What to do for a patient on perampanel (Perampanel) and levetiracetam (Levetiracetam) for post-traumatic seizures due to subdural hematoma (SDH) who is experiencing neurological adverse effects?

Management of Neurological Adverse Effects in a Patient on Perampanel and Levetiracetam for Post-Gliotic Seizures

Reduce the perampanel dose immediately or discontinue it entirely, as perampanel is the most likely culprit for neurological adverse effects in this dual-therapy regimen, with dizziness, gait disturbance, somnolence, and aggression being the most common neurological side effects. 1, 2, 3

Immediate Assessment and Intervention

Identify the Specific Neurological Adverse Effects

• Common perampanel-related neurological adverse effects include: dizziness (37-39%), gait disturbance/ataxia/falls (20%), somnolence, aggressive mood and behavior (24%), irritability, and balance disorders 1, 2, 3
• Levetiracetam adverse effects are typically milder: transient irritability, imbalance, tiredness, or lightheadedness, with only 11% of patients reporting any adverse effects in loading studies [@28@ via 4]
• Perampanel causes treatment discontinuation in 9.5-28.2% of patients due to adverse effects, compared to only 4.8% with placebo, making it the more problematic agent 2, 3

Dose Reduction Strategy for Perampanel

• Slow titration of perampanel significantly reduces adverse events, particularly gait disturbance (0% with slow titration vs 26% with rapid titration) 1
• Reduce perampanel by 2 mg decrements at intervals of at least 1-2 weeks rather than abrupt discontinuation, as this allows assessment of symptom resolution while maintaining some seizure control 1
• Psychiatric adverse effects (depression, aggression) occur more frequently at higher perampanel doses, so dose reduction should be prioritized if these symptoms are present 2, 3

Alternative Management if Seizure Control is Lost

Switch to Alternative Second-Line Agents

• Valproate is the preferred alternative second-line agent with 88% efficacy in controlling refractory seizures and minimal cardiovascular side effects 5
• Dosing for valproate: 30 mg/kg IV loading dose infused at 6 mg/kg per hour, followed by maintenance infusion of 1-2 mg/kg per hour 5
• If valproate is contraindicated (hepatic dysfunction, pregnancy risk), continue levetiracetam monotherapy at optimized doses (30-40 mg/kg loading if needed) 5, 6

Avoid Enzyme-Inducing Antiepileptic Drugs

• Phenytoin, phenobarbital, and carbamazepine should be avoided as they have significant cytochrome P450 effects and higher adverse effect profiles 4
• Non-enzyme-inducing AEDs (levetiracetam, valproic acid, topiramate) are preferred to avoid drug interactions and metabolic complications 4

Monitoring and Follow-Up

Assess for Serious Neurological Complications

• Monitor for suicidality (2.1% incidence with perampanel vs 1.0% with placebo), which requires immediate psychiatric consultation if present 3
• Evaluate for cognitive decline using standardized assessments, as perampanel can cause cognitive side effects that impact quality of life 2
• Check for weight gain (>7% body weight increase in 14.6% of perampanel patients vs 7.1% placebo), which may indicate metabolic adverse effects 2

Seizure Prophylaxis Considerations

• Prophylactic anticonvulsants should only be continued in patients with a history of seizures, not routinely for all post-traumatic cases 4
• Consider discontinuation of anticonvulsants after the perioperative period if the patient had no seizure history prior to the subdural hematoma 4
• Levetiracetam monotherapy at the lowest effective dose is appropriate for long-term seizure prophylaxis in post-traumatic cases with documented seizures 4

Key Clinical Pitfalls to Avoid

• Do not continue both agents at full doses if neurological adverse effects are present, as this unnecessarily exposes the patient to cumulative toxicity 1, 2
• Do not abruptly discontinue perampanel without tapering, as this may precipitate breakthrough seizures 1
• Do not add a third antiepileptic agent before optimizing or discontinuing the offending medication, as polypharmacy increases adverse effect risk 4
• Female patients may experience higher rates of adverse events with perampanel (statistically significant difference, p=0.046), warranting closer monitoring in this population 1