Neonatal seizures and hypoxic-ischaemic encephalopathy

• Neonatal seizures are most often acute, provoked events rather than epilepsy. In term infants the commonest trigger is hypoxic-ischaemic encephalopathy; other triggers include stroke, infection, bleeding and metabolic disturbances. ^[1][3]
• Most visible "fits" in a newborn are not seizures, and many true seizures produce no visible movement at all. The gold standard for diagnosis is continuous video electroencephalography, and treatment decisions should be guided by it. ^[1][3]
• Phenobarbital remains the recommended first-line antiseizure medication for neonates, with phenytoin or carbamazepine preferred when a channelopathy is likely. Acute antiseizure medication should be stopped before discharge once acute provoked seizures have ceased. ^[1][3]
• Hypoxic-ischaemic encephalopathy is caused by oxygen deprivation around birth. Therapeutic hypothermia (cooling to 33 to 34 degrees C for 72 hours, started within 6 hours) is the standard neuroprotective treatment for term and near-term infants with moderate to severe disease. ^[2]
• Prognosis depends on the cause and severity: very mild disease has a good outcome, whereas profound hypoxia produces multi-organ injury, seizures and long-term disability even with optimal care. ^[2]

By the end of this page you should be able to:

1. Explain why the newborn brain is unusually prone to seizures and why most neonatal seizures are acute and provoked. ^[1]
2. Classify a paroxysmal event in a neonate as epileptic or non-epileptic, and describe the proper use of EEG monitoring. ^[1]
3. Outline the investigation and initial management of a neonate with suspected seizures, including glucose, electrolytes, infection and imaging. ^[1]
4. State the first-line and second-line antiseizure medications used in neonates and when to discontinue them. ^[1][3]
5. List the inclusion and exclusion criteria for therapeutic hypothermia and describe how it is delivered and monitored. ^[2]
6. Discuss prognosis after neonatal seizures and hypoxic-ischaemic encephalopathy, including the result of cooling and its limits. ^[1][2]

A neonatal seizure is rarely a stand-alone disease. In the first month of life it is usually the symptom of an acute injury to the developing brain or of a rare neonatal epilepsy syndrome. Hypoxic-ischaemic encephalopathy is the commonest single cause in term infants, and seizures are both a marker of injury and a potential contributor to further injury. ^[1][3]

The challenge for the clinician is twofold. First, neonates do not present like older children: their seizures are often subtle (eye deviation, sucking, apnoea, tonic posturing) and many true seizures occur without any visible movement. Second, the therapies that work in adults (for example rapid escalation of multiple antiseizure drugs) are less well validated in neonates, and the brain is still developing. ^[1]

Management therefore combines three parallel tasks: treating any immediately reversible cause, supporting the brain with measures such as therapeutic hypothermia when indicated, and using antiseizure medication carefully and only when needed. ^[1][2][3]

A neonatal seizure is a paroxysmal alteration in neurological function caused by abnormal, hypersynchronous neuronal discharge in the first 28 days of life (up to 44 weeks postmenstrual age in preterm infants). Events may be electroclinical (clinical signs accompanied by an EEG correlate) or electrographic-only (EEG seizure without visible movement). ^[1][3]

The International League Against Epilepsy classification of seizures in the neonate therefore includes both. In term infants most such seizures are acute and provoked; in preterm infants a substantial proportion are electrographic-only and would be missed without monitoring. ^[1][3]

Epilepsy syndromes with onset in the neonatal period are a separate, smaller group (estimated about 10 to 15% of neonates with seizures). They include self-limited neonatal epilepsy (usually KCNQ2/KCNQ3 or SCN2A mutations, with spontaneous remission), early infantile epileptic encephalopathy (Ohtahara syndrome), early myoclonic encephalopathy, focal epilepsy syndromes of infancy, and pyridoxine-dependent epilepsy. These are usually diagnosed after the acute period and require specific treatment and genetic testing. ^[1][3]

• Neonatal seizures occur in about 1 to 3 per 1000 live births in full-term infants (contemporary cohorts report 2.29 to 4 per 1000) and 10 to 30 per 1000 in preterm or low-birth-weight infants, with rates up to about 130 per 1000 in some preterm cohorts. ^[1][3]
• Preterm infants have been reported at 14.28 per 1000, often as electrographic-only seizures, while other preterm cohorts report up to about 130 per 1000. ^[3]
• Hypoxic-ischaemic encephalopathy occurs in roughly 1.5 to 3.5 per 1000 live births in high-income countries and up to 26 to 30 per 1000 in low-income countries, depending on the source. ^[2][6]
• Mortality among infants with hypoxic-ischaemic encephalopathy ranges from 10 to 60%, with major neurodevelopmental disability in many survivors. ^[2]
• In acute provoked disease medication can usually be stopped before discharge; neonatal epilepsy syndromes are diagnosed in about 15% of neonates with seizures. ^[1]

Acute provoked seizures dominate (about 85%). ^[3] The main categories are:

Risk factors include prematurity, low birth weight, low Apgar scores, acidosis, need for resuscitation, maternal infection, gestational diabetes, hypertensive disorders of pregnancy, multiple pregnancy, congenital anomalies and a family history of neonatal seizures. ^[1][2]

Hypoxic-ischaemic encephalopathy is brain injury caused by oxygen deprivation and reduced perfusion around the time of birth. Recognised antecedents include placental insufficiency, cord prolapse or compression, shoulder dystocia, uterine rupture, maternal hypotension or haemorrhage, chorioamnionitis and prolonged or obstructed labour. Many cases have no single identifiable sentinel event. ^[2]

Several developmental features make the neonatal brain hyperexcitable:

• Synapse and dendritic spine density peaks in the first weeks of life. ^[1]
• Excitatory glutamate receptors (NMDA and AMPA) are overexpressed and have prolonged current decay. ^[1]
• Inhibitory GABA signalling is developmentally less effective: GABA receptor binding is low, and the neonatal chloride gradient can make GABA depolarising rather than hyperpolarising, so GABA-agonist antiseizure drugs (including benzodiazepines) are less potent than in adults. ^[1]
• There is greater expression of the GABA alpha-4 subunit, which reduces benzodiazepine sensitivity. ^[1]

Hypoxic-ischaemic injury evolves in phases, which is why timing of treatment matters:

1. Primary energy failure. Severe hypoxia stops oxidative phosphorylation; ATP falls, the Na+/K+ pump fails, calcium enters cells and primary neuronal death begins. In moderate injury, perfusion is maintained to the brainstem at the expense of the cerebral cortex, thalamus and basal ganglia. ^[2]
2. Latent phase (about 30 minutes to 6 hours). If oxygen is restored, intracellular processes partly recover while inflammation and apoptotic cascades continue. This window is when therapeutic hypothermia is thought to be most effective. ^[2]
3. Secondary phase (6 to 72 hours). Free-radical injury, mitochondrial failure, cell death and clinical deterioration (often with seizures) occur. ^[2]
4. Tertiary phase (weeks to months). Remodelling and late cell death shape the final neurological outcome. ^[2]

Seizures themselves are believed to add to injury by increasing metabolic demand and excitotoxicity, which is one reason both electrographic and clinical seizures are treated and why EEG monitoring is used. ^[1][3]

Ask about the three periods:

• Antenatal: maternal infection (TORCH group), gestational diabetes, hypertensive disease, consanguinity, medication or substance use, fetal concerns. ^[1]
• Perinatal: fetal heart rate patterns, mode of delivery, meconium, cord gases, Apgar scores, resuscitation. ^[1]
• Postnatal: timing of onset of abnormal movements, semiology, duration, colour change, apnoea, fever, feeding. ^[1]

• Mental state (encephalopathy staging in hypoxic-ischaemic injury), tone, posture and primitive reflexes. ^[1][2]
• Head size and fontanelle (microcephaly, bulging fontanelle). ^[1]
• Dysmorphic features, neurocutaneous markers (ash-leaf macules, port-wine stain) and tone abnormalities that suggest genetic or structural disease. ^[1]
• Evidence of systemic illness (temperature instability, jaundice, hepatosplenomegaly, rash) that points to infection or metabolic disease. ^[1]

Neonatal seizures are classified by the ILAE as:

• Motor: automatisms, clonic, epileptic spasms, myoclonic, tonic.
• Non-motor: autonomic (apnoea, colour change, salivation), behavioural arrest.
• Sequential: a combination in sequence.
• Electrographic only: no visible movement. ^[1][3]

In a term infant an epileptic seizure is suspected when apnoea occurs with abnormal eye or mouth movements, hypertension or tachycardia rather than the benign desaturation of sleep apnoea. ^[1]

Many movements in newborns are not seizures, and treating them is both unnecessary and potentially harmful.

Electrographic verification is required whenever doubt remains: many suspected paroxysmal events in the newborn prove to have a normal EEG and are not seizures. ^[1]

• Continuous video EEG is the gold standard; the American Clinical Neurophysiology Society traditionally recommends 24 hours of monitoring for at-risk neonates, although its 2025 guidance makes such recommendations conditional and of low-to-moderate quality depending on risk category. ^[1][3]
• A routine 60-minute EEG is insufficient: it takes a median of about 7 hours to capture an electrographic seizure. ^[1]
• If no seizure is recorded after 24 hours, monitoring can be stopped except in infants with hypoxic-ischaemic encephalopathy undergoing therapeutic hypothermia, in whom monitoring should continue through cooling and rewarming. ^[1][3]
• Once seizures are detected, EEG should continue until the infant has been seizure-free for 24 to 48 hours. ^[1]
• Amplitude-integrated EEG is a bedside (usually single-channel or dual-channel) alternative when continuous video EEG is unavailable, but it is less sensitive and specific and is prone to artefact. ^[1][3]

Monitoring is essential because treatment guided by EEG reduces unnecessary exposure to antiseizure medication. ^[1]

Initial laboratory evaluation:

• Blood glucose, sodium, potassium, calcium, magnesium, phosphate.
• Blood gas (pH, base deficit, lactate).
• Full blood count, blood culture and, when meningitis is possible, cerebrospinal fluid analysis (including herpes simplex virus testing).
• Ammonia, pyruvate, lactate, amino acids, urine organic acids and acylcarnitine profile when a metabolic disorder is suspected.
• Genetic testing (chromosomal microarray, epilepsy panel), escalating to whole-exome or whole-genome sequencing if no cause is found. ^[1]

• Magnetic resonance imaging is the preferred modality for any neonate with seizures; it best defines hypoxic-ischaemic injury, stroke, malformation and haemorrhage. ^[1]
• Add magnetic resonance angiography or venography when a vascular event is suspected. ^[1]
• Magnetic resonance spectroscopy is useful when an inborn error of metabolism is suspected. ^[1]
• Cranial ultrasound is a bedside option in unstable infants for haemorrhage or hydrocephalus. ^[1]
• Avoid computed tomography because of radiation. ^[1]

The modified Sarnat examination is used to classify encephalopathy. An infant is staged by six categories (level of consciousness, activity, posture, tone, primitive reflexes and autonomic function) and receives moderate or severe staging when at least 3 of the 6 categories are abnormal in that direction. ^[2]

Seizures are part of the examination category: a confirmed seizure automatically qualifies an infant as having moderate to severe encephalopathy for treatment purposes, provided the demographic and biochemical criteria below are also met. ^[2]

All three groups of criteria must be met. ^[2]

Demographic:

• Gestation of 36 weeks or more.
• Birth weight of 1800 g or more.
• Within 6 hours of birth.

Biochemical (from cord or infant blood gas within the first hour):

• pH 7.0 or lower, or base deficit 16 mmol/L or higher; or
• pH 7.0 to 7.15 or base deficit 10 to 15.9 mmol/L plus either an acute perinatal event, or an Apgar score of 5 or less at 10 minutes, or assisted ventilation for at least 10 minutes after birth.

Examination: moderate to severe encephalopathy as above.

Contraindications include gestation under 36 weeks, birth weight under 1800 g, age over 6 hours (some centres consider up to 24 hours), major congenital abnormality, inevitable death, significant active bleeding, major intracranial haemorrhage and imperforate anus in selective head cooling. ^[2]

1. Support airway, breathing and circulation. Obtain intravenous access. ^[1]
2. Treat reversible causes immediately: give glucose if hypoglycaemic; correct electrolytes; treat suspected infection with antibiotics, antivirals and (in herpes risk) aciclovir. ^[1]
3. Arrange continuous EEG monitoring and imaging as above. ^[1]
4. Discuss cooling early if hypoxic-ischaemic encephalopathy is suspected, because the 6-hour window is short. ^[2]

The International League Against Epilepsy task force recommends: ^[1][3][4]

• First-line: phenobarbital for all neonates requiring an antiseizure medication, regardless of cause, except that when a channelopathy is likely (for example a suggestive family history), a sodium-channel blocker (phenytoin or carbamazepine) is preferred. ^[1][3]
• Second-line: phenytoin, levetiracetam, midazolam or lidocaine for seizures not controlled by first-line treatment; in infants with cardiac disease levetiracetam may be preferred. ^[1][3]
• Pyridoxine trial: a trial of intravenous pyridoxine 100 mg, repeated up to 4 times to a maximum cumulative dose of 500 mg, may be attempted under EEG and cardiopulmonary monitoring in infants with features of vitamin-B6-dependent epilepsy or in drug-resistant seizures without an identified cause. Long-term pyridoxine is 15 to 30 mg/kg/day (up to 200 mg/day in neonates). ^[1]
• Discontinuation: after cessation of acute provoked (electroclinical or electrographic) seizures without evidence of neonatal-onset epilepsy, antiseizure medication should be stopped before discharge, regardless of MRI or EEG findings; in practice within about a week. StatPearls (Gunasekaran 2024) supports discontinuation after 72 hours of seizure freedom in acute provoked disease, whereas the ILAE 2023 special report does not specify a 72-hour seizure-free interval and recommends discontinuation before discharge once provoked seizures have ceased. ^[1][3][4]
• Treatment target: evidence suggests treating neonatal seizures (including electrographic-only seizures) to achieve a lower seizure burden may improve neurodevelopment and reduce later epilepsy. ^[3]

Doses are checked against the local neonatal formulary.

Therapeutic hypothermia is the standard neuroprotective treatment for term and near-term infants (36 weeks or more) with moderate to severe hypoxic-ischaemic encephalopathy, and should be started within 6 hours of birth. ^{[2] [5]}

• Method: whole-body cooling to 33 to 34 degrees C, or selective head cooling to 34 to 35 degrees C; 72 hours of cooling followed by passive or controlled rewarming at 0.5 degrees C per hour. ^[2]
• Setting: experienced units with trained staff; NICE supports the procedure in carefully selected neonates where governance, consent and audit arrangements are in place, and encourages entry into the national cooling register. ^[5]
• Monitoring: continuous cardiorespiratory, EEG and blood tests; functional imaging typically at 4 to 10 days. ^[2]
• Low-resource settings: passive cooling (turn off the warmer, remove blankets, monitor temperature every 15 to 30 minutes) can be used as a bridge until transfer to a centre with a cooling device. ^[2]

Important limits, from the opened StatPearls and NICE-aligned sources: ^[2]

• Preterm infants (under 36 weeks): cooling is contraindicated in the standard protocol, and a recent randomised trial of infants at 33 to 35 weeks found no benefit and possibly worse outcomes.
• Mild hypoxic-ischaemic encephalopathy: there is no clear evidence of benefit; long-term studies are ongoing.
• Late initiation (6 to 24 hours): a bayesian analysis suggested a 64% probability of benefit, but this is not standard practice in most centres.
• Longer or deeper cooling (120 hours or 32 degrees C): no added benefit at 18 months compared with 72 hours or 33.5 degrees C.
• Low- and middle-income countries: evidence from meta-analyses is mixed; some experts advocate continuing cooling, others report little benefit with more bleeding and thrombocytopenia.
• Hypothermia reduces seizure burden in hypoxic-ischaemic encephalopathy, but seizures often reappear during or after rewarming, so EEG monitoring should extend beyond the rewarming phase. ^[3]

• Of hypoxic injury: hypoxic-ischaemic encephalopathy, seizures, multi-organ dysfunction, later cerebral palsy, cognitive impairment and epilepsy. ^[2]
• Of therapeutic hypothermia: bradycardia, hypotension, prolonged QT, pulmonary vasoconstriction and worsening oxygenation, electrolyte disturbances (hypokalaemia, hyponatraemia, hypomagnesaemia, hypophosphataemia), coagulopathy, increased infection risk, feed intolerance and altered drug metabolism. ^[2]
• Of treatment during rewarming: seizures, apnoea and rebound hypotension. ^[2]
• Developmental: neonatal seizures can disrupt synaptogenesis; infants of very low birth weight with seizures have an increased risk of cerebral palsy. ^[1]

Prognosis depends principally on the underlying cause, the severity of brain injury and, in hypoxic-ischaemic encephalopathy, the findings on EEG and MRI. ^[1][2]

• Acute provoked seizures: if the underlying cause resolves, seizures are short-lived and medication can usually be stopped before discharge; the outlook is determined by the brain injury, not the seizure. ^[1]
• Neonatal epilepsy syndromes: self-limited neonatal epilepsy usually remits spontaneously and carries a good prognosis; KCNQ2 encephalopathy produces moderate to severe disability; early infantile and early myoclonic encephalopathies have poor outcomes with early death in many cases. ^[1]
• Hypoxic-ischaemic encephalopathy: mortality is 10 to 60%, with major long-term disability in many survivors. Therapeutic hypothermia improves survival and neurodevelopmental outcome in moderate to severe disease without significantly increasing severe disability among survivors. ^[2]
• Markers: a burst-suppression or severely abnormal background on EEG, persistence of seizures beyond 3 days and abnormal neurological examination predict poorer outcomes and need follow-up. ^[1][3]
• Infants in whom therapy is deferred, withdrawn or impossible should still receive comfort-focused care and family support. ^[2]

• High-quality antenatal and intrapartum care, appropriate fetal monitoring and timely obstetric intervention reduce hypoxic injury. ^[2][5]
• Thermoregulation, gradual reduction of hypothermia and early glucose management in every at-risk birth prevent avoidable brain injury. ^[2]
• Systematic EEG monitoring of infants undergoing therapeutic hypothermia detects seizures that would otherwise be missed. ^[1][3]

• Preterm infants have the highest seizure rates, often as electrographic-only events, and the evidence for therapeutic hypothermia is limited and unfavourable in late-preterm neonates. ^[1][2]
• Mild hypoxic-ischaemic encephalopathy carries a measurable risk of lower cognitive scores; whether cooling helps is still under investigation. ^[2]
• Infants with channelopathies need early genetic diagnosis, because carbamazepine or phenytoin is preferred to phenobarbital in those cases. ^[1][3]
• Families need clear discussion of diagnosis, uncertainty of prognosis and access to community support. ^[1]

• Hypoxic-ischaemic encephalopathy is far more common in developing countries (up to 30 per 1000 births), so prevention and basic resuscitation have large impact. ^[2]
• Where no cooling device exists, passive cooling with close temperature monitoring is a bridge to transfer. ^[2]
• Phenobarbital and basic glucose and electrolyte correction are usually available; continuous EEG often is not, so a lower-cost amplitude-integrated monitor or careful clinical observation with predefined pathways should be used. ^[1][3]
• The benefit of cooling in low-resource settings remains debated, so outcomes should be monitored locally. ^[2]

• Most neonatal seizures (about 85%) are acute and provoked, most often by hypoxic-ischaemic encephalopathy in term infants; the rest include stroke, infection, haemorrhage, metabolic derangement and neonatal epilepsy syndromes. ^[1][3]
• Diagnosis requires EEG: continuous video EEG is the gold standard; 60 minutes is insufficient; monitoring continues until 24 to 48 hours seizure-free, and throughout cooling and rewarming in hypoxic-ischaemic encephalopathy. ^[1][3]
• A 24-hour EEG that captures no seizure permits discontinuation, except in infants with hypoxic-ischaemic encephalopathy undergoing therapeutic hypothermia. ^[1]
• Phenobarbital is first-line for most neonatal seizures; phenytoin or carbamazepine is preferred when a channelopathy is likely. ^[1][3]
• Second-line options are phenytoin, levetiracetam, midazolam or lidocaine; pyridoxine is tried in suspected vitamin-B6-dependent or resistant seizures. ^[1]
• Antiseizure medication should be stopped before discharge once acute provoked seizures have ceased, and in practice within about a week. ^[1][3]
• Treating seizures (including electrographic-only) to a lower burden may improve outcome. ^[3]
• Hypoxic-ischaemic encephalopathy is staged with the modified Sarnat examination; therapeutic hypothermia requires 36 weeks or more gestation, 1800 g or more and presentation within 6 hours. ^[2]
• Whole-body cooling is 33 to 34 degrees C for 72 hours, with controlled rewarming at 0.5 degrees C per hour. ^[2]
• NICE supports cooling in carefully selected neonates in experienced units and encourages recording in the national cooling register. ^[5]
• Hypothermia reduces seizure burden in hypoxic-ischaemic encephalopathy, but seizures recur during or after rewarming, so EEG monitoring is continued. ^[2][3]
• Cooling has limited or unfavourable evidence in late-preterm infants, mild encephalopathy, initiation after 6 hours and some low- and middle-income settings. ^[2]
• Prognosis is worst for early infantile and early myoclonic epileptic encephalopathies; outcomes for hypoxic-ischaemic encephalopathy improve with cooling but remain guarded in severe disease. ^[1][2]

Plain text only: hypoxic-ischaemic encephalopathy management, neonatal encephalopathy, perinatal asphyxia, neonatal resuscitation and transition at birth, neonatal EEG interpretation, childhood epilepsy, cerebral palsy, neurodevelopmental follow-up.