Should levetiracetam (Keppra) be added as a second antiepileptic drug in a patient who experienced a breakthrough seizure requiring hospitalization while on single‑agent therapy?

Should Levetiracetam Be Added as Second Antiepileptic Drug After Breakthrough Seizure Requiring Hospitalization?

Yes, adding levetiracetam as a second antiepileptic drug is appropriate for a patient with breakthrough seizures requiring hospitalization, but only after optimizing the first medication to maximum tolerated dose and confirming medication compliance. 1

Critical First Steps Before Adding a Second Agent

Before escalating to combination therapy, you must systematically rule out reversible causes and verify adequate monotherapy:

• Check serum drug levels of the current antiepileptic medication to confirm therapeutic concentrations and assess compliance, as non-compliance is the most common cause of breakthrough seizures 1
• Search for precipitating factors including sleep deprivation, alcohol use, medication non-compliance, intercurrent illness, hypoglycemia, hyponatremia, and drug toxicity or withdrawal 2, 1
• Optimize the current medication to maximum tolerated dose before adding a second agent, as inadequate dosing often masquerades as treatment failure 1
• Consider EEG monitoring to distinguish true epileptic seizures from psychogenic seizures or detect subclinical seizure activity 1

When to Add Levetiracetam as Second Agent

Adding levetiracetam is indicated when:

• The patient has failed adequate monotherapy at maximum tolerated doses with documented therapeutic drug levels 1
• Compliance has been verified and precipitating factors addressed 1
• Breakthrough seizures persist despite optimization of the first agent 1

Why Levetiracetam Is an Excellent Second Agent

Levetiracetam offers several advantages as adjunctive therapy:

• Minimal drug-drug interactions because it does not induce cytochrome P450 enzymes, making it safer in patients requiring concomitant medications 3, 4, 5, 6
• No clinically significant pharmacokinetic interactions with other antiepileptic drugs 5, 6
• Favorable safety profile with no cognitive impairment or drug-induced weight gain 5, 6
• Rapid and complete absorption with high oral bioavailability and primarily renal elimination 5, 6
• Proven efficacy in reducing seizure frequency in both pediatric and adult patients with refractory partial-onset seizures 5, 6

Evidence for Adjunctive Levetiracetam

Multiple randomized controlled trials demonstrate that adjunctive levetiracetam reduces seizure frequency in patients with refractory partial-onset seizures to a significantly greater extent than placebo 5, 6. The drug is approved worldwide as adjunctive treatment for partial-onset seizures with or without secondary generalization 5, 6.

Practical Dosing Strategy

For chronic epilepsy management (not acute status epilepticus), levetiracetam is typically:

• Started at lower doses and titrated gradually to minimize adverse effects 5, 6
• Dosed twice daily for the immediate-release formulation, though extended-release once-daily formulations exist that may improve compliance 7
• Adjusted based on renal function, as the drug is primarily renally eliminated 5, 6

Important Monitoring Considerations

• Question the patient about seizure occurrences at each follow-up visit to assess treatment efficacy 1
• Obtain serum levels of both agents to ensure therapeutic ranges and assess compliance 1
• Monitor for behavioral adverse effects, as levetiracetam has been associated with irritability and behavioral changes in some patients 3, 5, 6
• Watch for additive sedation when combining with other antiepileptic drugs 3

Critical Pitfalls to Avoid

• Do not add a second agent without first optimizing monotherapy to maximum tolerated doses 1
• Do not assume treatment failure without verifying compliance through drug level monitoring 1
• Do not abruptly discontinue either medication, as gradual tapering is essential to prevent withdrawal seizures 1
• Avoid valproate in women of childbearing potential due to teratogenic risks; levetiracetam is preferred in this population 1, 4

Special Population Considerations

In brain tumor patients, levetiracetam is particularly attractive because it does not induce the P450 system and avoids significant drug interactions with chemotherapy agents 4, 8. Emerging evidence suggests levetiracetam may even increase sensitivity of glioblastoma tumors to temozolomide 8.

In patients with hepatic impairment, levetiracetam may be particularly useful because it lacks hepatic metabolism and has minimal potential for drug interactions 9.

Alternative Second Agents

If levetiracetam is contraindicated or not tolerated, alternative adjunctive agents include:

• Lamotrigine (requires slow titration over several weeks to minimize rash risk) 1
• Lacosamide (available in IV formulation with comparable tolerability to oral) 1