What is the best antiepileptic (Anti-Seizure Medication, ASM) regimen adjustment for a 45-year-old man with nonmotor focal seizures and intellectual disability, currently taking lamotrigine (Lamictal) and levetiracetam (Keppra), experiencing frequent seizures and behavioral issues?

Management of Behavioral Side Effects in a Patient with Focal Seizures and Intellectual Disability

Adding brivaracetam is the best option for this 45-year-old man with focal seizures experiencing behavioral side effects from levetiracetam.

Current Situation Assessment

• 45-year-old male with nonmotor focal seizures and intellectual disability
• Currently on lamotrigine and levetiracetam
• Partial response (2-3 seizures/week vs. 2-3 daily previously)
• Experiencing aggression and anger on levetiracetam
• Previous failed trials: phenobarbital (sedation), phenytoin (gingival hyperplasia), topiramate and zonisamide (ineffective, rash with zonisamide)

Rationale for Adding Brivaracetam

Behavioral Side Effects of Levetiracetam

Levetiracetam is known to cause significant behavioral side effects, particularly in patients with intellectual disability. The FDA label specifically notes that "non-psychotic behavioral disorders (reported as aggression and irritability) occurred in 5% of levetiracetam-treated patients" and "non-psychotic mood disorders (reported as depressed mood, depression, and mood swings) occurred in 6.7% of levetiracetam-treated patients" 1.

Advantages of Brivaracetam

1. Better Behavioral Profile: Brivaracetam has demonstrated fewer and less severe behavioral adverse events compared to levetiracetam in multiple studies 2. This is particularly important for this patient who is already experiencing behavioral issues.

2. Similar Mechanism with Better Tolerability: Brivaracetam is an analog of levetiracetam with 15-30 times greater affinity for SV2A and faster brain permeability, maintaining efficacy while reducing side effects 3.

3. Proven Effectiveness: Real-world evidence from the EXPERIENCE study showed that brivaracetam achieved ≥50% seizure reduction in 36.9% of patients at 12 months, with seizure freedom in 14.9% 4.

4. Smooth Transition: Switching from levetiracetam to brivaracetam can be done at a 10:1-15:1 ratio without titration, allowing for a seamless transition while maintaining seizure control 3.

Why Other Options Are Less Optimal

Changing to Valproate

While valproate is effective for focal seizures 5, it has significant disadvantages:

• Potential for drug interactions with other medications
• Risk of hepatotoxicity requiring monitoring
• Weight gain and metabolic effects
• Not specifically addressing the behavioral issues as effectively as brivaracetam

Adding Perampanel

Perampanel has limitations:

• Associated with its own behavioral side effects including aggression and irritability
• May compound existing behavioral issues
• Requires slow titration which delays therapeutic effect

Discontinuing Levetiracetam without Replacement

Simply discontinuing levetiracetam and continuing lamotrigine monotherapy would:

• Risk breakthrough seizures due to reduced medication coverage
• Fail to optimize seizure control (patient still has 2-3 seizures weekly)
• Not follow the principle of "rational polytherapy" for refractory epilepsy

Implementation Plan

1. Initiate Brivaracetam:

   • Start brivaracetam at a dose equivalent to current levetiracetam (typically 10:1 ratio)
   • Can be initiated without titration when switching directly from levetiracetam

2. Taper Levetiracetam:

   • Gradually taper levetiracetam over 2-4 weeks while maintaining brivaracetam
   • Monitor closely for seizure breakthrough during transition

3. Continue Lamotrigine:

   • Maintain current lamotrigine dose as it appears to be contributing to seizure control
   • No significant interaction expected between lamotrigine and brivaracetam

4. Follow-up Monitoring:

   • Assess behavioral symptoms within 2-4 weeks
   • Monitor seizure frequency
   • Adjust brivaracetam dose as needed for optimal seizure control

Potential Pitfalls and Considerations

• Withdrawal Seizures: Antiepileptic drugs should be withdrawn gradually to minimize the potential of increased seizure frequency 1
• Behavioral Monitoring: While brivaracetam has fewer behavioral side effects than levetiracetam, continue to monitor for any behavioral changes
• Cost and Access: Ensure insurance coverage for brivaracetam as it is a newer medication
• Patient-Specific Factors: Consider the patient's intellectual disability when explaining medication changes to both patient and caregivers

By adding brivaracetam and transitioning away from levetiracetam, we can address both the behavioral side effects and maintain or improve seizure control in this patient with focal epilepsy and intellectual disability.