How does antiepileptic drug (AED) management differ between children with focal epilepsy and those with generalized epilepsy?

Antiepileptic Drug Management: Focal vs. Generalized Epilepsy in Children

In children with focal epilepsy, antiepileptic drug (AED) selection prioritizes newer agents like lamotrigine, oxcarbazepine, or levetiracetam for their superior tolerability while maintaining efficacy comparable to carbamazepine, whereas children with generalized epilepsy require syndrome-specific treatment with valproic acid remaining the most effective broad-spectrum option, though ethosuximide is preferred for pure absence seizures. 1, 2

Key Differences in Drug-Resistance Patterns

The fundamental distinction begins with prognosis and treatment trajectory:

• Focal epilepsies demonstrate significantly higher drug resistance rates (~30% fail two AEDs) compared to generalized epilepsies, making surgical evaluation a critical consideration earlier in the treatment algorithm for refractory focal cases. 3
• Children with focal epilepsy have approximately 20% drug resistance risk with associated poor long-term cognitive and psychosocial outcomes. 3
• Focal epilepsy surgery achieves seizure freedom in approximately 65% of appropriately selected drug-resistant cases, whereas generalized epilepsies rarely have surgical options. 3

Focal Epilepsy: AED Selection Algorithm

First-Line Monotherapy Options

• Lamotrigine demonstrates the best tolerability profile with 81% probability of being optimal for minimizing treatment discontinuation due to adverse effects, while maintaining efficacy equivalent to carbamazepine for focal seizures. 4
• Oxcarbazepine is recommended as first-line treatment for localization-related epilepsy with partial-onset seizures, offering similar efficacy to phenytoin and valproic acid but with better tolerability. 2, 5
• Levetiracetam achieves 73% seizure freedom rates in children with partial epilepsy, comparable to carbamazepine's 65%, with fewer adverse events (45% vs. 70%). 6
• Newer AEDs (levetiracetam, lamotrigine, oxcarbazepine, topiramate) should be prioritized over carbamazepine despite carbamazepine's historical "gold standard" status, as they demonstrate equivalent efficacy with superior safety profiles and fewer drug interactions. 4

Critical Prescribing Considerations for Focal Epilepsy

• Carbamazepine shows the greatest risk of patient discontinuation due to intolerable adverse reactions among all AEDs studied. 4
• Oxcarbazepine causes acute hyponatremia in 2.7% of patients, though usually asymptomatic, requiring monitoring. 5
• AED initiation can be delayed until a second seizure in most children with focal epilepsy and may be avoided altogether in self-limited childhood focal epilepsies. 1

Generalized Epilepsy: Syndrome-Specific Treatment

Absence Seizures (Childhood Absence Epilepsy)

• Ethosuximide and valproic acid are superior to lamotrigine for absence seizures, making them the preferred first-line agents. 1
• Lamotrigine is considered first-line for generalized epilepsies with primarily absence seizures in some protocols, though this conflicts with evidence showing ethosuximide/valproate superiority. 2

Mixed Generalized Epilepsies

• For Lennox-Gastaut syndrome or juvenile myoclonic epilepsy, zonisamide or topiramate are first-line agents. 2
• Valproic acid remains the most effective drug for generalized epilepsies with a broad range of seizure types, maintaining its role despite newer alternatives. 1

Epileptic Spasms (West Syndrome)

• Treatment selection is etiology-dependent: vigabatrin for tuberous sclerosis, adrenocorticotropic hormone (ACTH) for cryptogenic cases, and zonisamide for severe symptomatic etiologies other than tuberous sclerosis. 2

Imaging and Surgical Evaluation Differences

Focal Epilepsy Imaging Requirements

• MRI with dedicated epilepsy protocols (3T scanners, 1mm isotropic voxels, high-resolution coronal hippocampal sequences) is essential for focal epilepsy to identify structural lesions including hippocampal sclerosis, tumors, focal cortical dysplasia, and vascular malformations. 3, 7
• FDG-PET and ictal/interictal SPECT are valuable adjuncts in drug-resistant focal epilepsy, particularly for non-lesional cases or multifocal abnormalities, to localize seizure onset for surgical planning. 3
• Approximately 50% of CT examinations show positive findings in focal epilepsy, contrasting sharply with generalized seizures. 3

Generalized Epilepsy Imaging Approach

• MRI is rarely indicated in neurologically normal children with generalized seizures because positive intracranial findings occur in only 2% of low-risk patients, given the genetic underpinnings of most generalized epilepsies. 3, 8, 7
• CT shows positive findings in only 6% of generalized seizure cases. 3
• For atypical presentations or neurologically abnormal children with generalized seizures, MRI should be considered to evaluate for structural causes. 9

Treatment Failure and Escalation Pathways

When Two AEDs Fail

• After failure of two appropriate AEDs at therapeutic doses in focal epilepsy, immediate consideration of epilepsy surgery, vagal nerve stimulation, or ketogenic diet is warranted rather than continuing medication trials. 1, 2
• This surgical evaluation threshold is specific to focal epilepsy and does not apply to generalized epilepsies where surgical options are limited. 3

Monotherapy vs. Polytherapy

• Single drug therapy (monotherapy) is the goal for both focal and generalized epilepsy, associated with better compliance, fewer adverse effects, and lower cost. 2
• AED therapy achieves seizure freedom in approximately 70% of all children with epilepsy. 1

Common Pitfalls and Caveats

• Certain AEDs may aggravate specific seizure types—this is a critical consideration when selecting therapy, particularly avoiding carbamazepine in certain generalized epilepsy syndromes. 2
• Oxcarbazepine has clinically significant interactions with phenytoin and oral contraceptives, requiring monitoring in adolescent females. 5
• The presence of any focal feature to a seizure is independently associated with clinically relevant abnormalities on neuroimaging, making recognition critical for appropriate workup. 7
• Focal seizures have recurrence rates up to 94%, considerably higher than generalized seizures at 72%, influencing treatment initiation decisions. 7

AED Discontinuation Considerations

• After 2 years or more of seizure freedom, slow weaning over 6 weeks or longer should be considered if recurrence risk is acceptable. 1
• Approximately 70% of patients remain seizure-free after discontinuation, and most who experience recurrence achieve control with restarting an AED. 1