Treating Seizures and Improving Newborn Outcomes for Infants with Hypoxic-Ischemic Encephalopathy

INTRODUCTION

Hypoxic-ischemic encephalopathy (HIE) is the most common cause of neonatal seizures.¹ Seizures in neonates with HIE peak in the first days after birth and are often subclinical.¹ Thus, these seizures are most accurately diagnosed by electroencephalography (EEG). Neonatal seizures are a medical emergency; early and effective treatment to resolve seizures may lead to improved long-term neurodevelopmental outcomes. This study will outline the approach to timely evaluation and evidencebased treatment of HIE-associated seizures to improve outcomes in this population.

EVALUATION OF NEONATAL SEIZURES

Continuous Electroencephalographic Monitoring

Continuous electroencephalographic (cEEG) monitoring is the gold standard for seizure detection in neonates. The American Clinical Neurophysiology Society guideline recommends cEEG to detect seizures in high-risk populations such as newborns with HIE.² The EEG is used to detect electrographic seizures, confirm response to antiseizure medication (ASM), assess the interictal background to evaluate the degree of encephalopathy, and monitor the evolution of background changes over time. These data guide seizure treatment and inform discussions of prognosis for neonates with HIE.

Seizures and Status Epilepticus in Hypoxic-Ischemic Encephalopathy

About half of neonates with HIE who are treated with therapeutic hypothermia have EEG-confirmed seizures, and up to 20% have status epilepticus.^3–7 Among neonates with HIE who are not cooled, the risk of seizures is even higher.^8–10 Up to half of the seizures in HIE are clinically silent, and electroclinical uncoupling results in an even higher proportion of subclinical seizures after treatment with ASM.^3,11,12 Thus, evaluation and management of neonatal seizures are key aspects of neurocritical care for infants with HIE.

Predictors of Seizures in Neonates with Hypoxic-Ischemic Encephalopathy

Although the risk of acute provoked seizures is high among neonates with HIE, clinical characteristics (eg, gestational age, Apgar scores, and initial pH) do not reliably distinguish infants at highest risk.³ While a suspected clinical seizure confers a risk for detecting seizures on EEG,^13,14 the initial EEG background pattern is, by far, the strongest predictor of seizures among neonates with HIE.^10,15 Among neonates with HIE treated with therapeutic hypothermia, excessive EEG background discontinuity or any severely abnormal background pattern (including burst suppression, depressed and undifferentiated, or inactive recording) is associated with an increased risk of acute provoked neonatal seizures.^3,6,13 The risk for acute seizures is independent of treatment with ASM prior to EEG initiation. Conversely, the risk of seizures is low when the initial EEG background is normal or mildly abnormal and has retained sleep–wake cycling.^5,13,16

Timing of Seizures in Neonates with Hypoxic-Ischemic Encephalopathy

It is imperative that clinicians remain vigilant, with frequent assessment of the cEEG when the interictal background is moderately or severely abnormal, particularly in the first 24 hours, given the high risk of seizures. The median age at first seizure in HIE is ~4 to 20 hours after birth, and the maximum seizure burden is typically reached between 12 and 24 hours.^3,6,7,9 The timing of seizures is a manifestation of the secondary injury phase, when additional cell death occurs due to ongoing energy failure that results in increased excitotoxic neurotransmitter release, inflammation, and cytotoxic[isip] edema.¹⁷

With therapeutic hypothermia, the onset of seizures may be delayed and seizures may persist past the period of active cooling.^3,4,6,7 Therefore, many centers recommend cEEG monitoring throughout cooling and rewarming for all neonates treated with therapeutic hypothermia. Importantly, if seizures persist or worsen after active cooling, alternative diagnoses (eg, neonatal-onset epilepsy) must be considered.

NEURODEVELOPMENTAL OUTCOMES FOLLOWING HYPOXIC-ISCHEMIC ENCEPHALOPATHY-ASSOCIATED NEONATAL SEIZURES

Seizures and Brain Injury

Animal studies reveal that prolonged seizures in neonates induce or worsen brain injury via an increase in metabolic demands and formation of reactive oxygen species and inflammation that can cause tissue damage.^18, This can lead to altered neuronal connectivity, receptor expression, and synaptic plasticity and, thereby, can result in long-lasting adverse effects on neurodevelopment.¹⁸ In human neonates with HIE, seizure severity is associated with disruptions in brain metabolism as evidenced by an increase in lactate/choline ratio in the watershed areas and deep gray nuclei, as well as a decrease in the N-acetylaspartate/choline ratio in the watershed areas.¹⁹ This effect is independent of the underlying structural patterns of brain injury seen on MRI for neonates with HIE.

More severe brain injury is also seen in neonates with higher seizure burden. Among 56 neonates with HIE who received therapeutic hypothermia and cEEG, 30% had confirmed seizures (30% of whom had status epilepticus and 40% had subclinical/EEG-only seizures).²⁰ Neonates with seizures were more likely to have a moderate–severe injury on brain MRI compared to those without (59% vs 26%), and all infants with status epilepticus had a moderate–severe injury.²¹ Furthermore, the brain injury pattern was more often a cortical or near total injury among the neonates with seizures, providing critical evidence regarding the association between neonatal seizures and brain injury and suggesting a possible amplification of injury in the setting of high seizure burden.

Mortality

In neonates with HIE, high seizure burden and severe brain injury are significant risk factors for mortality.^1,22–24 In a prospective, multicenter study of 426 neonates with clinical and/or electrographic seizures of various etiologies, 17% died or were transferred to hospice care prior to discharge. Neonates with seizures due to HIE were at particularly high risk for death (21%–26%).^1,23 In the era of therapeutic hypothermia, deaths commonly follow the withdrawal of intensive care among neonates with severe HIE given their poor prognosis; half of these infants have seizures.²² A high seizure burden (≥7 total seizures) and status epilepticus are both independently associated with higher risk of death compared with a lower seizure burden (<7) or absence of status epilepticus.¹

Cognitive and Motor Outcomes

Neonates with HIE and seizures are known to have high rates of long-term neurodisability (Table 1).^21,24–27 A prospective, multicenter study assessed the association of clinical neonatal seizures with the neurodevelopment of 77 term infants with HIE.²¹ Cognitive and motor testing included a full scale IQ (FSIQ) using the Weschler scale of intelligence and the Gross Motor Function Classification System (GMFCS) (score ≥3 corresponding to a functional deficit and diagnosis of cerebral palsy) at 4 years of age. A composite seizure score ranging from 0 to 10 was assigned based on seizure frequency, timing of onset, ASMs, and EEG abnormalities. Severe seizures (cumulative seizure score ≥4) occurred in 14.3% of patients, mild-to-moderate seizures (cumulative seizure score 1–3) occurred in 18.2%, and no seizures were seen in the rest. Infants with severe seizures had more basal ganglia predominant injury on MRI while those with mild–moderate seizures had more watershed pattern of injury. After adjusting for degree of brain injury on MRI, there was a significant association between the presence and severity of seizures and developmental outcomes. Infants with severe seizures had a 30 point lower FSIQ (2 standard deviations) and infants with mild-to-moderate seizures had a 14 point lower FSIQ (1 standard deviation) compared with infants who had no seizures. The GMFCS scores were also significantly worse among neonates with seizures than those without.²¹ In a second study, neonates with HIE and clinical seizures were assessed for outcomes including global developmental delay (significant delay in ≥2 domains) and cerebral palsy at age 2 years. Of these 62 neonates, 53% had global developmental delay and 45% had cerebral palsy.²⁶

Table 1.

Outcomes at 12–24 mo following neonatal seizures in hypoxic-ischemic encephalopathy

	McBride et al,25 2000	Glass et al,21 2009	Kharoshanykaya et al,27 2016	Basti et al,28 2020	Sewell et al,29 2023	Jagadish et al,30 2024
N	23	41	29	24	274	67
Normal (%)	44	–	17	77	66	46
Mortality (%)	30	39	24	–	5	–
Developmental delay (%)	56	61	62	11	34	54
Cerebral Palsy (%)	37	–	34	7	25	–
Epilepsy (%)	–	–	17	4	27	13

Adapted from Ref.²³

The causal effect of seizures on developmental outcome is supported by studies demonstrating a relationship between higher seizure burden and worse outcomes. This is particularly relevant for infants with HIE—who have a stronger correlation between seizure burden and worse Bayley III and Vineland II scores at the age of 17 to 31 months compared with infants with other acute provoked neonatal seizure etiologies.³¹ An observational study on neonates with moderate–severe HIE assessed their neurodevelopmental outcomes at age 2 to 4 years.²⁷ Among the 47 neonates with HIE, 62% had cEEG-confirmed seizures. Seizures alone were not significantly associated with abnormal outcome; rather, seizure burden was more relevant. There was a 9 fold greater chance of an abnormal outcome with a total seizure burden greater than 40 minutes and an 8 fold greater chance of an abnormal outcome with maximal hourly seizure burden greater than 13 minutes per hour. This effect persisted after adjusting for HIE severity and treatment with therapeutic hypothermia.²⁷ In a subgroup of neonates with HIE, those with the highest cumulative duration of electrographic seizures had increased rates of death, microcephaly, and severe cerebral palsy.²⁵ Among neonates with status epilepticus, the total duration has been associated with worse scores on the Griffiths Mental Developmental Scale at the age of 18 months.³²

Risk of Postneonatal Epilepsy

Following neonatal seizures in infants with HIE, 10% to 15% of survivors develop postneonatal epilepsy.^20,27,33 The provoked seizures subside, but recurrent unprovoked seizures (epilepsy) emerge after a quiescent period. Risk factors include neonatal seizures—especially status epilepticus—higher number of ASMs needed to control the seizures, severe encephalopathy, and/or severe injury on brain MRI.^20,33

Prior to cooling, moderate–severe HIE was considered the most common symptomatic etiology of infantile epileptic spasms syndrome (IESS). Infants with HIE who do not receive therapeutic hypothermia are 6 times more likely to develop IESS by the age of 2 years than cooled infants.³⁴ In a prospective, multicenter study of the incidence and risk factors associated with the development of IESS among 204 survivors of acute symptomatic neonatal seizures, 12 (6%) developed IESS, of whom half had HIE.³⁵ Risk factors for IESS were stratified into a risk model and included (1) a severely abnormal EEG or 3 days or more with seizures recorded on EEG, (2) a deep gray or brainstem injury on MRI, and (3) an abnormal tone on discharge examination. IESS risk was 0% if none of these risk factors were present, 4% if 1 or 2 risk factors were present, and 57% if all 3 were present. Application of this risk model could aid parent counseling, tailored surveillance, and rapid diagnosis and treatment of IESS in high-risk infants.

Treating Electrographic Seizures

Neonatal seizures are defined by their EEG signatures—repetitive, evolving ictal rhythms with amplitude of 2 μV or greater, and duration of at least 10 seconds.³⁶ Electrographic only (or subclinical) seizures occur without obvious clinical manifestations and can only be detected by EEG.³⁷ Electroclinical seizures are confirmed on EEG and have associated clinical signs.³⁶

Neonates with subclinical seizures have higher mortality rates than neonates with reported clinical seizures.¹ This may be, in part, due to the higher seizure burden encountered in those with subclinical seizures as they can be unrecognized for longer periods compared with clinical seizures. Neonates with subclinical seizures have MRI injury scores similar to those with electroclinical seizures—suggesting that subclinical and clinical seizures can be associated with similar degrees of brain injury.²⁰ Importantly, studies that include only neonates with clinically apparent seizures (without EEG confirmation) may inadvertently include infants whose paroxysmal events were not seizures.

Several randomized controlled trials (RCTs) have compared neonates with HIE who receive treatment of electrographic seizures versus treatment of only clinically apparent seizures. All of these studies excluded neonates with status epilepticus as the consensus among experts in the field is that such infants require aggressive treatment. In a multicenter RCT, 19 neonates with HIE were assigned to receive treatment of both amplitude-integrated EEG (aEEG)-diagnosed seizures and clinical seizures while 14 neonates were assigned to receive treatment of only clinically apparent seizures. The median duration of electrographic seizures (as quantified by aEEG) was longer in the clinical only treatment group (503 minutes) compared with the clinical plus aEEG-treated group (196 minutes), although the result did not reach statistical significance. Additionally, there was a trend toward more severe injury on MRI and longer seizure duration among neonates treated based only on clinical observation.³⁸

In a similarly designed trial of 35 neonates with moderate–severe HIE and cEEG-confirmed seizures, 15 received treatment of electrographic and clinical seizures and 20 received treatment of only clinical seizures. In the cEEG group, there was a significantly shorter time to treatment after seizure onset, a decrease in the cumulative electrographic seizure burden, a decrease in the overall number of seizures, and lower MRI injury scores compared to the clinical treatment group.³⁹ Cognitive, language, and motor outcomes using Bayley Scales of Infant Development (BSID) were assessed at 18 to 24 months for all infants in the study (including the 26 without seizures). The neurodevelopmental outcomes between the 2 seizure treatment groups were not different, but when all babies (including those without seizures) were included, increased seizure burden was associated with worse scores across all domains on the BSID.

More recently, a larger (but still underpowered) trial randomized 86 neonates in each treatment arm (aEEG-guided vs clinical seizure treatment).⁴⁰ There was no difference in 2 year outcomes, including death or severe disability (ie, cerebral palsy, BSID scores 2 standard deviations below mean in any domain, blindness, or deafness) between the aEEG seizure treatment group and the clinical seizure treatment group. However, the authors acknowledge major study limitations. First, the study was underpowered due to early closure because of low recruitment and loss of clinical equipoise. Second, the study utilized aEEG, not cEEG, which affected the accuracy of seizure detection. Third, many babies were transferred from referring hospitals and were not monitored with aEEG until more than 12 hours after birth, which may have resulted in underdiagnosis of seizures and a delay of treatment in both groups. Although the quality of evidence for seizure treatment is limited, there is expert consensus to treat electrographic seizures as quickly as possible as a strategy to optimize neurodevelopmental outcome and minimize risk of postneonatal epilepsy.

MANAGEMENT OF ACUTE PROVOKED NEONATAL SEIZURES IN HYPOXIC-ISCHEMIC ENCEPHALOPATHY

Evidence for Current Guidelines

First-line and second-line medications for seizures in hypoxic-ischemic encephalopathy

By reducing brain injury, therapeutic hypothermia is a valuable advancement that decreases seizure burden in treated infants.^8,41 Therapeutic hypothermia is standard of care in neonates with moderate-to-severe HIE; however, up to 50% of treated infants continue to have seizures.^6,7,20 Neonates with high seizure burden may have reduced response to ASMs⁴²; this suggests that rapid treatment initiation may offer important benefits.

Most ASM treatment guidelines are based on studies of all infants with seizures, regardless of etiology.^43–45 As HIE is the most common cause of neonatal seizures,¹ these guidelines are directly relevant to this patient population. Phenobarbital has a long history of use as a first-line ASM for early-life seizures, supported by observational data and several RCTs.^46–48 Phenobarbital is recommended as a first-line treatment of neonatal seizures because it is easier to use (due to more predictable pharmacokinetics) than phenytoin⁴⁸ and has a better response rate and longer duration of seizure-freedom than levetiracetam.⁴⁷ Phenobarbital also has stable clearance and does not require dose adjustment with therapeutic hypothermia.⁴⁹

Based on animal and human studies, prolonged use of phenobarbital raises concerns for impaired neurodevelopment.⁵⁰ However, as failure to adequately control seizures is associated with poorer survival and worse neurodevelopmental outcomes,^20,21,27 phenobarbital continues to be recommended as the first-line treatment in the acute setting.⁴³ Importantly, treatment success is likely time-sensitive. Early treatment can result in significantly reduced seizure burden.⁵¹

Only about 50% of infants with HIE respond to initial phenobarbital doses.^2,4,52 However, due to a paucity of data from RCTs, there is no clear evidence-based recommendation to support a specific second-line ASM. The most recent guidelines, therefore, recommend phenytoin, midazolam, lidocaine, or levetiracetam as second-line medications.^43,48 In the setting of therapeutic hypothermia, additional considerations include drug clearance and comorbid conditions related to other organ injury. Based on limited data, the clearance of midazolam (delivered in a continuous intravenous infusion) and levetiracetam does not appear to be affected by therapeutic hypothermia. Phenytoin clearance may be decreased by therapeutic hypothermia⁵³ and may be more likely to cause or exacerbate bradycardia in this setting.⁵⁴ Both midazolam and phenytoin may contribute to excessive sedation, respiratory depression,^46,55 or hypotension,⁴⁶ particularly among infants with severe HIE and end-organ injury.⁵⁵ Lidocaine clearance is decreased by therapeutic hypothermia, and dose adjustments are necessary; clinical dosing algorithms are available.⁵⁶ Importantly, due to the risk of cardiac arrhythmia, lidocaine is contraindicated for neonates who have received phenytoin.⁵⁷

Based upon concern for side effects and the suggestion that treatment with levetiracetam may be less detrimental to neurodevelopment than prolonged treatment with phenobarbital or phenytoin,⁵⁸ levetiracetam has been used more frequently in recent years.⁵⁹ However, a high-quality RCT demonstrated clearly that levetiracetam is much less effective than phenobarbital as a first-line ASM (28% seizure cessation with levetiracetam vs 80% with phenobarbital; P < .001, relative risk 0.35 [95% confidence interval 0.22–0.56]) and suggested that levetiracetam also has very limited efficacy as a second-line treatment.⁴⁷ Therefore, levetiracetam is not recommended as a first-line ASM for neonatal seizures. Additionally, phenytoin/fosphenytoin may be more effective than levetiracetam.⁶⁰ When levetiracetam is used, doses of 40 to 60 mg/kg have a better efficacy than lower doses.⁶¹

Status epilepticus/refractory seizures

When infants with HIE develop seizures that are refractory to first-line and second-line ASMs, continuous infusions are commonly recommended. Options include midazolam, lidocaine, and pentobarbital.

Midazolam.

In the United States, a midazolam infusion is the mainstay of treatment of refractory neonatal seizures. Retrospective evidence demonstrates highly variable response rates, with rates of seizure resolution reported to range from essentially 0% up to 100%.^48,54,55 High rates of response to midazolam have been reported specifically in infants with HIE.⁶² Notably, studies with better response rates used higher midazolam doses than those with lower reported rates of response.⁵⁵

Lidocaine.

A lidocaine infusion may be used as a second-line therapy; however, in practice, it is often initiated after multiple medications have been administered without success. Rates of seizure control using lidocaine range from 20% to 70%.⁶³ At least one study has reported a higher response rate to lidocaine than to midazolam.⁶⁴ However, lidocaine is not recommended for infants with cardiac concerns⁴³ and is contraindicated if the neonate has previously received phenytoin. While no published data are available, we suggest that neonates who have received lacosamide should also be excluded from exposure to lidocaine due to concerns about induced arrhythmia.

Pentobarbital.

Pentobarbital use in neonates has been described in case studies only.⁶⁵ This infusion can be considered in an intubated patient whose seizures persist despite other treatment options, including phenobarbital and midazolam.⁴⁸

Based on the studies reviewed earlier, and the International League Against Epilepsy (ILAE) consensus guideline that standard treatment pathways be developed and implemented consistently to facilitate efficient, evidence-based treatment,⁴³ we provide a suggested treatment algorithm for seizures in the setting of HIE (Fig. 1).

Fig. 1.

ASM treatment algorithm for recurrent neonatal seizures^a after HIE. ^aRecurrent clear clinical seizures later confirmed on EEG or electrographic seizures. ^bFollow goal levels 1–2 hours after final loading dose. ^cSecure airway prior to initiating these infusions. ^dDosing, safety, and efficacy data are not available for these medications. FOSPHT, fosphenytoin; LEV, levetiracetam; MDZ, midazolam.

Other antiseizure medications with limited evidence

Emerging therapies.

There are multiple emerging treatments for neonatal seizures. Of critical importance, none of the ASMs described later in this article currently have sufficient data to support a recommendation for routine clinical practice. Lessons learned from levetiracetam—for which initial noncontrolled and retrospective studies suggested efficacy but an RCT clearly demonstrated the lack of efficacy—should inform a cautious approach to clinical adoption of untested treatments.

Bumetanide

An open-label trial (with no control group) of bumetanide as second-line therapy after phenobarbital for infants with HIE was halted prematurely due to hearing loss in several treated infants and insufficient evidence for seizure reduction.⁶⁶ A subsequent, double-blind, pilot RCT of bumetanide following phenobarbital treatment of infants with seizures (not specific to HIE, although infants with HIE were included) demonstrated no increase in hearing impairment in the bumetanide group compared with controls, despite using a higher dose of bumetanide.⁶⁷ Further, this pilot RCT suggested a temporary reduction in seizure burden among neonates with high seizure burden. However, the small sample size and short-term efficacy endpoint do not support current clinical use of bumetanide for neonatal seizure treatment. Notably, among infants with HIE, bumetanide pharmacokinetics were altered by hypothermia.⁶⁷ Overall, bumetanide remains a promising option but requires further investigation before it can be recommended for routine use.

Ketamine

Ketamine is used for children and adults with refractory status epilepticus (RSE), with response rates up to 73% in children.⁶⁸ A recent study of ketamine for RSE included 19 infants aged less than 30 days, with an overall 46% rate of RSE termination (both in infants and older children) and an additional 28% of patients with seizure reduction. Only 4% of all included patients had adverse effects (ie, hypertension or delirium).⁶⁹ Case series have suggested efficacy and safety of ketamine among infants with RSE following HIE.⁷⁰ While these preliminary results are promising, further rigorous investigation is advised before administering ketamine for neonates with HIE outside of a research protocol setting.

Brivaracetam

Brivaracetam is an analog of levetiracetam and has a Food and Drug Administration (FDA) indication for infants aged older than 1 month. A small (n = 6), single-arm study of newborns suggested that brivaracetam was safe and effective for treatment of refractory seizures, with similar pharmacokinetics to those in older children and adults.⁷¹ Three infants in the study had seizures secondary to HIE. Therefore, brivaracetam is a promising option worthy of additional study but is not currently recommended for routine use.

Lacosamide

Lacosamide is a sodium-channel-modulating ASM with an intravenous formulation that can be administered as a loading dose. It is, therefore, being used with increasing frequency among children and infants, although the FDA indication is for children aged 4 years or older. A case series demonstrated safety of lacosamide among newborn infants, with close cardiac monitoring for key side effects.⁷² Only a minority (5%) of patients were found to have atrial bigeminy. As animal studies suggest a neuroprotective effect of lacosamide following hypoxic-ischemic injury,⁷³ further human studies are warranted for this population.

Antiseizure medication cessation

Acute provoked seizures in the setting of neonatal HIE have a predictable timecourse⁶ and should resolve within several days. Based on data that demonstrate that stopping ASMs is safe, does not increase the risk for postneonatal epilepsy, and does not harm neurodevelopment,⁷⁴ the 2023 ILAE guideline recommends that ASMs be routinely discontinued for neonates with acute provoked seizures prior to hospital discharge. Importantly, this guidance specifies that ASMs may be discontinued after resolution of the acute provoked neonatal seizures regardless of interictal EEG findings or neuroimaging abnormalities. Neonates at high risk for postneonatal epilepsy, including those who had 3 or more days of seizures, a severely abnormal EEG background, and an abnormal tone on discharge neurologic examination, should be closely followed by a child neurologist. ^35,75 Families must be counseled about the risk for IESS and linked with appropriate primary care and specialist follow-up.

SUMMARY

Neonatal seizures are common following hypoxic-ischemic brain injury. These acute provoked seizures are often subclinical, which makes cEEG monitoring a vital tool during therapeutic hypothermia. EEG background patterns are important predictors of seizures in the acute period and are associated with later neurodevelopmental outcomes. Timely and effective treatment with ASMs may improve overall outcomes. Phenobarbital remains the recommended first-line therapy, with several options for second-line treatments, and more ASMs currently under investigation. Following acute provoked seizure resolution, early discontinuation of ASMs is safe and does not affect the future risk of epilepsy in infants with HIE.

KEY POINTS.

• Continuous electroencephalographic monitoring is recommended for neonates with hypoxic-ischemic encephalopathy (HIE) to screen for seizures and evaluate evolution of the interictal background.

• Early recognition and effective treatment of seizures are key priorities for neonatal neurointensive care.

• First-line antiseizure medication remains phenobarbital while second line may include fosphenytoin, levetiracetam, or continuous infusions.

• Early discontinuation of antiseizure medication is safe in neonates with HIE following cessation of acute provoked seizures.

Best Practices.

Best practice/guidelines/care path objectives:

• Duration of EEG monitoring in neonates with HIE

• Using the EEG background to predict long-term outcomes

• Treatment of electrographic and electroclinical seizures

• Neurodevelopmental outcomes following acute provoked seizures in HIE

• Treatment algorithm for neonatal seizures associated with HIE

• Early discontinuation of antiseizure medications following acute provoked seizures in HIE

What changes in current practice are likely to improve outcome?

• Prompt diagnosis of seizures and rapid initiation of effective treatment may improve long-term neurodevelopmental outcomes for neonates with HIE.

• Clinical algorithm (see Fig. 1)

Pearls/Pitfalls at the point of care

• Accurate diagnosis of seizures with EEG is important to initiate appropriate treatment, evaluate treatment response, and avoid unnecessary exposure to antiseizure medication.

• Delay in seizure treatment may amplify brain injury and worsen neurodevelopmental outcomes.

• Seizures following acute injury in HIE are provoked; continued prophylactic antiseizure medication after hospital discharge does not prevent or delay the onset of epilepsy.

Major recommendations

• CEEG monitoring is recommended for neonates with HIE.

• Early recognition and effective treatment of seizures are key priorities for neonatal neurointensive care.

• Phenobarbital remains the first-line antiseizure medication to treat recurrent seizures, while second-line treatment may include fosphenytoin, levetiracetam, or continuous infusions.

• Early discontinuation of antiseizure medication is safe following cessation of acute provoked seizures in neonates with HIE.

Bibliographic Sources

Shellhaas RA, Chang T, Tsuchida T, et al. The American Clinical Neurophysiology Society’s Guideline on Continuous Electroencephalography Monitoring in Neonates. J Clin Neurophysiol. 2011;28(6):611 to 617.

Pressler RM, Abend NS, Auvin S, et al. Treatment of seizures in the neonate: Guidelines and consensus-based recommendations—Special report from the ILAE Task Force on Neonatal Seizures. Epilepsia. 2023;64(10):2550 to 2570.