What are the alternative treatments for absence seizures when Keppra (levetiracetam) fails?

Treatment of Absence Seizures When Levetiracetam (Keppra) Fails

When levetiracetam fails to control absence seizures, switch to either ethosuximide or valproate as these are the first-line agents with proven efficacy for absence epilepsy, not levetiracetam.

Why Levetiracetam Often Fails for Absence Seizures

Levetiracetam lacks a specific indication for absence epilepsy and demonstrates poor efficacy in clinical practice 1. In a clinical study of 72 children with absence epilepsy treated with levetiracetam, the medication was discontinued in 74% of patients due to incomplete seizure control (59%) or intolerable side effects (41%) 1. Only about one-quarter of children with absence epilepsy became seizure free with levetiracetam 1. This high failure rate underscores that levetiracetam should not be considered a first-line agent for absence seizures.

Recommended Alternative Treatments

First-Line Options After Levetiracetam Failure

Ethosuximide is the optimal choice for pure absence seizures based on the highest quality evidence 2:

• In a large randomized controlled trial of 453 children with childhood absence epilepsy, ethosuximide achieved seizure freedom in 45% of patients at 12 months, significantly superior to lamotrigine (21%, P < 0.001) and equivalent to valproate (44%) 2
• Ethosuximide had fewer intolerable adverse events (25%) compared to valproate (33%) and lamotrigine (20%) 2
• Ethosuximide controls absences in approximately 70% of patients 3

Valproate should be preferred if the patient has both absence and generalized tonic-clonic seizures 2:

• Valproate controls absences in 75% of patients, generalized tonic-clonic seizures in 70%, and myoclonic jerks in 75% 3
• Ethosuximide is ineffective for tonic-clonic seizures, making it unsuitable as monotherapy when multiple seizure types coexist 3, 2
• Valproate achieved 44% seizure freedom at 12 months, equivalent to ethosuximide 2

Important Contraindications and Warnings

Avoid valproate in females of childbearing potential due to teratogenicity risk 3:

• Valproate carries significant risk of birth defects and should be avoided in women who may become pregnant 4
• If valproate must be used in women, consider lower doses and extended-release preparations to minimize adverse effects 5

Second-Line and Combination Therapy

Lamotrigine can be considered but has lower efficacy 2:

• Lamotrigine achieved only 21% seizure freedom at 12 months, significantly inferior to both ethosuximide and valproate 2
• Lamotrigine may control absences and generalized tonic-clonic seizures in 50-60% of patients but may worsen myoclonic jerks 3
• Skin rashes are common with lamotrigine 3

Combination therapy for resistant cases 3:

• Low doses of lamotrigine added to valproate may have dramatic beneficial effects 3
• Combinations of ethosuximide, valproate, or lamotrigine may be needed for resistant absence seizures 3
• Clonazepam is particularly useful for absences with myoclonic components 3
• Acetazolamide may serve as a useful adjunctive drug 3

Clinical Algorithm for Treatment Selection

1. Determine seizure types present:

   • Pure absence seizures only → Choose ethosuximide
   • Absence + generalized tonic-clonic seizures → Choose valproate (unless female of childbearing potential)
   • Absence + myoclonic jerks → Choose valproate

2. Consider patient-specific factors:

   • Female of childbearing potential → Avoid valproate; choose ethosuximide or consider lamotrigine despite lower efficacy
   • Concerns about weight gain → Prefer ethosuximide over valproate
   • History of psychiatric symptoms → Monitor carefully with any agent

3. If monotherapy fails:

   • Add lamotrigine to valproate at low doses 3
   • Consider clonazepam for myoclonic components 3
   • Trial acetazolamide as adjunctive therapy 3

Common Pitfalls to Avoid

Do not continue escalating levetiracetam doses indefinitely 1:

• When effective, levetiracetam controls absence epilepsy at relatively low doses (29 ± 13 mg/kg/day) 1
• Patients requiring continued dose escalation (mean 42 ± 20 mg/kg/day in treatment failures) should prompt early medication transition 1

Do not use enzyme-inducing anticonvulsants (phenytoin, carbamazepine, phenobarbital) 4:

• These agents are no longer recommended due to side-effect profiles and drug interactions 4
• They may also worsen absence seizures 6

Recognize that many antiepileptic drugs can aggravate absence seizures 6:

• Both old and new antiepileptic drugs may worsen typical and atypical absence seizures 6
• Monitor closely for seizure exacerbation when switching medications