How should I manage a 2.5‑year‑old girl (~14.5 kg) who developed frequent blinking movements after starting levetiracetam (Keppra) for a seizure two weeks ago?

Management of Levetiracetam-Induced Behavioral Side Effects in a 2.5-Year-Old

Discontinue levetiracetam immediately and transition to an alternative antiepileptic medication, as the frequent blinking movements represent a behavioral adverse effect (tics) that is well-documented with levetiracetam use in pediatric patients.

Understanding the Clinical Presentation

The blinking tics that developed after starting levetiracetam are consistent with non-psychotic behavioral disorders, which occur in 5% of levetiracetam-treated patients compared to 0% of placebo patients in clinical trials 1. In pediatric populations specifically, behavioral symptoms are strongly associated with levetiracetam treatment 1. These tics represent a drug-induced adverse effect rather than seizure activity, and continuation of the medication will likely perpetuate or worsen these symptoms 1.

Levetiracetam-induced seizure aggravation (LISA) and behavioral side effects can occur across all age groups and epilepsy types, manifesting as increased seizure frequency, status epilepticus, or—as in this case—new behavioral symptoms like tics 2. The literature documents that reducing or stopping levetiracetam decreased seizures and behavioral symptoms in affected patients 2.

Immediate Management Steps

1. Discontinue Levetiracetam Gradually

• Taper levetiracetam over 1–2 weeks rather than stopping abruptly, as antiepileptic drugs including levetiracetam should be withdrawn gradually to minimize the potential for increased seizure frequency 1.
• Monitor closely during the taper for any breakthrough seizure activity 1.

2. Transition to an Alternative Antiepileptic Drug

For a 2.5-year-old child (14.5 kg) with a single seizure episode two weeks ago, consider the following evidence-based alternatives:

• Valproate is contraindicated in this female child of any age due to significantly increased risks of fetal malformations and neurodevelopmental delay that would affect her throughout her reproductive years 3.

• Phenobarbital 3–5 mg/kg/day divided twice daily is a reasonable alternative for pediatric seizure management, though it carries risks of sedation and behavioral effects 4.

• Lacosamide may be considered for children ≥4 years old with focal-onset seizures, offering minimal drug-drug interactions and a favorable side effect profile without the cognitive impairment or behavioral issues seen with levetiracetam 5. However, this child is only 2.5 years old, making lacosamide off-label.

• Consider observation without chronic antiepileptic therapy if this was truly a first unprovoked seizure, as the number needed to treat to prevent one recurrence within two years is 14, and initiating antiepileptic drugs after a single seizure carries significant risk of adverse effects that may outweigh benefits 3.

3. Evaluate Whether Long-Term Antiepileptic Therapy Is Indicated

• Do not initiate or continue antiepileptic drug therapy after a first unprovoked seizure unless specific high-risk features are present 3.
• Arrange outpatient EEG to assess seizure recurrence risk, as an abnormal EEG predicts higher risk of recurrence 3.
• Obtain neuroimaging (MRI preferred over CT in non-emergent settings) to evaluate for structural epileptogenic lesions, particularly in temporal and orbitofrontal regions 3.

Critical Monitoring During Transition

• Watch for withdrawal seizures during the levetiracetam taper, as abrupt discontinuation increases seizure risk 1.
• Monitor for resolution of tics after levetiracetam discontinuation; behavioral symptoms typically improve or resolve completely once the medication is stopped 2.
• Ensure close outpatient neurology follow-up within 1–2 weeks to reassess seizure control and behavioral symptoms 3.

Common Pitfalls to Avoid

• Do not continue levetiracetam hoping the tics will resolve spontaneously—behavioral adverse effects are well-documented with levetiracetam and typically require medication discontinuation 1, 2.
• Do not abruptly stop levetiracetam without a taper, as this increases the risk of withdrawal seizures 1.
• Do not assume the tics represent seizure activity—these are behavioral side effects of the medication, not epileptic phenomena 1.
• Do not automatically start another antiepileptic drug without first determining whether long-term therapy is truly indicated after a single seizure 3.

Evidence Strength and Nuances

The FDA drug label explicitly documents that behavioral symptoms including tics, aggression, and irritability are associated with levetiracetam treatment in pediatric patients, with non-psychotic behavioral disorders occurring in 5% of treated patients versus 0% of placebo 1. This represents high-quality, regulatory-grade evidence directly applicable to this case.

Recent literature confirms that levetiracetam-induced adverse effects can manifest across all age groups and that discontinuation leads to symptom improvement 2. The 2025 systematic review emphasizes that clinicians should consider levetiracetam-induced problems in the differential diagnosis of any new symptoms following treatment initiation 2.

The decision to pursue long-term antiepileptic therapy after a single seizure should be individualized based on EEG findings, neuroimaging results, and seizure recurrence risk factors 3.