First-Line Treatment for Absence Epilepsy
Ethosuximide is the optimal first-line treatment for childhood absence epilepsy when absence seizures occur in isolation, offering superior efficacy (45% seizure freedom at 12 months) with fewer attentional side effects compared to alternatives. 1, 2, 3
Treatment Selection Algorithm
For Pure Absence Seizures (No Other Seizure Types)
Ethosuximide should be the initial empirical monotherapy for children and adolescents with typical absence seizures occurring in isolation, as it is FDA-approved specifically for absence (petit mal) epilepsy control. 1, 3
A landmark randomized controlled trial of 453 children demonstrated that ethosuximide achieved 45% seizure freedom at 12 months compared to only 21% with lamotrigine (P < 0.001), establishing clear superiority. 2, 3
Ethosuximide causes significantly less attentional dysfunction (33% of patients) compared to valproate (49% of patients; P = 0.03), making it preferable for school-age children where cognitive function is critical. 3
For Absence Seizures Plus Generalized Tonic-Clonic Seizures
Valproate becomes the preferred first-line agent when absence seizures coexist with generalized tonic-clonic seizures, as ethosuximide is ineffective against tonic-clonic seizures. 4, 2, 5
Valproate is FDA-approved for both simple and complex absence seizures and demonstrates 44% seizure freedom at 12 months—equivalent to ethosuximide for absence control—while also controlling tonic-clonic seizures in 70% of patients. 4, 3, 5
Valproate controls absences in approximately 75% of patients overall, with broad-spectrum efficacy across multiple seizure types. 5
Second-Line and Alternative Options
When First-Line Agents Fail
Lamotrigine represents the third-choice option after ethosuximide and valproate, with demonstrated efficacy in both add-on and monotherapy for childhood absence epilepsy, though significantly less effective than the other two agents (21% seizure freedom vs. 44-45%). 2, 3, 6
If any of the three drugs (ethosuximide, valproate, or lamotrigine) fails as monotherapy, one of the other two should be tried before considering combination therapy. 5, 7
Low-dose lamotrigine added to valproate may have dramatic beneficial effects in resistant cases, representing an effective combination strategy. 5
Additional Adjunctive Options
Clonazepam may be useful as adjunctive therapy, particularly for absences with myoclonic components. 5
Acetazolamide can serve as an adjunctive drug in refractory cases. 5
Critical Contraindications and Pitfalls
Medications That Worsen Absence Seizures
Never use carbamazepine for absence epilepsy, as it may paradoxically worsen absence seizures despite being effective for other seizure types. 7
Phenytoin, primidone, and phenobarbital are only partially effective at best and should be avoided as first-line agents. 7
Oxcarbazepine and vigabatrin may worsen absence seizures and should be avoided. 7
Tiagabine may induce absence status epilepticus and is contraindicated. 7
Special Population Considerations
Avoid valproate in women of childbearing potential when possible due to significant teratogenicity risks and neurodevelopmental effects on the fetus, despite its high efficacy. 7
Consider ethosuximide or lamotrigine as alternatives in young women, though lamotrigine's safety in pregnancy requires further confirmation. 7
Valproate causes weight gain in many patients, which may be unacceptable to adolescents and young adults. 7
Tolerability Profile Comparison
Treatment failure due to intolerable adverse events occurred most frequently with valproate (33%) compared to ethosuximide (25%) and lamotrigine (20%) in the definitive comparative trial. 2, 3
The superior tolerability of ethosuximide, combined with its efficacy, reinforces its position as optimal initial therapy for pure absence epilepsy. 2, 3
Monitoring and Treatment Goals
Hyperventilation testing can precipitate typical absences in approximately 90% of untreated patients, serving as a useful diagnostic and monitoring tool. 5
Treatment success should be defined as complete seizure freedom without intolerable adverse effects, not merely seizure reduction. 3
EEG normalization and negative hyperventilation testing represent important secondary outcome measures beyond clinical seizure freedom. 5