How to manage a patient with focal seizures on levetiracetam (750 mg bd) and perampanel (2 mg od) experiencing dizziness, irritability, gait abnormalities, and anorexia?

Management of Adverse Effects in a Patient on Levetiracetam and Perampanel

The patient's symptoms of dizziness, irritability, gait abnormalities, and anorexia are likely adverse effects from the current antiepileptic regimen, particularly from perampanel, and warrant immediate dose adjustment by reducing or temporarily holding perampanel while maintaining levetiracetam for seizure control. 1, 2

Identifying the Culprit Medication

The symptom constellation strongly suggests perampanel-related adverse effects:

• Dizziness is the most common adverse event with perampanel, occurring more frequently than with placebo in clinical trials 2
• Irritability and hostile behavior are well-documented perampanel adverse effects, particularly problematic in younger patients 1, 2
• Gait abnormalities align with perampanel's known risk of ataxia and falls, especially concerning in elderly patients but relevant across age groups 2
• Anorexia is a documented adverse effect of levetiracetam (3% vs 2% placebo) 1

The FDA labeling for levetiracetam specifically lists dizziness (9% vs 4% placebo), irritability, and anorexia as treatment-emergent adverse events 1. However, perampanel at 2 mg daily is more likely the primary contributor to dizziness and gait issues based on its adverse event profile 2.

Immediate Management Algorithm

Step 1: Assess Severity and Safety Risk

• Evaluate fall risk immediately given gait abnormalities 2
• Screen for suicidal ideation or severe behavioral changes, as both medications carry warnings for psychiatric symptoms 1
• Check if symptoms interfere with activities of daily living or pose injury risk

Step 2: Medication Adjustment Strategy

For perampanel (current dose 2 mg daily):

• Temporarily hold or reduce to 1 mg daily if symptoms are moderate to severe, as slower titration minimizes adverse events 2
• Consider bedtime dosing if not already implemented, which reduces dizziness risk 2
• Reassess after 1-2 weeks; if symptoms resolve, may cautiously re-titrate at 1 mg increments every 2-4 weeks 2

For levetiracetam (current dose 750 mg BD = 1500 mg/day):

• Maintain current dose initially, as it provides seizure control and the dose is within therapeutic range 3
• If anorexia is severe or irritability persists after perampanel adjustment, consider reducing levetiracetam by 250 mg BD (to 500 mg BD) 1

Step 3: Monitor for Drug Interactions

• Check if patient is on enzyme-inducing AEDs (carbamazepine, phenytoin, phenobarbital), as these lower perampanel levels and may have contributed to the 2 mg dose selection 1, 2
• Review all concomitant medications that may worsen dizziness (antihypertensives, sedatives, other CNS depressants) 2

Evidence-Based Rationale

Perampanel tolerability is dose-dependent: Post hoc analysis of the FAME trial showed significantly higher responder rates with low-dose perampanel (4-6 mg: 88.6%) versus high-dose (8-12 mg: 40.0%), with better tolerability at lower doses 4. Even at 2 mg, individual susceptibility varies.

Levetiracetam's behavioral effects: FDA labeling documents that levetiracetam causes behavioral changes including aggression, agitation, anger, anxiety, and irritability 1. The drug also causes dizziness (9% vs 4% placebo) and somnolence (15% vs 8% placebo) 1.

Combined toxicity consideration: When perampanel is added to levetiracetam, the 50% responder rate was 85% in one analysis, but both drugs share overlapping adverse effect profiles (dizziness, irritability, somnolence) 5, 4. The additive CNS effects may be contributing to this patient's symptoms.

Critical Pitfalls to Avoid

• Do not abruptly discontinue either medication without a taper plan, as this risks breakthrough seizures in a patient with structural epilepsy (post-gliotic frontal region) 6
• Do not increase doses in an attempt to improve seizure control while these adverse effects are present; this will worsen tolerability 2
• Do not attribute all symptoms to "expected side effects" without intervention; these symptoms significantly impact quality of life and medication adherence 7
• Do not overlook psychiatric screening; both medications carry FDA warnings for suicidal ideation and behavioral changes requiring immediate reporting 1

Alternative Considerations if Symptoms Persist

If reducing perampanel does not resolve symptoms within 2-3 weeks:

• Consider switching from levetiracetam to an alternative (valproate, lamotrigine, or lacosamide) as levetiracetam's behavioral side effects may be contributing 1, 5
• Evaluate whether perampanel should be discontinued entirely and replaced with a better-tolerated adjunctive agent 7
• Reassess seizure control; if patient has been seizure-free for extended period, discuss potential for medication reduction with neurology 6

The priority is restoring quality of life while maintaining seizure control, which requires immediate dose modification rather than continuing current regimen.