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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.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1471-2431-13-52
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.
Objective:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
doi:10.1212/WNL.0b013e31829bfe41
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.
doi:10.1136/archdischild-2013-303710
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.
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1186/1471-2431-13-194
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.
Introduction
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.
doi:10.1186/2193-1801-3-373
PMCID: PMC4117861  PMID: 25089256
Amplitude-integrated electroencephalography; Continuous conventional electroencephalography; Therapeutic hypothermia; Cardiac arrest; Hypoxic ischemic encephalopathy; Seizures
7.  Early amplitude-integrated electroencephalography predicts brain injury and neurological outcome in very preterm infants 
Scientific Reports  2015;5:13810.
Early amplitude-integrated electroencephalography (aEEG) has been widely used in term infants with brain injury to predict neurodevelopmental outcomes; however, the prognostic value of early aEEG in preterm infants is unclear. We evaluated how well early aEEG could predict brain damage and long-term neurodevelopmental outcomes in very preterm infants compared with brain imaging assessments. We found that severe aEEG abnormalities (p = 0.000) and aEEG total score < 5 (p = 0.006) within 72 h after birth were positively correlated with white-matter damage, but aEEG abnormalities were not associated with intracranial hemorrhage (p = 0.186). Severe abnormalities in aEEG recordings, head ultrasound, and cranial magnetic resonance imaging (MRI) were all positively correlated with poor outcome at 18 months corrected age. The predictive power of poor outcomes of the aEEG and MRI combination was the same as the aEEG, MRI, and head ultrasound combination with a sensitivity of 52.4%, specificity of 96.2%, positive predictive value of 78.6%, and negative predictive value of 88.4%. These results indicate that severely abnormal aEEG recordings within 72 h after birth can predict white-matter damage and long-term poor outcomes in very preterm infants. Thus aEEG can be used as an early marker to monitor very preterm infants.
doi:10.1038/srep13810
PMCID: PMC4562298  PMID: 26348553
8.  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.
doi:10.1136/adc.2004.064964
PMCID: PMC1721875  PMID: 15846017
9.  Evolution of Encephalopathy during Whole Body Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy 
The Journal of Pediatrics  2011;160(4):567-572.e3.
Objective
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.
Results
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.
Conclusions
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.
doi:10.1016/j.jpeds.2011.09.018
PMCID: PMC3299861  PMID: 22050871
Neurological examinations; neonates; clinical biomarker; death; disability
10.  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
11.  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.
doi:10.1007/s11940-012-0200-y
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
12.  Early single-channel aEEG/EEG predicts outcome in very preterm infants 
Aim
To characterize early amplitude-integrated electroencephalogram (aEEG) and single-channel EEG (aEEG/EEG) in very preterm (VPT) infants for prediction of long-term outcome.
Patients
Forty-nine infants with median (range) gestational age of 25 (22–30) weeks.
Methods
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.
Results
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%).
Conclusion
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.
doi:10.1111/j.1651-2227.2012.02677.x
PMCID: PMC3437495  PMID: 22530996
Burst suppression; Cranial ultrasound; Interburst interval; Neurodevelopmental impairment; Seizure
13.  A random forest model based classification scheme for neonatal amplitude-integrated EEG 
BioMedical Engineering OnLine  2014;13(Suppl 2):S4.
Background
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).
Methods
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.
Results
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.
doi:10.1186/1475-925X-13-S2-S4
PMCID: PMC4304248  PMID: 25560269
14.  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.
doi:10.1371/journal.pone.0078960
PMCID: PMC3827298  PMID: 24236076
15.  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
16.  Evaluation of cerebral function in high risk term infants by using a scoring system based on aEEG 
Translational Pediatrics  2014;3(4):278-286.
Objective
To investigate the relationship between the amplitude integrated electroencephalogram (aEEG) findings and neurodevelopmental outcomes of high-risk term infants with neurological disorders and develop a scoring system for assessment of the cerebral function.
Methods
The neurological outcome was assessed at 12- to 18-month of age by using the Bayley Scales of Infant Development II. Valuation of the classification of aEEG background pattern, epileptic electrical activity and sleep-weak cycle (SWC) was conducted to develop a new scoring system. The correlation between the summarized scores and outcome analyzed, and the predictive test of the score system was calculated.
Results
A total of 81 infants (39 with asphyxia, 10 with hypoglycemia, 15 with acute bacterial meningoencephalitis, 10 with hyperbilirubinemia and 7 with inborn errors of metabolism) enrolled in the study. The neurological outcome was positive correlated with the background pattern, electrical activity, SWC and summarized scores of the score system based on aEEG. The scoring system has a higher r value, specificity, PPV and lower sensitivity compared with the separate entities such as background pattern, seizures and SWC. The area under the receiver operator characteristics (ROC) curve for predicting outcome by the scoring system was 0.93 (95% CI, 0.878-0.990), with the cut-off value of 7.5.
Conclusions
aEEG maybe a potential tool for monitoring cerebral function in term infants at risk for poor neurodevelopmental outcomes. Our proposed scoring system based on aEEG could quantify information provided by aEEG objectively and could be a good predictor for neurological outcome.
doi:10.3978/j.issn.2224-4336.2014.10.03
PMCID: PMC4728834  PMID: 26835347
Amplitude integrated electroencephalogram (aEEG); full-term infant; neurological disorders
17.  Normative Amplitude Integrated EEG (aEEG) Measures in Preterm Infants 
Objective
Assessing qualitative patterns of amplitude integrated EEG (aEEG) maturation of preterm infants requires personnel with training in interpretation and an investment of time. Quantitative algorithms provide a method for rapidly and reproducibly assessing an aEEG recording independent of provider skill level. Although there are several qualitative and quantitative normative datasets in the literature, this study provides the broadest array of quantitative aEEG measures in a carefully selected and followed cohort of preterm infants with mild or no visible injury on term equivalent MRI and subsequently normal neurodevelopment at 2 and 7 years of age.
Study Design
A two-channel aEEG recording was obtained on days 4,7,14, and 28 of life for infants born ≤30 weeks EGA. Measures of amplitude and continuity, spectral edge frequency, percentage of trace in interburst interval, interburst interval length, and frequency counts of smooth delta waves, delta brushes and theta bursts were obtained. MRI was obtained at term-equivalent age (TEA) and neurodevelopmental testing was conducted at 2 and 7 years of corrected age.
Result
Correlations were found between increasing post-menstrual age (PMA) and decreasing maximum amplitude (R=−0.23, p=0.05), increasing minimum amplitude (R=0.46, p=0.002), and increasing spectral edge frequency (R=0.78, p=4.17x10−14). Negative correlations were noted between increasing PMA and counts of smooth delta waves (R=−0.39, p=0.001), delta brushes (R=−0.37, p=0.003), and theta bursts (R=−0.61, p=5.66x10−8). Increasing PMA was also associated with a decreased amount of time spent in the interburst interval (R=−0.38, p=0.001) and a shorter length of the maximum IBI (R=−0.27, p=0.03).
Conclusion
This analysis supports a strong correlation between quantitatively determined aEEG measures and PMA, in a cohort of preterm infants with normal TEA neuroimaging and neurodevelopmental outcomes at 7 years of age, which is both predictable and reproducible. These “normative” quantitative values support the pattern of maturation previously identified by qualitative analysis.
doi:10.1038/jp.2014.225
PMCID: PMC4447544  PMID: 25521561
spectral edge frequency; Bayesian inference; developmental outcomes; quantitative aEEG
18.  Video-EEG monitoring in newborns with hypoxic-ischemic encephalopathy treated with hypothermia 
Neurology  2011;76(6):556-562.
Background:
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.
Objective:
To describe evolution of EEG background and incidence of seizures during TH, and to identify EEG patterns predictive for MRI brain injury.
Methods:
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.
Results:
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).
Conclusions:
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.
doi:10.1212/WNL.0b013e31820af91a
PMCID: PMC3053178  PMID: 21300971
19.  Artefacts in the amplitude-integrated EEG background pattern of a full-term asphyxiated neonate caused by diaphragm spasms 
BMJ Case Reports  2012;2012:bcr1220115363.
The amplitude-integrated EEG (aEEG) is used to detect neonatal seizures in neonates with asphyxia, and despite limited data-information compared with standard EEG, aEEG is increasingly used as routine monitoring in neonatal intensive care units due to the logistic advantages. In addition, the aEEG background is of prognostic value in these infants. However, aEEG artefacts can lead to an erroneous interpretation of the background pattern. We report a full-term infant with severe perinatal asphyxia with diaphragm spasms that caused a significant alteration in aEEG background pattern. After administration of a neuromuscular blocker, the aEEG background transformed from discontinuous low-voltage pattern to a flat trace. The aEEG background pattern can be misinterpreted by electrical activity of non-cerebral origin. Administration of neuromuscular blockers is a rapid method to differentiate between cerebral and muscular activity on the aEEG when EEG is not (yet) available.
doi:10.1136/bcr.12.2011.5363
PMCID: PMC4543159  PMID: 22669876
20.  Impact of hypothermia on predictors of poor outcome: how do we decide to redirect care? 
SUMMARY
Therapeutic hypothermia is now considered the standard of care for neonates with neonatal encephalopathy due to perinatal asphyxia. Outcomes following hypothermia treatment are favorable, as demonstrated in recent meta-analyses, but 45–50% of these neonates still suffer major disability or die due to global multi-organ injury or after redirection of care from life support due to severe brain injury. The ability to determine which patients are at highest risk of severe neurologic impairment and death and those in whom redirection of care should be considered is limited. This is especially true in the first few days after birth and in situations where the brain might be more significantly affected than other organ systems, making it difficult to discuss redirection of care. Clinical history, neurologic examination, serum biomarkers, neurophysiology [amplitude-integrated electroencephalography (aEEG) or EEG], near-infrared spectroscopy, and magnetic resonance imaging have all been studied as predictors of severe neurologic injury and poor outcome, although none is 100% predictive. Serial evaluation over time seems to be an important element to facilitate discussion regarding anticipated poor prognosis and decision-making for transition to comfort care. Thus far, brain monitoring in the form of aEEG and conventional EEG seem to be the best objective tools to identify the highest-risk patients. A delay or lack of recovery of the aEEG background during hypothermia treatment is an established important predictor of poor outcome (death or disability). This paper highlights the prognostic indicators that have been considered and focuses on aEEG as an important predictor of death or severe disability, which may facilitate conversations regarding redirection of care.
doi:10.1016/j.siny.2014.12.011
PMCID: PMC4375009  PMID: 25577654
Neonatal encephalopathy; Therapeutic hypothermia; Amplitude-integrated EEG; Magnetic resonance imaging; Redirection of care
21.  Prognostic value of the recovery time of continuous normal voltage in amplitude-integrated electroencephalography in out-of-hospital cardiac arrest patients treated with therapeutic hypothermia: a retrospective study 
Background
The early prediction of neurological outcomes in postcardiac arrest patients treated with therapeutic hypothermia (TH) remains challenging. Amplitude-integrated electroencephalography (aEEG) is a type of quantitative EEG. A particular cutoff time from the return of spontaneous circulation (ROSC) to the recovery of a normal aEEG trace for predicting a good neurological outcome has not yet been established. The purpose of the present study was to examine the relation between neurological outcomes and the continuous normal voltage (CNV) recovery time in adult comatose survivors of cardiac arrest treated with TH and identify the recovery time cutoff for predicting a good neurological outcome.
Methods
We retrospectively evaluated adult survivors of cardiac arrest with initial shockable rhythm treated with TH and monitored with aEEG. A good outcome was defined as a cerebral performance category (CPC) of 1 or 2 at hospital discharge. A CNV trace was considered as the normal aEEG trace, and the CNV recovery time was defined as the time from ROSC to the initial CNV trace.
Results
The study included 30 patients, and of these patients, 22 had recovery of CNV trace. The median CNV recovery time was shorter among patients with a good outcome than that among those with a poor outcome (10.7 h [interquartile range (IQR), 7.4–15.8 h] vs. 28.6 h [IQR, 26.9–29.3 h]; p = 0.003). The area under the receiver operating characteristic curve of the CNV recovery time for predicting a good neurological outcome was 0.95 (95 % CI 0.86–1; p = 0.003), and the optimal cutoff was 23 h. The recovery of CNV trace within 23 h had a sensitivity of 89 %, specificity of 100 %, positive predictive value of 100 %, and negative predictive value of 86 % for predicting a good neurological outcome in all the patients, including the eight patients without recovery of CNV trace.
Conclusions
A CNV recovery time cutoff of 23 h might help predict a good neurological outcome in adult survivors of cardiac arrest treated with TH.
doi:10.1186/s40560-016-0152-5
PMCID: PMC4818927  PMID: 27042311
Amplitude-integrated electroencephalography; Cardiac arrest; Neurological outcome; Therapeutic hypothermia
22.  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.
doi:10.4081/pr.2014.5532
PMCID: PMC4292060  PMID: 25635216
hypothermia; neonates; magnetic resonance imaging; long term; electroencephalogram monitoring
23.  Moderate hypothermia within 6 h of birth plus inhaled xenon versus moderate hypothermia alone after birth asphyxia (TOBY-Xe): a proof-of-concept, open-label, randomised controlled trial 
The Lancet. Neurology  2016;15(2):145-153.
Summary
Background
Moderate cooling after birth asphyxia is associated with substantial reductions in death and disability, but additional therapies might provide further benefit. We assessed whether the addition of xenon gas, a promising novel therapy, after the initiation of hypothermia for birth asphyxia would result in further improvement.
Methods
Total Body hypothermia plus Xenon (TOBY-Xe) was a proof-of-concept, randomised, open-label, parallel-group trial done at four intensive-care neonatal units in the UK. Eligible infants were 36–43 weeks of gestational age, had signs of moderate to severe encephalopathy and moderately or severely abnormal background activity for at least 30 min or seizures as shown by amplitude-integrated EEG (aEEG), and had one of the following: Apgar score of 5 or less 10 min after birth, continued need for resuscitation 10 min after birth, or acidosis within 1 h of birth. Participants were allocated in a 1:1 ratio by use of a secure web-based computer-generated randomisation sequence within 12 h of birth to cooling to a rectal temperature of 33·5°C for 72 h (standard treatment) or to cooling in combination with 30% inhaled xenon for 24 h started immediately after randomisation. The primary outcomes were reduction in lactate to N-acetyl aspartate ratio in the thalamus and in preserved fractional anisotropy in the posterior limb of the internal capsule, measured with magnetic resonance spectroscopy and MRI, respectively, within 15 days of birth. The investigator assessing these outcomes was masked to allocation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00934700, and with ISRCTN, as ISRCTN08886155.
Findings
The study was done from Jan 31, 2012, to Sept 30, 2014. We enrolled 92 infants, 46 of whom were randomly assigned to cooling only and 46 to xenon plus cooling. 37 infants in the cooling only group and 41 in the cooling plus xenon group underwent magnetic resonance assessments and were included in the analysis of the primary outcomes. We noted no significant differences in lactate to N-acetyl aspartate ratio in the thalamus (geometric mean ratio 1·09, 95% CI 0·90 to 1·32) or fractional anisotropy (mean difference −0·01, 95% CI −0·03 to 0·02) in the posterior limb of the internal capsule between the two groups. Nine infants died in the cooling group and 11 in the xenon group. Two adverse events were reported in the xenon group: subcutaneous fat necrosis and transient desaturation during the MRI. No serious adverse events were recorded.
Interpretation
Administration of xenon within the delayed timeframe used in this trial is feasible and apparently safe, but is unlikely to enhance the neuroprotective effect of cooling after birth asphyxia.
Funding
UK Medical Research Council.
doi:10.1016/S1474-4422(15)00347-6
PMCID: PMC4710577  PMID: 26708675
24.  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.
Objective
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.
Results
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.
Conclusions
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.
doi:10.1016/j.jpeds.2013.10.067
PMCID: PMC4006934  PMID: 24332821
25.  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.
doi:10.1007/s10545-010-9198-z
PMCID: PMC3757261  PMID: 20865336

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