What is the evidence supporting the use of 2 or 3 antiepileptic drugs (AEDs) in children with epilepsy who have failed initial monotherapy?

Evidence for Combination Antiepileptic Drug Therapy in Pediatric Epilepsy

Direct Answer

Combination therapy with 2 antiepileptic drugs should be considered only after failure of 1-2 adequate monotherapy trials in children with epilepsy, while combinations of 3 drugs may benefit a small subset of patients, but combinations of 4 or more drugs are unlikely to provide additional seizure control and should be avoided. 1

When to Initiate Combination Therapy

After Monotherapy Failure

• Start with monotherapy using carbamazepine for focal onset seizures or valproic acid for generalized seizures in children, as recommended by the American Academy of Pediatrics 2
• Consider adding a second AED only after documented failure of 1-2 different monotherapy regimens due to lack of efficacy (not intolerance alone) 1
• Approximately 60% of children with epilepsy will achieve seizure control on their first or second monotherapy trial, meaning the remaining 40% may require combination therapy 3

Evidence for Two-Drug Combinations

• A combination of two AEDs can achieve seizure freedom in patients who failed monotherapy, with evidence supporting mechanistically rational combinations 1
• High-certainty evidence from network meta-analysis shows that for focal seizures, lamotrigine and levetiracetam perform best as monotherapy options, making them logical first choices before considering combination therapy 4
• For generalized onset seizures, sodium valproate remains superior to other treatments, though lamotrigine or levetiracetam are suitable alternatives, particularly for girls of childbearing potential where valproate must be avoided 2, 4

Evidence for Three-Drug Combinations

Limited Benefit Beyond Two Drugs

• A few patients will become seizure-free with a combination of three AEDs, but this represents a small minority 1
• Treatment with combinations of four or more AEDs is unlikely to be successful and should be avoided 1
• The diminishing returns with each additional AED reflect the reality that approximately 40% of epilepsy patients have pharmacoresistant disease that will not respond to additional medications 3

Rational Drug Selection for Combinations

Mechanistic Approach

• Combine AEDs with different mechanisms of action rather than similar mechanisms, as this approach is more likely to be successful 5
• The combination of lamotrigine and valproate has demonstrated synergistic efficacy, representing the best-studied rational combination 5
• However, avoid valproate in girls and women of childbearing potential due to teratogenic risks 2

Specific Pediatric Considerations

• For children with intellectual disability, use valproic acid or carbamazepine instead of phenytoin or phenobarbital due to lower risk of behavioral adverse effects 2
• Phenobarbital as a cost-effective alternative should be reserved for situations where availability of first-line agents can be assured 2

Critical Pitfalls to Avoid

Drug Load and Toxicity

• Avoid excessive drug load when combining AEDs, as this is associated with increased toxicity without proportional benefit 1
• Monitor for cumulative adverse effects including drowsiness/fatigue, headache, gastrointestinal disturbances, dizziness, and rash, which are common across all AEDs 4

Pharmacokinetic Interactions

• Be aware that older AEDs (phenytoin, carbamazepine, phenobarbital) cause complex pharmacokinetic drug interactions that complicate combination therapy 1
• Newer AEDs like lamotrigine, levetiracetam, and gabapentin have fewer pharmacokinetic interactions, making them preferable for combination regimens 4

Inappropriate Combinations

• Do not combine drugs with similar mechanisms of action, as this provides no mechanistic advantage 5
• Do not progress to 4 or more drug combinations, as evidence shows this is futile 1

Treatment Algorithm

Step 1: Initial Monotherapy

• Focal seizures: Start carbamazepine 2
• Generalized seizures: Start valproic acid (avoid in females of childbearing potential) 2

Step 2: Second Monotherapy Trial

• Focal seizures: Switch to lamotrigine or levetiracetam 4
• Generalized seizures: Switch to lamotrigine or levetiracetam if valproate contraindicated or failed 4

Step 3: Two-Drug Combination

• Add a second AED with different mechanism of action after 1-2 failed monotherapy trials 1, 5
• Consider lamotrigine + valproate combination for synergistic effect (if valproate not contraindicated) 5

Step 4: Three-Drug Combination (Rarely)

• Consider only in highly selected patients who showed partial response to two-drug combination 1
• Reassess diagnosis and compliance before adding third drug 1

Step 5: Discontinuation Consideration

• Consider discontinuation of AEDs after 2 seizure-free years rather than indefinitely adding medications 2

Quality of Evidence

The evidence supporting combination therapy is largely empirical rather than based on robust randomized controlled trials 1. The network meta-analysis providing high-certainty evidence for monotherapy choices included 14,789 participants from 39 trials, but specific evidence for optimal combination strategies remains limited 4. Current practice recommendations for combination therapy are based on moderate-quality observational data and expert consensus 1, 5.