEG examined for seizures. Survivors were assessed at 2 years corrected age with a neurological examination and Bayley Scales of Infant Development-II. Poor outcome was defined as death or survival with neurodevelopmental impairment. Good outcome was defined as survival without impairment.
Thirty infants had good outcome. Poor outcome (n = 19) was associated with depressed aEEG/EEG already during the first 12 h (p = 0.023), and with prolonged IBI and higher IB% at 24 h. Seizures were present in 43% of the infants and associated with intraventricular haemorrhages but not with outcome. Best predictors of poor outcome were burst-suppression pattern [76% correctly predicted; positive predictive value (PPV) 63%, negative predictive value (NPV) 91%], IBI > 6 sec (74% correctly predicted; PPV 67%, NPV 79%) and IB% > 55% at 24 h age (79% correctly predicted; PPV 72%, NPV 80%). In 35 infants with normal cerebral ultrasound during the first 3 days, outcome was correctly predicted in 82% by IB% (PPV 82%, NPV 83%).
Long-term outcome can be predicted by aEEG/EEG with 75–80% accuracy already at 24 postnatal hours in VPT infants, also in infants with no early indication of brain injury.
PMCID: PMC3437495  PMID: 22530996
Burst suppression; Cranial ultrasound; Interburst interval; Neurodevelopmental impairment; Seizure
12.  A random forest model based classification scheme for neonatal amplitude-integrated EEG 
BioMedical Engineering OnLine  2014;13(Suppl 2):S4.
Modern medical advances have greatly increased the survival rate of infants, while they remain in the higher risk group for neurological problems later in life. For the infants with encephalopathy or seizures, identification of the extent of brain injury is clinically challenging. Continuous amplitude-integrated electroencephalography (aEEG) monitoring offers a possibility to directly monitor the brain functional state of the newborns over hours, and has seen an increasing application in neonatal intensive care units (NICUs).
This paper presents a novel combined feature set of aEEG and applies random forest (RF) method to classify aEEG tracings. To that end, a series of experiments were conducted on 282 aEEG tracing cases (209 normal and 73 abnormal ones). Basic features, statistic features and segmentation features were extracted from both the tracing as a whole and the segmented recordings, and then form a combined feature set. All the features were sent to a classifier afterwards. The significance of feature, the data segmentation, the optimization of RF parameters, and the problem of imbalanced datasets were examined through experiments. Experiments were also done to evaluate the performance of RF on aEEG signal classifying, compared with several other widely used classifiers including SVM-Linear, SVM-RBF, ANN, Decision Tree (DT), Logistic Regression(LR), ML, and LDA.
The combined feature set can better characterize aEEG signals, compared with basic features, statistic features and segmentation features respectively. With the combined feature set, the proposed RF-based aEEG classification system achieved a correct rate of 92.52% and a high F1-score of 95.26%. Among all of the seven classifiers examined in our work, the RF method got the highest correct rate, sensitivity, specificity, and F1-score, which means that RF outperforms all of the other classifiers considered here. The results show that the proposed RF-based aEEG classification system with the combined feature set is efficient and helpful to better detect the brain disorders in newborns.
PMCID: PMC4304248  PMID: 25560269
13.  The Prognostic Value of Amplitude-Integrated EEG in Full-Term Neonates with Seizures 
PLoS ONE  2013;8(11):e78960.
Neonatal seizures pose a high risk for adverse outcome in survived infants. While the prognostic value of amplitude-integrated electroencephalogram (aEEG) is well established in neonates with encephalopathy and asphyxia, neonatal seizure studies focusing on the direct correlation between early aEEG measurement and subsequent neurologic outcome are scarce. In this study, the prognostic value of aEEG features was systematically analyzed in 143 full-term neonates to identify prognostic indicators of neurodevelopmental outcome. Neonatal aEEG features of background pattern, cyclicity, and seizure activity, as well as the etiology of neonatal seizures, were significantly associated with neurodevelopmental outcome at one year of age. aEEG background pattern was highly associated with neurologic outcomes (χ2 = 116.9), followed by aEEG cyclicity (χ2 = 87.2) and seizure etiology (χ2 = 79.3). Multiple linear regression showed that the four predictors explained 71.2% of the variation in neurological outcome, with standardized β coefficients of 0.44, 0.24, 0.22, and 0.14 for the predictors of aEEG background pattern, cyclicity, etiology, and aEEG seizure activity, respectively. This clinically applicable scoring system based on etiology and three aEEG indices would allow pediatricians to assess the risk for neurodevelopmental impairment and facilitate an early intervention in newborns developing seizures.
PMCID: PMC3827298  PMID: 24236076
14.  Amplitude integrated EEG 3 and 6 hours after birth in full term neonates with hypoxic-ischaemic encephalopathy 
AIM—To assess the prognostic value of amplitude integrated EEG (aEEG) 3 and 6 hours after birth.
METHODS—Seventy three term, asphyxiated infants were studied (from two different centres), using the Cerebral Function Monitor (CFM Lectromed). The different aEEG tracings were compared using pattern recognition (flat tracing mainly isoelectric (FT); continuous extremely low voltage (CLV); burst-suppression (BS); discontinuous normal voltage (DNV); continuous normal voltage (CNV)) with subsequent outcome.
RESULTS—Sixty eight infants were followed up for more than 12 months (range 12 months to 6 years).Twenty one out of 68 infants (31%) showed a change in pattern from 3 to 6 hours, but this was only significant in five cases (24%). In three this changed from BS to CNV with a normal outcome. One infant showed a change in pattern from CNV to FT and had a major handicap at follow up. Another infant showed a change in pattern from DNV to BS, and developed a major handicap at follow up. The other 16 infants did not have any significant changes in pattern: 11 infants had CLV, BS, or FT at 3 and 6 hours and died (n = 9) in the neonatal period or developed a major handicap (n = 2). Five infants had a CNV or DNV pattern at 3 and 6 hours, with a normal outcome. The sensitivity and specificity of BS, together with FT and CLV, for poor outcome at 3 hours was 0.85 and 0.77, respectively; at 6 hours 0.91 and 0.86, respectively. The positive predictive value (PPV) was 78% and the negative predictive value (NPV) 84% 3 hours after birth. At 6 hours the PPV was 86% and the NPV was 91%.
CONCLUSION—aEEG could be very useful for selecting those infants who might benefit from intervention after birth asphyxia.

PMCID: PMC1720950  PMID: 10375357
15.  Video-EEG monitoring in newborns with hypoxic-ischemic encephalopathy treated with hypothermia 
Neurology  2011;76(6):556-562.
Therapeutic hypothermia (TH) is becoming standard of care in newborns with hypoxic-ischemic encephalopathy (HIE). The prognostic value of the EEG and the incidence of seizures during TH are uncertain.
To describe evolution of EEG background and incidence of seizures during TH, and to identify EEG patterns predictive for MRI brain injury.
A total of 41 newborns with HIE underwent TH. Continuous video-EEG was performed during hypothermia and rewarming. EEG background and seizures were reported in a standardized manner. Newborns underwent MRI after rewarming. Sensitivity and specificity of EEG background for moderate to severe MRI brain injury was assessed at 6-hour intervals during TH and rewarming.
EEG background improved in 49%, remained the same in 38%, and worsened in 13%. A normal EEG had a specificity of 100% upon initiation of monitoring and 93% at later time points. Burst suppression and extremely low voltage patterns held the greatest prognostic value only after 24 hours of monitoring, with a specificity of 81% at the beginning of cooling and 100% at later time points. A discontinuous pattern was not associated with adverse outcome in most patients (73%). Electrographic seizures occurred in 34% (14/41), and 10% (4/41) developed status epilepticus. Seizures had a clinical correlate in 57% (8/14) and were subclinical in 43% (6/14).
Continuous video-EEG monitoring in newborns with HIE undergoing TH provides prognostic information about early MRI outcome and accurately identifies electrographic seizures, nearly half of which are subclinical.
PMCID: PMC3053178  PMID: 21300971
16.  Chronological changes of the amplitude-integrated EEG in a neonate with molybdenum cofactor deficiency 
Journal of Inherited Metabolic Disease  2010;33(Suppl 3):401-407.
Molybdenum cofactor (Moco) deficiency is a rare neurometabolic disorder, characterized by neurological impairment and refractive seizures, due to toxic accumulation of sulfite in the brain. Earlier it was suggested that in Moco-deficient humans maternal clearance of neurotoxic metabolites prevents prenatal brain damage. However, limited data are available about the time profile in which neurophysiologic deterioration occurs after birth. The amplitude-integrated electroencephalography (aEEG) is a bedside method in neonates to monitor cerebral recovery after hypoxic-ischemic insults, detect epileptic activity, and evaluate antiepileptic drug treatment. We describe a chronological series of changes in aEEG tracings in a neonate with Moco deficiency. He presented with myoclonic spasms and hypertonicity a few hours after birth, however, the aEEG pattern was still normal. Within 2 days, the aEEG rapidly changed into a burst suppression pattern with repetitive seizures. After antiepileptic treatment, the aEEG remained abnormal. In this patient, the normal aEEG pattern at birth may have been due to maternal clearance of sulfite in utero. After birth, accumulation of sulfite causes progressive brain damage, reflected by the progressive depression of the aEEG tracings. This is in agreement with the results from a Moco-deficient mouse model, suggesting that maternal sulfite clearance suppresses prenatal brain damage. To our knowledge, this is the first case report describing the chronological changes in the aEEG pattern in a Moco-deficient patient. Insight into the time profile in which neurologic deterioration in Moco-deficient humans occurs is essential, especially when potential treatment strategies are being evaluated.
PMCID: PMC3757261  PMID: 20865336
17.  Electroencephalogram and Magnetic Resonance Imaging Comparison as a Predicting Factor for Neurodevelopmental Outcome in Hypoxic Ischemic Encephalopathy Infant Treated with Hypothermia 
Pediatric Reports  2014;6(3):5532.
Hypoxic-ischemic encephalopathy (HIE) is an important cause of acute neurological damage in newborns at (or near) term. Several trials in recent years have shown that moderate hypothermia by total body cooling or selective head is an effective intervention to reduce mortality and major disability in infants survived a perinatal hypoxic-ischemic attack. Follow-up in these patients is very important to establish neurodevelopmental outcome, and specific markers can lead us to detect predicting sign for good or poor outcome. We reported a few cases of newborn with HIE treated with hypothermia, in whom the comparison between electroencephalogram (EEG) and magnetic resonance imaging (MRI) represents the first marker for neurodevelopment outcome prediction. The continuous EEG monitoring showed a depressed EEG activity with diffuse burst depression in 7 patients. No epileptic abnormalities were registered. In 10 out of 20 patients no abnormalities of the background activity and no epileptic abnormalities were observed. We found that a depressed EEG activity during the first 72 h of life and a diffused alteration of basal ganglia at MRI were correlated with a poor neurodevelopmental outcome at 18 months of follow-up.
PMCID: PMC4292060  PMID: 25635216
hypothermia; neonates; magnetic resonance imaging; long term; electroencephalogram monitoring
18.  Biomarkers for Severity of Neonatal Hypoxic-Ischemic Encephalopathy and Outcomes in Newborns Receiving Hypothermia Therapy 
The Journal of pediatrics  2013;164(3):468-74.e1.
To evaluate serum neuronal and inflammatory biomarkers to determine whether measurements of umbilical cords at birth can stratify severity of hypoxic-ischemic encephalopathy (HIE), whether serial measurements differ with hypothermia-rewarming, and whether biomarkers correlate with neurological outcomes.
Study design
This is a prospective cohort of inborn term newborns with varying degrees of HIE by neurological assessment. Neuronal glial fibrillary acidic protein (GFAP), ubiquitin carboxyl-terminal hydrolase L1, and inflammatory cytokines were measured in serum from umbilical artery at 6–24, 48, 72, and 78 hours of age. Neurodevelopmental outcomes (Bayley Scales of Infant and Toddler Development-III scales) were performed at 15–18 months.
Twenty neonates had moderate (n = 17) or severe (n = 3) HIE and received hypothermia; 7 had mild HIE and were not cooled. At birth, serum GFAP and ubiquitin carboxyl-terminal hydrolase L1 increased with the severity of HIE (P < .001), and serial GFAP remained elevated in neonates with moderate to severe HIE. Interleukin (IL)-6, IL-8, and vascular endothelial growth factor were greater at 6–24 hours in moderate to severe vs mild HIE (P < .05). The serial values were unaffected by hypothermia-rewarming. Elevated GFAP, IL-1, IL-6, IL-8, tumor necrosis factor, interferon, and vascular endothelial growth factor at 6–24 hours were associated with abnormal neurological outcomes.
The severity of the hypoxic-ischemic injury can be stratified at birth because elevated neuronal biomarkers in cord serum correlated with severity of HIE and outcomes.
PMCID: PMC4006934  PMID: 24332821
19.  Perinatal Acidosis and Hypoxic-Ischemic Encephalopathy in Preterm Infants of 33 to 35 Weeks’ Gestation 
The Journal of pediatrics  2011;160(3):388-394.
To determine the frequency of hypoxic-ischemic encephalopathy (HIE) in preterm infants of 33 to 35 weeks’ gestational age on the basis of physiological screening for perinatal acidosis and neurological assessment of encephalopathy and to correlate neurodevelopmental outcomes with brain magnetic resonance imaging findings.
Study design
This retrospective cohort study included all inborn infants of 33 to 35 weeks’ gestation admitted to the neonatal intensive care unit at Parkland Memorial Hospital with perinatal acidosis from October 2005 to September 2008. Their medical records were reviewed, and pertinent data were recorded.
Of 1305 newborns, 2.5% (n = 33) had perinatal acidosis, and 27% (n = 9) of these had HIE (2, mild; 4, moderate; 3, severe). Persistence of metabolic acidosis on the first arterial blood gas obtained in the first hour of age was significantly associated with HIE (P < .005). Magnetic resonance imaging results were abnormal in 3 of 4 infants with moderate HIE and in both survivors with severe HIE. Death or disability occurred in no infants with mild or moderate HIE, but in all infants with severe HIE.
Screening criteria for HIE that use biochemical and neurological assessments as performed in term newborns can be applied to preterm infants of 33 to 35 weeks’ gestation.
PMCID: PMC3740949  PMID: 22033298
20.  Low Voltage aEEG as predictor of Intracranial Hemorrhage in preterm infants 
Pediatric neurology  2011;44(5):364-369.
The objectives of this prospective cohort study were to identify amplitude-integrated electroencephalography (aEEG) background patterns predictive of severe intracranial hemorrhage. Thirty ventilated preterm newborns <1000 grams were assessed using an aEEG cerebral function monitor and ultrasound measurement of cerebral blood flow (CBF) velocity at time of surfactant administration and tracheal suctioning simultaneously during first 48 hours of life. Birth weight was 624 ± 200 g (mean ± SD) and gestational age was 25 ± 2 weeks. Background electrical activity was predominantly discontinuous in 72% of infants. A sharp increase in electrical activity/burst density was observed during surfactant administration and tracheal suctioning in most infants with a 33.5 % increase in mean CBF velocity. Burst suppression with low voltage was identified in 57% infants with grade 3-4 Intracranial hemorrhage, while no infant without hemorrhage exhibited this pattern (P = .014). We conclude that aEEG low voltage burst suppression might have useful clinical applications with 100% positive vale for severe intracranial hemorrhage.
PMCID: PMC3160756  PMID: 21481745
21.  Hepatic Dysfunction in Asphyxiated Neonates: Prospective Case-Controlled Study 
This study was performed to determine the occurrence of hypoxic hepatitis in full-term neonates after perinatal asphyxia and to correlate between the rise in enzymes and severity of asphyxia with Apgar score and hypoxic ischemic encephalopathy (HIE) grading of the neonates.
This prospective case-controlled study was conducted in a tertiary-level hospital in India for a period of 12 months. The study group A comprised 70 newborns suffering from birth asphyxia, while 30 healthy neonates were included in group B (control). All biochemical parameters of liver function, ie, serum alanine transferase (ALT), aspartate transferase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), total protein, serum albumin, bilirubin (total and direct), and international normalized ratio (INR), were measured on postnatal days 1, 3, and 10 in both study and control groups.
In group A, 22.8% newborns had severe (Apgar score 0–3), 47.1% had moderate (Apgar score 4–5), and 30% had mild (Apgar score 6–7) birth asphyxia at five minutes. In all, 14.28% babies were in HIE stage I, 25.73% babies were in HIE stage II, and 11.42% babies were in HIE stage III. The rest of the newborns, 48.57%, were normal. The prevalence of liver function impairment was seen in 42.85% of asphyxiated neonates. On day 1, ALT, AST, ALP, LDH, PT, and INR were significantly higher, and total protein and serum albumin were significantly lower in group A than in group B. However, ALT and AST correlated well with increasing severity of HIE score. On day 3, there was a rising trend observed in the concentration of mean LDH as HIE staging of neonates progressed from stage 0 to stage III, and among various HIE stages, the difference in LDH was statistically significant.
We concluded that AST, ALT at 24 hours, and LDH at 72 hours of animation can be a utilitarian diagnostic tool to differentiate asphyxiated neonates from non-asphyxiated neonates and to discover the severity of perinatal asphyxia because of easy accessibility and feasibility of tests. The outcomes of this survey would be useful for physicians who receive neonates for whom birth details are not easily documented as most of the time the referred newborn infants lack asphyxia history either because the attendants do not know clearly the whole birth history or it was an unattended delivery, or the referring health-care professional has not been observant because of legal threats. The neurological assessment also becomes difficult and inconclusive as ventilator treatment, sedative drugs, and anticonvulsant therapy would produce an evaluation of severity of hypoxic ischemic brain disease and neurological insult difficult.
PMCID: PMC4294631
birth asphyxia; hypoxic ischemic encephalopathy; hepatic dysfunction
22.  Prediction of Early Childhood Outcome of Term Infants using Apgar Scores at 10 Minutes following Hypoxic-Ischemic Encephalopathy 
Pediatrics  2009;124(6):1619.
Death or severe disability is so common following an Apgar score of 0 at 10 minutes in observational studies that the Neonatal Resuscitation Program suggests considering discontinuation of resuscitation after 10 minutes of effective CPR.
To determine if Apgar scores at 10 minutes are associated with death or disability in early childhood following perinatal hypoxic-ischemic encephalopathy (HIE).
Design, Setting, and Patients
This is a secondary analysis of infants enrolled in the NICHD Neonatal Research Network hypothermia trial. Infants ≥ 36 weeks gestation had clinical and/or biochemical abnormalities at birth, and encephalopathy at < 6 hours. Logistic regression and classification and regression tree (CART) analysis was used to determine associations between Apgar scores at 10 minutes and neurodevelopmental outcome adjusting for covariates. Associations are expressed as odds ratios (OR) and 95% confidence interval (CI).
Main Outcome Measure
Death or disability (moderate or severe) at 18–22 months of age.
Twenty of 208 infants were excluded (missing data). More than 90% of infants had Apgar scores of 0–2 at 1 minute and Apgars at 5 and 10 minutes shifted to progressively higher values; at 10 minutes 27% of infants had Apgar scores of 0–2. After adjustment each point decrease in Apgar score at 10 minutes was associated with a 45% increase in the odds of death or disability (OR 1.45, CI 1.22–1.72). Death or disability occurred in 76, 82 and 80% of infants with Apgar scores at 10 minutes of 0, 1 and 2, respectively. CART analysis indicated that Apgar scores at 10 minutes were discriminators of outcome.
Apgar scores at 10 minutes provide useful prognostic data before other evaluations are available for infants with HIE. Death or moderate/severe disability is common but not uniform with Apgar scores < 3; caution is needed before adopting a specific time interval to guide duration of resuscitation.
PMCID: PMC2821195  PMID: 19948631
Apgar scores; Hypoxic-Ischemic Encephalopathy; cardiopulmonary resuscitation
23.  Concurrent erythropoietin and hypothermia treatment improve outcomes in a term nonhuman primate model of perinatal asphyxia 
Developmental neuroscience  2013;35:10.1159/000355460.
Up to 65% of untreated infants suffering from moderate to severe hypoxic-ischemic encephalopathy (HIE) are at risk of death or major disability. Therapeutic hypothermia (HT) reduces this risk to approximately 50% (number needed to treat 7-9). Erythropoietin (Epo) is a neuroprotective treatment that is promising as an adjunctive therapy to decrease HIE-induced injury because Epo decreases apoptosis, inflammation, and oxidative injury, and promotes glial cell survival, and angiogenesis. We hypothesized that HT and concurrent Epo will be safe, effective, improve survival and reduce moderate-severe cerebral palsy (CP) in a term nonhuman primate model of perinatal asphyxia.
35 Macaca nemestrina were delivered after 15-18 min of umbilical cord occlusion (UCO) and randomized to saline (n=14), HT only (n=9) or HT+Epo (n=12). There were 12 unasphyxiated controls. Epo (3500 U/kg × 1 followed by 3 doses of 2500 U/Kg, or Epo 1000 U/kg/d × 4 doses) was given on days 1, 2, 3, and 7. Timed blood samples were collected to measure plasma Epo concentrations. Animals underwent MRI/MRS and diffusion tensor imaging (DTI) at < 72 hours of age and again at 9 months. A battery of weekly developmental assessments was performed.
UCO resulted in death or moderate-severe CP in 43% of saline, 44% of HT, and 0% of HT+Epo treated animals. Compared to non-UCO control animals, UCO animals exhibit poor weight gain, behavioral impairment, poor cerebellar growth and abnormal brain DTI. Compared to UCO saline, UCO HT+Epo improved motor and cognitive responses, cerebellar growth, DTI measures, and produced a death/disability relative risk reduction of 0.911 (95% CI −0.429 to 0.994), an absolute risk reduction of 0.395 (95% CI 0.072 to 0.635), and a number needed to treat of 2 (95% CI 14 to 2). HT+Epo effects on DTI included improved mode of anisotropy, fractional anisotropy, relative anisotropy and volume ratio as compared to UCO saline treated infants. No adverse drug reactions were noted in animals receiving Epo, nor were there any hematology, liver, or kidney laboratory effects.
HT+Epo treatment improved outcomes in nonhuman primates exposed to UCO. Adjunctive use of Epo combined with HT may improve the outcomes of term human infants with HIE and clinical trials are warranted.
PMCID: PMC3873854  PMID: 24192275
Hypoxic-ischemic encephalopathy; spectroscopy; diffusion tensor imaging; cerebellum; pharmacokinetics; choline
24.  Predictive value of early neuroimaging, pulsed Doppler and neurophysiology in full term infants with hypoxic-ischaemic encephalopathy. 
To evaluate their prognostic value, five different non-invasive techniques were used on 34 full term infants with hypoxic-ischaemic encephalopathy (HIE) within six hours of delivery. Cranial ultrasonography, the resistance index (RI) of the middle cerebral artery obtained with Doppler ultrasonography, somatosensory evoked potentials (SEPs), visual evoked potentials (VEPs) and the cerebral function monitor (CFM) were used. According to the criteria of Sarnat, 11 infants developed mild, seven moderate, and 16 severe encephalopathy. The CFM had the highest positive (PPV 84.2%) and negative predictive value (NPV 91.7%). All but one of the infants with a continuous pattern had a good outcome. The CFM of 11 cases with a suppression-burst pattern changed to a continuous pattern over 24 to 48 hours in four infants, and was associated with a normal outcome in three. All five cases with an isoelectric CFM died. The SEPs also provided useful information (PPV 81.8%; NPV 91.7%). VEPs were often delayed during the first hours or life and did not carry a poor prognosis in five of 14 cases (PPV 77.3%). Both ultrasonography and Doppler RI were of little value, as they were almost always normal at this early stage. In 34 full term infants with HIE, studied within 6 hours of life, the CFM and SEPs provided the most useful information about the expected course of encephalopathy and subsequent neurodevelopmental outcome.
PMCID: PMC2528491  PMID: 7583610
25.  Predictive value of plasma and cerebrospinal fluid tumour necrosis factor-α and interleukin-1β concentrations on outcome of full term infants with hypoxic-ischaemic encephalopathy 
AIM—To determine the predictive value of plasma and cerebrospinal fluid (CSF) tumour necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) concentrations on the outcome of hypoxic-ischaemic encephalopathy (HIE) in full term infants.
METHODS—Thirty term infants with HIE were included in the study. HIE was classified according to the criteria of Sarnat and Sarnat. Blood and CSF were obtained within the first 24 hours of life and stored until assay. Five infants died soon after hypoxic insult. Neurological examinations and Denver Developmental Screening Test (DDST) were performed at 12 months in the survivors.
RESULTS—At the age of 12 months neurological examination and DDST showed that 11 infants were normal; 14 had abnormal neurological findings and/or an abnormal DDST result. Eleven normal infants were classified as group 1 and 19 infants (14 with abnormal neurological findings and/or an abnormal DDST and five who died) as group 2.CSF IL-1β and TNF-α concentrations in group 2 were significantly higher than those in group 1. Plasma IL-1β and TNF-α concentrations were not significantly different between the two groups. IL-1β, but not TNF-α concentrations, in group 2 were even higher than those in group 1, although non-survivors were excluded from group 2. When the patients were evaluated according to the stages of Sarnat, the difference in the three groups was again significant. Patients whose CSF samples were taken within 6 hours of the hypoxic insult had higher IL-1β and TNF-α concentrations than the patients whose samples were taken after 6hours.
CONCLUSIONS—Both cytokines probably contribute to the damage sustained by the central nervous system after hypoxic insult. IL-1β seems to be a better predictor of HIE than TNF-α.

PMCID: PMC1720860  PMID: 10194989

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