In a term newborn with moderate hypoxic‑ischemic encephalopathy who has had 72 hours of seizure‑free amplitude‑integrated electroencephalography (aEEG) monitoring, when should antiseizure medication be stopped, and should levetiracetam (added after phenobarbital) be discontinued before phenobarbital?

Discontinuation of Antiseizure Medications in Term Neonates with Moderate HIE After 72 Hours Seizure-Free on aEEG

In a term neonate with moderate HIE who has been seizure-free for 72 hours on aEEG monitoring, antiseizure medications can be discontinued before hospital discharge, with levetiracetam stopped first, followed by phenobarbital.

Timing of Medication Discontinuation

The evidence strongly supports discontinuing antiseizure medications before discharge in neonates with HIE who remain seizure-free during continuous monitoring. Implementation of continuous video-EEG monitoring protocols has been associated with significantly fewer infants discharged on antiseizure medications (p=0.008), without adverse consequences 1. This practice reflects a shift toward time-limited, targeted use of antiseizure medications rather than prolonged prophylactic therapy.

Key Principles for Discontinuation:

• 72 hours of seizure-free monitoring is sufficient to consider medication withdrawal in the absence of ongoing electrographic seizures 1
• Continuous aEEG/EEG monitoring provides the necessary evidence that seizures have resolved and are not merely subclinical 1
• The absence of both clinical and electrographic seizures after 72 hours indicates the acute seizure risk has passed 1

Order of Medication Discontinuation: Levetiracetam First

Levetiracetam should be discontinued before phenobarbital for several important reasons:

Rationale for Stopping Levetiracetam First:

• Levetiracetam has a shorter half-life (approximately 5 hours in children 4-12 years, likely similar in term neonates) compared to phenobarbital's extremely prolonged half-life of 45-500 hours in neonates 2
• Phenobarbital provides longer-lasting anticonvulsant coverage as levetiracetam is weaned, given its extended elimination time 2
• Levetiracetam appears to have less potential neurotoxic effects than phenobarbital on the developing brain, making it the preferred agent to discontinue first while maintaining some anticonvulsant coverage 3
• Phenobarbital's prolonged half-life means therapeutic levels persist for days to weeks after discontinuation, providing a safety buffer 2

Practical Discontinuation Strategy:

• Stop levetiracetam abruptly or with rapid taper (over 24-48 hours) while continuing phenobarbital at maintenance dose
• Monitor clinically for 24-48 hours after levetiracetam discontinuation while still on phenobarbital
• Then discontinue phenobarbital if no seizure recurrence, either abruptly or with brief taper
• No need for prolonged outpatient phenobarbital in the absence of ongoing seizures, as prophylactic antiseizure medications do not prevent late seizures 2

Evidence Against Prophylactic Continuation

Risk scores should not be used to guide continuation of antiepileptic drugs in the absence of evidence that they prevent late seizures 2. Multiple meta-analyses have demonstrated that seizure prophylaxis does not prevent either early (<14 days) or long-term seizures 2.

Specific Evidence:

• Prophylactic antiseizure drugs are not associated with preventing late seizures after brain injury 2
• Cognitive function might be negatively affected by prolonged antiseizure medication exposure 2
• Reduced phenobarbital burden after implementing continuous EEG monitoring was associated with improved outcomes 1

Common Pitfalls to Avoid

Critical Mistakes:

• Do not continue antiseizure medications "just in case" without documented ongoing seizures, as this exposes the infant to unnecessary medication burden without proven benefit 2, 1
• Do not discharge on phenobarbital alone for prolonged periods based solely on HIE diagnosis, as this represents prophylactic use without evidence of efficacy 2
• Do not stop phenobarbital first, as its long half-life provides protective coverage while discontinuing levetiracetam 2
• Do not assume seizure-free status without adequate EEG monitoring, as 14% of infants without clinical seizures may have electrographic seizures 1

Monitoring Requirements Before Discontinuation

Ensure adequate EEG monitoring has been completed before making discontinuation decisions:

• Minimum 48 hours of continuous monitoring detects 94% of electrographic seizures 2
• 72 hours of monitoring is optimal for neonates with HIE undergoing therapeutic hypothermia 1
• Clinical assessment alone is insufficient, as subclinical seizures occur in a significant proportion of infants 1

Special Considerations for Moderate HIE

Moderate HIE has better outcomes with therapeutic hypothermia (33% reduction in death or major neurodevelopmental disability, RR 0.67) compared to severe HIE 4, 5. This favorable prognosis supports earlier medication discontinuation in seizure-free infants, as the underlying brain injury is less severe and ongoing seizure risk is lower.