Adult on levetiracetam (Keppra) develops involuntary lip‑smacking—is this a seizure automatism or a drug side effect, and how should the levetiracetam dose be adjusted?

Lip-Smacking on Levetiracetam: Seizure Automatism vs. Drug Side Effect

In an adult on levetiracetam who develops involuntary lip-smacking, this is most likely a focal seizure with automatism (indicating breakthrough seizure activity) rather than a drug side effect, and the levetiracetam dose should be increased to 30 mg/kg/day (typically 2000–3000 mg/day in divided doses) after confirming compliance and ruling out precipitating factors.

Clinical Reasoning: Why This Is Likely a Seizure

Lip-smacking is a classic automatism of focal (temporal lobe) seizures and is not a recognized adverse effect of levetiracetam. 1, 2 The documented behavioral side effects of levetiracetam include agitation, hostility, irritability, mood disturbances, and rarely psychosis—but not involuntary oral movements or automatisms. 3, 2, 4

Documented Levetiracetam Side Effects (What This Is NOT)

• Behavioral/psychiatric: Agitation, hostility, irritability, mood symptoms, psychosis (13.3% of adults experience psychiatric effects; only 0.7% severe). 3, 4
• CNS-related: Somnolence, asthenia, dizziness, headache—all sedative effects, not movement disorders. 5, 2, 4
• Pediatric-specific: Nervousness and hostility are more common in children. 2, 4

Movement disorders and automatisms are conspicuously absent from the levetiracetam adverse effect profile across all major reviews and clinical trials. 5, 2, 6, 4

Immediate Diagnostic Steps

1. Assess for Breakthrough Seizure Activity

• Obtain urgent EEG to detect ongoing electrical seizure activity, as nonconvulsive seizures occur in >50% of cases with altered consciousness and are often only detectable by EEG. 1
• Document seizure characteristics: Frequency, duration, associated symptoms (altered awareness, postictal confusion), and any witnessed generalized convulsive activity. 1

2. Identify Precipitating Factors

Before escalating therapy, systematically evaluate for reversible causes of breakthrough seizures: 1

• Medication non-compliance (most common cause—check serum levetiracetam levels). 1
• Sleep deprivation, alcohol use, intercurrent illness. 1
• Metabolic derangements: Hypoglycemia, hyponatremia. 1
• Drug interactions or withdrawal syndromes. 1

3. Check Serum Levetiracetam Level

• Verify therapeutic dosing and compliance before assuming treatment failure. 1
• Levetiracetam has linear pharmacokinetics with 66% renal excretion unchanged; subtherapeutic levels usually indicate non-adherence. 6

Dose Optimization Algorithm

Current Evidence-Based Dosing

If seizures persist despite adequate first-line dosing, escalate levetiracetam to the maximum effective dose before adding a second agent. 1, 7, 8

Standard Maintenance Dosing

• Initial/standard dose: 1000 mg/day (500 mg twice daily). 5
• Therapeutic range: 1000–3000 mg/day in divided doses. 5, 2
• Optimal dose for refractory seizures: 30 mg/kg/day (approximately 2000–3000 mg/day for average adults). 1, 7, 8

Evidence for Higher Dosing

• Levetiracetam 3000 mg/day significantly increased seizure-free rates in refractory partial seizures, while 1000–2000 mg/day showed unclear effects on seizure freedom. 5
• In status epilepticus, 30 mg/kg IV (2000–3000 mg) achieves 68–73% efficacy, establishing this as the evidence-based target dose. 1, 8
• Doses up to 60 mg/kg/day have been safely administered in pediatric and young adult populations without serious adverse events. 1, 7

Practical Dose Escalation

1. Confirm current dose and compliance (check serum level). 1
2. If on <3000 mg/day, increase to 1500 mg twice daily (3000 mg/day total). 7, 8, 5
3. Titrate gradually (increase by 500–1000 mg/day every 1–2 weeks) to minimize CNS side effects. 5, 2
4. Monitor for behavioral changes (irritability, hostility) during titration, especially in patients with prior psychiatric history. 3, 4

When to Add a Second Agent

Only consider adding a second antiepileptic drug after levetiracetam has been optimized to maximum tolerated dose (typically 3000 mg/day) and compliance is confirmed. 1

Preferred Adjunctive Options

• Lamotrigine: Requires slow titration over several weeks to reduce rash risk. 1
• Lacosamide: Available IV for acute management; comparable tolerability to oral formulation. 1
• Avoid valproate in women of childbearing potential due to teratogenicity and neurodevelopmental risks. 1

Critical Pitfalls to Avoid

1. Misattributing Seizure Symptoms to Drug Side Effects

Automatisms (lip-smacking, chewing, picking movements) are seizure phenomena, not medication adverse effects. 1, 2 Stopping or reducing levetiracetam in this scenario will worsen seizure control.

2. Premature Polytherapy

Adding a second agent before optimizing levetiracetam monotherapy increases drug interactions, adverse event burden, and non-compliance risk. 1 The number needed to treat (NNT) for preventing one recurrence with early AED initiation is only 14, highlighting limited benefit of premature escalation. 1

3. Ignoring Compliance Issues

Non-compliance is the most common cause of breakthrough seizures. 1 Always verify adherence with serum levels before assuming treatment failure.

4. Overlooking Behavioral Side Effects

Levetiracetam causes behavioral disturbances in 13.3% of adults, with severe symptoms (depression, agitation, hostility) in 0.7%. 3 Risk is higher in patients with prior psychiatric history or in children. 3, 4 If behavioral symptoms emerge, consider switching to lamotrigine or lacosamide rather than adding a second agent. 1

Monitoring After Dose Adjustment

• Neurological assessments every 15 minutes during the first 2 hours after any IV loading dose, then every 30 minutes for 6 hours, then hourly until 24 hours. 8
• Outpatient follow-up: Question about seizure occurrences at each visit; arrange outpatient EEG to assess treatment efficacy. 1
• Monitor for delayed behavioral adverse effects (somnolence, irritability, mood changes), which can emerge beyond the initial titration period. 3, 4

Renal Dose Adjustments

Levetiracetam clearance is decreased in renal impairment; adjust doses based on creatinine clearance: 8

• CrCl >80 mL/min: 500–1500 mg every 12 hours (standard dosing).
• CrCl 50–80 mL/min: 500–1000 mg every 12 hours.
• CrCl 30–50 mL/min: 250–750 mg every 12 hours.
• CrCl <30 mL/min: 250–500 mg every 12 hours.
• ESRD on dialysis: 500–1000 mg every 24 hours.