Residency · Residency · Neurology

Neonatal Neurology: Hypoxic-Ischemic Encephalopathy and Neonatal Seizures

Introduction

Neonatal neurological disorders represent some of the most consequential conditions in medicine, as the developing brain is uniquely vulnerable to injury. Hypoxic-ischemic encephalopathy (HIE) is the most common cause of neonatal encephalopathy in term infants and remains a major cause of cerebral palsy and neurodevelopmental disability worldwide. Neonatal seizures frequently accompany HIE and other neonatal brain injuries, demanding specialized recognition and management.

Hypoxic-Ischemic Encephalopathy

Pathophysiology

HIE results from impaired cerebral blood flow and oxygen delivery during the perinatal period. Primary energy failure involves ATP depletion, loss of ion homeostasis, excitotoxic glutamate release, and intracellular calcium accumulation. The latent phase spanning 6-15 hours represents partial recovery of oxidative metabolism and constitutes the therapeutic window for neuroprotection. Secondary energy failure occurs between 6 and 48 hours with mitochondrial dysfunction, apoptosis, inflammation, and further neuronal death. The tertiary phase over days to weeks involves ongoing inflammation, epigenetic changes, and impaired neurogenesis and repair.

Patterns of Injury

The watershed pattern (partial prolonged asphyxia) involves injury to the parasagittal cortex and subcortical white matter and is associated with prolonged moderate hypoxia. The basal ganglia-thalamic pattern (acute profound asphyxia) involves bilateral symmetric injury to the putamina, ventrolateral thalami, perirolandic cortex, and brainstem, and is associated with acute severe hypoxia from sentinel events such as uterine rupture or cord prolapse. The pattern of injury correlates with outcome, with the basal ganglia-thalamic pattern carrying a worse prognosis for motor and cognitive outcomes.

Clinical Assessment (Sarnat Staging)

Stage I (mild) presents with a hyperalert infant with normal or increased tone and no seizures, generally carrying a good prognosis. Stage II (moderate) shows lethargy, hypotonia, common seizures, and weak primitive reflexes with variable outcomes. Stage III (severe) manifests as stupor or coma, flaccid tone, absent reflexes, and prolonged seizures, with poor prognosis including high mortality or severe disability.

Therapeutic Hypothermia

Therapeutic hypothermia is the standard of care for moderate to severe HIE in term or near-term infants (gestational age 36 weeks or greater). The target core temperature is 33.5 degrees C for 72 hours, followed by slow rewarming at 0.5 degrees C per hour. It must be initiated within 6 hours of birth to maximize neuroprotective benefit. The mechanism involves reducing metabolic rate, excitotoxicity, apoptosis, inflammation, and free radical production during the secondary energy failure phase. The number needed to treat is approximately 7 to prevent death or major disability, as demonstrated in the TOBY, CoolCap, and NICHD trials. Contraindications include gestational age less than 36 weeks, birth weight less than 1800 g, severe congenital anomalies, and active uncontrolled bleeding.

Neonatal Seizures

Clinical Recognition

Neonatal seizures are often subtle and difficult to recognize clinically. Subtle seizures manifest as oral-buccal-lingual movements (lip smacking, tongue thrusting), eye deviation, cycling movements, and apnea. Clonic seizures involve rhythmic jerking that is focal or multifocal and represent the most reliably epileptic clinical seizure type in neonates. Tonic seizures are sustained posturing that may be focal or generalized; generalized tonic seizures are often non-epileptic brainstem release phenomena. Myoclonic seizures are brief shock-like jerks that may be epileptic or non-epileptic. Electroclinical dissociation is common, meaning clinical seizure manifestations may occur without EEG correlate (non-epileptic) or EEG seizures may occur without clinical manifestations (subclinical or electrographic-only seizures).

Etiology

HIE is the most common cause, accounting for 40-60% of neonatal seizures. Other causes include intracranial hemorrhage (intraventricular, subdural, subarachnoid), ischemic stroke (arterial or venous), CNS infection (bacterial meningitis, viral encephalitis, TORCH infections), metabolic disorders (hypoglycemia, hypocalcemia, hypomagnesemia, inborn errors of metabolism such as pyridoxine-dependent epilepsy and nonketotic hyperglycinemia), genetic and structural causes (cortical malformations, genetic epilepsy syndromes), and drug withdrawal from maternal opioid, SSRI, or barbiturate use.

Diagnosis

Continuous video-EEG (cEEG) monitoring is the gold standard for detecting neonatal seizures. EEG background assessment provides prognostic information, with patterns ranging from normal through mildly abnormal, moderately abnormal, burst suppression, to electrocerebral inactivity. MRI brain with diffusion-weighted imaging provides structural evaluation. A metabolic workup including glucose, calcium, magnesium, electrolytes, ammonia, lactate, amino acids, and urine organic acids should be obtained. A trial of pyridoxine (100 mg IV) during EEG monitoring should be administered if seizures are refractory, to diagnose pyridoxine-dependent epilepsy.

Treatment

The underlying cause should be corrected first, addressing glucose, calcium, magnesium levels, and treating infection. Phenobarbital is the first-line antiseizure medication with a loading dose of 20 mg/kg IV, with additional 10 mg/kg doses possible up to 40 mg/kg total. Levetiracetam is increasingly used as first-line or second-line with a loading dose of 40-60 mg/kg IV and a favorable safety profile. Phenytoin/fosphenytoin serves as second-line with a loading dose of 20 mg/kg PE IV. Benzodiazepines including midazolam infusion or lorazepam are used for acute seizure termination. Overtreatment should be avoided because antiseizure medications have potential neurotoxicity in the developing brain; medications should be discontinued before discharge if seizures have resolved and EEG has improved.

Prognostication in HIE

MRI

MRI obtained at 3-7 days of life is most sensitive for characterizing injury pattern and severity. Diffusion-weighted imaging (DWI) may show restricted diffusion as early as 24-48 hours but can pseudonormalize by day 7-10. Absence of normal signal intensity in the posterior limb of the internal capsule (PLIC) on T1-weighted imaging is an ominous sign. The basal ganglia-thalamic injury pattern predicts worse motor outcomes, particularly dyskinetic cerebral palsy.

EEG

Severely abnormal background patterns including burst suppression, low voltage, and electrocerebral inactivity are associated with poor outcomes. Recovery of normal sleep-wake cycling and background continuity by 48-72 hours is favorable.

Other Prognostic Tools

Amplitude-integrated EEG (aEEG) is a bedside trending tool whose pattern classification aids prognostication during hypothermia. MR spectroscopy showing an elevated lactate/NAA ratio in the basal ganglia predicts poor outcome. Clinical examination at discharge assessing feeding ability, tone, and alertness also contributes to prognosis.

Clinical Pearls

Therapeutic hypothermia must be initiated within 6 hours of birth for moderate to severe HIE, and transport to a cooling center should not be delayed. Neonatal seizures are frequently subclinical and require continuous EEG monitoring for detection, as clinical observation alone misses the majority of electrographic seizures. The MRI pattern of injury in HIE predicts specific neurodevelopmental outcomes: basal ganglia-thalamic injury predicts motor disability while watershed injury predicts cognitive impairment. Pyridoxine-dependent epilepsy should be considered in all neonates with refractory seizures, and a trial of pyridoxine during EEG monitoring is both diagnostic and therapeutic. Antiseizure medications should be weaned and discontinued before NICU discharge if seizures have resolved, as prolonged exposure to phenobarbital and phenytoin may impair brain development.

References

1. Shankaran S, Laptook AR, Ehrenkranz RA, et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med. 2005;353(15):1574-1584.
2. Glass HC, Shellhaas RA, Wusthoff CJ, et al. Contemporary profile of seizures in neonates: a prospective cohort study. J Pediatr. 2016;174:98-103.
3. Rutherford M, Ramenghi LA, Edwards AD, et al. Assessment of brain tissue injury after moderate hypothermia in neonates with hypoxic-ischaemic encephalopathy. Lancet Neurol. 2010;9(1):39-45.
4. Soul JS. Acute symptomatic seizures in term neonates: etiologies and treatments. Semin Fetal Neonatal Med. 2018;23(3):183-190.

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