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

doi:10.1016/j.jpeds.2013.01.041

The Journal of Pediatrics

Volume 163, Issue 2, August 2013, Pages 465-470

https://doi.org/10.1016/j.jpeds.2013.01.041 Get rights and content

Objective

To evaluate the electrographic seizure burden in neonates with hypoxic ischemic encephalopathy (HIE) treated with or without therapeutic hypothermia and stratified results by severity of HIE and severity of injury as assessed by magnetic resonance imaging (MRI).

Study design

Between 2007 and 2011, video-electroencephalography (EEG) monitoring was initiated in neonates with moderate to severe HIE. Seizure burden (in seconds) was calculated, and brain MRI scans were quantitatively scored. Data were analyzed by ANOVA, the Student t test, and the χ² test.

Results

Sixty-nine neonates with moderate or severe HIE were prospectively enrolled, including 51 who received therapeutic hypothermia and 18 who did not. The mean duration of video-EEG monitoring was longer in the therapeutic hypothermia group (72 ± 34 hours vs 48 ± 34 hours; P = .01). The therapeutic hypothermia group had a lower electrographic seizure burden (log units) after controlling for injury, as assessed by MRI (2.9 ± 0.6 vs 6.2 ± 0.9; P = .003). A reduction in seizure burden was seen in neonates with moderate HIE (P = .0001), but not in those with severe HIE (P = .80). Among neonates with injury assessed by MRI, seizure burden was lower in those with mild (P = .0004) and moderate (P = .02) injury, but not in those with severe injury (P = .90).

Conclusion

Therapeutic hypothermia was associated with reduced electrographic seizure burden in neonatal HIE. This effect was detected on video-EEG in infants with moderate HIE, but not in those with severe HIE. When stratified by injury as assessed by MRI, therapeutic hypothermia was associated with a reduced seizure burden in infants with mild and moderate injury, but not in those with severe injury.

Section snippets

Methods

Between 2007 and 2011, neonates born at ≥36 weeks gestational age with clinical evidence of moderate to severe HIE¹² with or without seizures, aged ≤24 hours, and managed with or without therapeutic hypothermia were prospectively enrolled for continuous video-EEG monitoring. This single-center study was conducted at St Louis Children's Hospital after approval from the Washington University Human Research Protection Office. Informed written consent was obtained from at least 1 parent for each

Results

Continuous EEG and MRI data were available for 69 of 74 neonates with moderate to severe HIE, including 51 (74%) in the therapeutic hypothermia group and 18 (26%) in the no therapeutic hypothermia group (Figure 1). The majority of infants in the study cohort who did not undergo therapeutic hypothermia (11 of 18) were born before the institution of therapeutic hypothermia in 2008. The other 7 of these 18 infants were born after therapeutic hypothermia was clinically available, but were outside

Discussion

This study supports the report by Low et al¹⁷ of an association between therapeutic hypothermia and a reduction in electrographic seizure burden in neonates with moderate HIE but not in those with severe HIE. Our findings further demonstrate that this reduction is limited to infants with mild to moderate injury and is not seen in those with severe injury as assessed by MRI. The long-term benefit of this seizure reduction with therapeutic hypothermia remains unclear. In an animal model, Wirrell

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Cited by (110)

The Association of Therapeutic Hypothermia With Seizure Burden in Neonates With Hypoxic-Ischemic Encephalopathy
2024, Pediatric Neurology
To compare seizure burden between newborn infants treated with therapeutic hypothermia (TH) and those that were not and to compare the need for antiseizure medications (ASM) in a cohort of infants who were diagnosed with neonatal hypoxic-ischemic encephalopathy (HIE).
This was a retrospective cohort study on infants born after 35 weeks’ gestation, diagnosed with moderate to severe HIE, monitored with amplitude-integrated electroencephalography (aEEG) and eligible for TH. Infants born before the implementation of TH in 2008 were compared with infants born thereafter who received TH. Seizure burden was assessed from aEEG as total time in minutes of seizures activity per hour of recording. Other clinical and demographic data were retrieved from a prospective local database of infants with HIE.
Overall, 149 of 207 infants were included in the study: 112 exposed to TH and 37 not exposed. Cooled infants had a lower seizure burden overall (0.4 vs 2.3 min/h, P < 0.001) and were also less likely to be treated with ASM (74% vs 100%, P < 0.001). In multivariable regression models, not exposed to TH, having a depressed aEEG background, and having higher Apgar scores were associated with higher seizure burden (incidence rate ratio: 4.78 for noncooled infants, P < 0.001); also, not exposed to TH was associated with a higher likelihood of multidrug ASM (odds ratio: 4.83, P < 0.001).
TH in infants with moderate to severe HIE is associated with significant reduction of seizure burden and ASM therapy.
Epilepsy Frequency and Risk Factors Three Years After Neonatal Seizures
2023, Pediatric Neurology
Neonatal seizures, one of the main risk factors for the development of epilepsy, remain a clinical concern. In children with neonatal seizures, early recognition of risk factors is important for the early diagnosis and appropriate treatment of epilepsy and for improving prognosis. In this study, we aimed to determine the frequency of and the risk factors for the development of epilepsy in patients with neonatal seizures.
The hospital files of 228 children who experienced seizures in the neonatal period were reviewed. The frequency of epilepsy and risk factors for the development of epilepsy were determined at age 36 months.
Epilepsy was diagnosed in 40.8% of the cases. Univariate analysis revealed family history of epilepsy, parental consanguinity, abnormal neurological examination findings, microcephaly, unresponsiveness to antiepileptic drugs or antiseizure medication, use of more than one antiepileptic drugs to antiseizure medication at discharge, status epilepticus, electroencephalography abnormalities, abnormal neuroimaging findings, invasive ventilation requirement, myoclonic seizures, central nervous system malformation, and congenital metabolic disease as risk factors for the development of epilepsy. Of these, a family history of epilepsy, abnormal neurological examination findings at discharge, and use of at least two antiepileptic drugs to antiseizure medication at discharge were found as independent risk factors in multivariate analysis.
Neonatal seizures appear to be associated with epilepsy in more than one-third of the patients. Of the newborns with seizures, those with a family history of epilepsy, abnormal neurological examination findings at discharge, and those using at least two antiepileptic drugs to antiseizure medication at discharge should be monitored more carefully for the development of epilepsy.
Leveraging electronic medical record-embedded standardised electroencephalogram reporting to develop neonatal seizure prediction models: a retrospective cohort study
2023, The Lancet Digital Health
Accurate prediction of seizures can help to direct resource-intense continuous electroencephalogram (CEEG) monitoring to neonates at high risk of seizures. We aimed to use data from standardised EEG reports to generate seizure prediction models for vulnerable neonates.
In this retrospective cohort study, we included neonates who underwent CEEG during the first 30 days of life at the Children's Hospital of Philadelphia (Philadelphia, PA, USA). The hypoxic ischaemic encephalopathy subgroup included only patients with CEEG data during the first 5 days of life, International Classification of Diseases, revision 10, codes for hypoxic ischaemic encephalopathy, and documented therapeutic hypothermia. In January, 2018, we implemented a novel CEEG reporting system within the electronic medical record (EMR) using common data elements that incorporated standardised terminology. All neonatal CEEG data from Jan 10, 2018, to Feb 15, 2022, were extracted from the EMR using age at the time of CEEG. We developed logistic regression, decision tree, and random forest models of neonatal seizure prediction using EEG features on day 1 to predict seizures on future days.
We evaluated 1117 neonates, including 150 neonates with hypoxic ischaemic encephalopathy, with CEEG data reported using standardised templates between Jan 10, 2018, and Feb 15, 2022. Implementation of a consistent EEG reporting system that documents discrete and standardised EEG variables resulted in more than 95% reporting of key EEG features. Several EEG features were highly correlated, and patients could be clustered on the basis of specific features. However, no simple combination of features adequately predicted seizure risk. We therefore applied computational models to complement clinical identification of neonates at high risk of seizures. Random forest models incorporating background features performed with classification accuracies of up to 90% (95% CI 83–94) for all neonates and 97% (88–99) for neonates with hypoxic ischaemic encephalopathy; recall (sensitivity) of up to 97% (91–100) for all neonates and 100% (100–100) for neonates with hypoxic ischaemic encephalopathy; and precision (positive predictive value) of up to 92% (84–96) in the overall cohort and 97% (80–99) in neonates with hypoxic ischaemic encephalopathy.
Using data extracted from the standardised EEG report on the first day of CEEG, we predict the presence or absence of neonatal seizures on subsequent days with classification performances of more than 90%. This information, incorporated into routine care, could guide decisions about the necessity of continuing EEG monitoring beyond the first day, thereby improving the allocation of limited CEEG resources. Additionally, this analysis shows the benefits of standardised clinical data collection, which can drive learning health system approaches to personalised CEEG use.
Children's Hospital of Philadelphia, the Hartwell Foundation, the National Institute of Neurological Disorders and Stroke, and the Wolfson Foundation.
Neonatal Encephalopathy
2023, Avery's Diseases of the Newborn
Neonatal encephalopathy describes a constellation of neurologic findings that are the final common pathway of many potential disease processes. The clinical picture of neonatal encephalopathy can be of primary neurological origin or secondary to congenital or acquired diseases.
Affected newborns may present immediately after birth or within the first few weeks of age. Presenting findings may be subtle or obvious, ranging from poor feeding to seizures, encephalopathy, respiratory failure, and shock. Magnetic resonance imaging techniques have improved diagnostic and prognostic capabilities for numerous types of diseases causing neonatal encephalopathy. Hypoxic-ischemic encephalopathy (HIE) is the most common cause of acute neonatal encephalopathy and accounts for 24% of neonatal death worldwide. Other common neurologic causes include genetic epilepsies, arterial ischemic stroke, and cerebral sinovenous thrombosis.
Inborn errors of metabolism presenting in the newborn period commonly are associated with neurologic symptoms, either secondary to accumulation of toxic metabolites, or the inability to meet the high energy demand of the brain. Infectious and genetic causes are also commonly found when evaluating a newborn with encephalopathy. Survivors of neonatal encephalopathy are at significant risk for moderate to severe long-term disabilities, including motor problems, epilepsy, language, cognition, hearing, or vision impairment, as well as neuropsychological difficulties.
Deep nuclei injury distribution in isolated “basal ganglia–thalamus” (BGT) versus combined “BGT and watershed” patterns of hypoxic–ischaemic injury (HII) in children with cerebral palsy
2022, Clinical Radiology
To compare frequency and distribution of deep nuclei involvement in isolated basal ganglia and ventrolateral thalamus (BGT) versus combined BGT and watershed (BGT-WS) hypoxic–ischaemic injury (HII).
A retrospective review was undertaken of the magnetic resonance imaging (MRI) reports of children (0–18 years) with isolated BGT or combined BGT-WS HII. The location and extent of deep nuclear injuries were compared between groups using Fisher's exact test.
Of 762 MRI reports, 435 (57%) had isolated BGT and 327 (43%) combined BGT-WS. Isolated BGT showed basal ganglia involvement in 85.1% (n=370) versus 49.8% (n=163) for combined BGT-WS (p<0.01). Sole putamen lesions were more common in isolated BGT (70.3%; 306) versus combined (19.3%; 63; p<0.01). Thalamic involvement was similar between isolated BGT (93.8%; 408) and combined BGT-WS (96.9%; 317; p>0.05). Sole ventrolateral nucleus involvement was more common in isolated BGT (66.6%; 291) while sole pulvinar lesions (25.1%; 82) and whole thalamus lesions (41.6%; 136) were more common in combined BGT-WS (p<0.01). Putamen and ventrolateral nucleus was the most frequent BGT lesion combination in isolated BGT (55.4%) but not in combined BGT-WS (8.6%; p<0.01).
Variations in the frequency of deep nuclear lesions between groups may reflect different underlying pathogenetic mechanisms. Therefore, combined BGT-WS patterns may not necessarily indicate a superimposed profound on partial prolonged HII, as other causes such as neonatal hypoglycaemia may cause these.
Severity of intrapartum fever and neonatal outcomes
2022, American Journal of Obstetrics and Gynecology
Citation Excerpt :
In patients with previous intrapartum fever or chorioamnionitis diagnosis, endometritis was diagnosed clinically if they had a persistent fever in the setting of uterine tenderness, foul smelling lochia, tachycardia, or leukocytosis. Our institutional criteria for initiating neonatal therapeutic hypothermia is moderate to severe hypoxic-ischemic encephalopathy at ≥36 weeks’ gestation at birth with any of the following: 10-minute Apgar score <5, prolonged resuscitation at birth, severe acidosis (pH <7.1) on cord or neonate blood gas analysis within 60 minutes of birth, or base deficit (>12 mmol/L) on cord or neonate blood gas analysis within 60 minutes of birth.21 Baseline patient characteristics were compared between each Tmax group using analysis of variance, Kruskal–Wallis, or Fisher exact tests, as appropriate.
The few studies that have addressed the relationship between severity of intrapartum fever and neonatal and maternal morbidity have had mixed results. The impact of the duration between reaching maximum intrapartum temperature and delivery on neonatal outcomes remains unknown.
To test the association of severity of intrapartum fever and duration from reaching maximum temperature to delivery with neonatal and maternal morbidity.
This was a secondary analysis of a prospective cohort of term, singleton patients admitted for induction of labor or spontaneous labor who had intrapartum fever (≥38°C). Patients were divided into 3 groups according to maximum temperature during labor: afebrile (<38°C), mild fever (38°C–39°C), and severe fever (>39°C). The primary outcome was composite neonatal morbidity (umbilical artery pH <7.1, mechanical ventilation, respiratory distress, meconium aspiration with pulmonary hypertension, hypoglycemia, neonatal intensive care unit admission, and Apgar <7 at 5 minutes). Secondary outcomes were composite neonatal neurologic morbidity (hypoxic-ischemic encephalopathy, hypothermia treatment, and seizures) and composite maternal morbidity (postpartum hemorrhage, endometritis, and maternal packed red blood cell transfusion). Outcomes were compared between the maximum temperature groups using multivariable logistic regression. Cox proportional-hazards regression modeling accounted for the duration between reaching maximum intrapartum temperature and delivery.
Of the 8132 patients included, 278 (3.4%) had a mild fever and 74 (0.9%) had a severe fever. The incidence of composite neonatal morbidity increased with intrapartum fever severity (afebrile 5.4% vs mild 18.0% vs severe 29.7%; P<.01). After adjusting for confounders, there were increased odds of composite neonatal morbidity with severe fever compared with mild fever (adjusted odds ratio, 1.93 [95% confidence interval, 1.07–3.48]). Severe fevers remained associated with composite neonatal morbidity compared with mild fevers after accounting for the duration between reaching maximum intrapartum temperature and delivery (adjusted hazard ratio, 2.05 [95% confidence interval, 1.23–3.43]). Composite neonatal neurologic morbidity and composite maternal morbidity were not different between patients with mild and patients with severe fevers.
Composite neonatal morbidity correlated with intrapartum fever severity in a potentially dose-dependent fashion. This correlation was independent of the duration from reaching maximum intrapartum temperature to delivery, suggesting that clinical management of intrapartum fever, in terms of timing or mode of delivery, should not be affected by this duration.

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: Funded by Thrasher Foundation. The authors declare no conflicts of interest.

^∗: Present address: Division of Neonatology, Department of Pediatrics, Akron Children's Hospital–Mahoning Valley, Boardman, OH.

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

Objective

Study design

Results

Conclusion

Section snippets

Methods

Results

Discussion

J Pediatr

Pediatr Neurol

Electroencephalogr Clin Neurophysiol

Brain Res

Pediatr Neurol

The clinical conundrum of neonatal seizures

Arch Dis Childhood Fetal Neonatal Ed

Seizure-associated brain injury in term newborns with perinatal asphyxia

Neurology

Postnatal epilepsy after EEG-confirmed neonatal seizures

Epilepsia

Neurology of the newborn

Non-expert use of the cerebral function monitor for neonatal seizure detection

Arch Dis Child Fetal Neonatal Ed

Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data

BMJ

Hypoxic-ischaemic encephalopathy: early and late magnetic resonance imaging findings in relation to outcome

Arch Dis Child Fetal Neonatal Ed

Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy

N Eng J Med

Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs

J Clin Invest

Neonatal encephalopathy following fetal distress: a clinical and electroencephalographic study

Arch Neurol

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