# Antiepileptic Drugs by Seizure Type

> Which antiepileptic drug is first-line for each seizure type?

Seizure type decides the drug. Map the ILAE classification onto first-line therapy, the mechanisms and toxicities that get tested, and the status epilepticus clock.

First-line antiepileptic therapy follows seizure type: ethosuximide for absence, valproate or levetiracetam for generalized tonic-clonic and myoclonic seizures, and lamotrigine, levetiracetam or carbamazepine for focal seizures. Status epilepticus starts with IV lorazepam. Carbamazepine, phenytoin and gabapentin worsen absence and myoclonic seizures, so classify the seizure before choosing a drug.

## Which antiepileptic drug is first-line for each seizure type?

The ILAE framework splits seizures by where they start: **focal onset** seizures begin in one hemisphere and are graded as **focal aware** (old simple partial) or **focal impaired awareness** (old complex partial), while **generalized onset** seizures engage both hemispheres at once and impair awareness in every subtype except myoclonic. That branch point drives therapy, because narrow-spectrum sodium-channel blockers such as carbamazepine and phenytoin aggravate generalized epilepsies.

Broad-spectrum agents -- valproate, levetiracetam, lamotrigine, topiramate -- cover both categories and are the safe answer when the stem never says where the seizure began; carbamazepine, oxcarbazepine, phenytoin and gabapentin are focal-only.

A focal seizure that spreads is called **focal to bilateral tonic-clonic** and still takes a focal-seizure drug, so the aura outranks the convulsion. Localize it with the logic of [stroke localization](/blog/stroke-localization-usmle).

## Seizure types, EEG findings and first-line drugs

| Seizure Type | Consciousness | Motor Features | EEG | First-Line | Avoid |
| --- | --- | --- | --- | --- | --- |
| Focal aware | Preserved | Jacksonian march, aura | Focal spikes, one lobe | Lamotrigine, levetiracetam | Ethosuximide |
| Focal impaired awareness | Impaired | Automatisms, postictal confusion | Focal temporal sharp waves | Lamotrigine, carbamazepine | Ethosuximide |
| Absence | Brief lapse, no postictal state | Blank stare, hyperventilation-provoked | 3 Hz spike-and-wave | Ethosuximide | Carbamazepine, phenytoin |
| Generalized tonic-clonic | Lost | Tonic then clonic phases, tongue biting | Generalized polyspike-and-wave | Valproate, levetiracetam | Ethosuximide |
| Myoclonic (juvenile myoclonic epilepsy) | Usually preserved | Morning jerks after sleep loss | 4-6 Hz polyspike-and-wave | Valproate; levetiracetam if pregnancy possible | Carbamazepine, phenytoin |
| Atonic (Lennox-Gastaut) | Impaired | Drop attacks, head injury | Slow spike-and-wave under 2.5 Hz | Valproate | Carbamazepine |
| Infantile spasms (West syndrome) | Impaired | Flexor spasm clusters, regression | Hypsarrhythmia | ACTH; vigabatrin in tuberous sclerosis (visual field loss) | Sodium-channel blockers |

Generalized spike-and-wave arises in a thalamocortical loop where T-type calcium currents in thalamic relay neurons fire rhythmic bursts, which is why ethosuximide -- a pure T-type blocker -- controls absence and does nothing for a convulsion. Sodium-channel blockers act on cortical repetitive firing instead, leaving the thalamic pacemaker untouched, so carbamazepine, phenytoin and gabapentin can make absence and myoclonic seizures more frequent. A spike confined to one lobe on EEG marks a cortical generator, and that is the seizure a sodium-channel drug suppresses.

## Antiepileptic drug mechanisms, uses and toxicities

| Drug | Mechanism | Seizure Type | Key Toxicity | Board Pearl |
| --- | --- | --- | --- | --- |
| Ethosuximide | Blocks thalamic T-type calcium channels | Absence only | GI upset, fatigue, headache | Useless in tonic-clonic seizures |
| Valproate | Sodium-channel block, inhibits GABA transaminase | Broad -- absence, tonic-clonic, myoclonic, atonic, focal | Hepatotoxicity, pancreatitis, neural tube defects, hyperammonemia | Broadest spectrum, most teratogenic |
| Phenytoin (IV fosphenytoin) | Prolongs sodium-channel inactivation | Focal, tonic-clonic, status | Gingival hyperplasia, hirsutism, drug-induced lupus, cerebellar atrophy | Zero-order kinetics; narrow therapeutic index |
| Carbamazepine (and oxcarbazepine) | Sodium-channel block | Focal seizures; trigeminal neuralgia | SIADH, agranulocytosis, aplastic anemia, Stevens-Johnson syndrome | Screen HLA-B*1502 in Asian ancestry; CYP450 inducer |
| Lamotrigine | Sodium-channel block | Focal, tonic-clonic, bipolar maintenance | Stevens-Johnson syndrome with fast titration | Valproate blocks its glucuronidation -- halve the dose |
| Levetiracetam | Binds the SV2A vesicle protein | Broad -- focal, tonic-clonic, myoclonic, status | Irritability, agitation, depression | No CYP interactions; ICU and pregnancy default |
| Topiramate | Sodium-channel block, GABA-A potentiation, carbonic anhydrase inhibition | Focal, tonic-clonic; migraine prophylaxis | Cognitive slowing, weight loss, kidney stones, glaucoma | Stones plus weight loss plus mental fog |
| Phenobarbital | ↑ duration of GABA-A chloride channel opening | Neonatal seizures; refractory status | Sedation, dependence, respiratory depression | Barbiturates increase opening duration |
| Benzodiazepines (lorazepam, midazolam) | ↑ frequency of GABA-A chloride channel opening | Abortive therapy in status epilepticus | Sedation, respiratory depression, tolerance | IV lorazepam first; IM midazolam without access |

## Drug selection rules that decide most questions

1. **Absence:** ethosuximide first, switching to **valproate** when the child also has generalized tonic-clonic seizures, since ethosuximide covers absence alone. Carbamazepine, phenytoin and gabapentin worsen absence and myoclonic seizures and are never correct.
2. **Generalized tonic-clonic:** valproate or levetiracetam; lamotrigine if pregnancy is possible.
3. **Focal seizures:** lamotrigine, levetiracetam, carbamazepine or oxcarbazepine.
4. **Status epilepticus** -- five minutes of continuous seizure, or repeated seizures without recovery -- runs on a clock: IV lorazepam (IM midazolam without access), then IV fosphenytoin, levetiracetam or valproate, then anesthetic midazolam or propofol under intubation. Check the glucose first.

## High-yield antiepileptic toxicities

- **Phenytoin:** gingival hyperplasia, hirsutism, drug-induced lupus, cerebellar atrophy with ataxia, megaloblastic anemia, zero-order kinetics and purple glove syndrome.
- **Valproate:** hepatotoxicity, pancreatitis, neural tube defects, and hyperammonemia causing encephalopathy with normal liver enzymes.
- **Carbamazepine:** SIADH, agranulocytosis and aplastic anemia, Stevens-Johnson syndrome linked to HLA-B*1502, and CYP450 induction that lowers warfarin and contraceptive levels.
- **Lamotrigine:** Stevens-Johnson syndrome and toxic epidermal necrolysis from rapid titration.

The wider pattern set is in [high-yield drug side effects](/blog/high-yield-drug-side-effects-usmle).

## Pregnancy and contraception change the choice

Valproate carries the highest teratogenic risk of any antiepileptic -- neural tube defects plus impaired cognitive outcomes -- so avoid it in anyone who could become pregnant. **Lamotrigine and levetiracetam** are preferred, and every patient of childbearing potential takes daily **folate**. Never stop therapy for pregnancy -- an uncontrolled convulsion endangers the fetus more than the drug.

Enzyme inducers -- carbamazepine, oxcarbazepine, phenytoin, phenobarbital, higher-dose topiramate -- speed estrogen and progestin metabolism and cause **oral contraceptive failure**, so pair them with an IUD. The interaction runs both ways: estrogen induces lamotrigine glucuronidation, and seizures break through when a combined pill starts.

## Exam-day cheat sheet

> **10-second exam strategy:** 3 Hz spike-and-wave staring spells -> ethosuximide. Morning myoclonus -> valproate. Convulsion with no focal onset -> valproate or levetiracetam. Aura, automatisms or a march -> lamotrigine, levetiracetam or carbamazepine. Actively seizing -> IV lorazepam. Possibly pregnant -> lamotrigine or levetiracetam, never valproate.

## How this is tested on the exam

- **Stem:** a 7-year-old with dozens of brief staring spells reproduced by hyperventilation, no postictal confusion. **Answer:** absence seizures -- ethosuximide, or valproate if tonic-clonic seizures coexist.
- **Stem:** a 16-year-old drops her toothbrush most mornings and convulsed after an all-nighter. **Answer:** juvenile myoclonic epilepsy -- valproate, or levetiracetam if pregnancy is possible.
- **Stem:** sodium of 121 with concentrated urine after starting a focal-seizure drug. **Answer:** carbamazepine-induced SIADH.

## Common wrong-answer traps

- **Choosing phenytoin or carbamazepine for absence seizures.** Both worsen absence and myoclonic seizures; ethosuximide or valproate is correct.
- **Starting valproate in a young woman without contraception counseling.** Teratogenicity makes lamotrigine or levetiracetam the tested answer, and rapid lamotrigine titration is what causes Stevens-Johnson syndrome.
- **Treating a provoked seizure with a chronic antiepileptic.** Correct the cause: eclampsia gets magnesium, not phenytoin.

More seizure and localization material sits in the [Neurology](/topics/neurology) hub.

## Sources

- [AAN practice guidelines](https://www.aan.com/practice/guidelines)
- [NBME](https://www.nbme.org/)
- [USMLE Step 1](https://www.usmle.org/step-exams/step-1)

Seizure pharmacology rewards drilling until each mechanism and toxicity comes back instantly. [Practice neurology pharmacology on StepGenie](https://dashboard.stepgenie.app/sign-up) and test yourself on the drugs you keep confusing.

## Frequently asked questions

### Which antiepileptic drug is first-line for absence seizures?

Ethosuximide is first-line for absence seizures because it blocks the thalamic T-type calcium channels that generate 3 Hz spike-and-wave activity. Choose valproate instead when the same child also has generalized tonic-clonic seizures, since ethosuximide treats absence alone. Valproate is the standard second-line agent, with lamotrigine behind it. Carbamazepine, phenytoin and gabapentin are wrong answers here because they worsen absence seizures.

### Why do carbamazepine and phenytoin worsen absence and myoclonic seizures?

Carbamazepine, phenytoin, oxcarbazepine and gabapentin are narrow-spectrum drugs that act on cortical sodium or calcium channels and do nothing to the thalamocortical circuit driving generalized absence and myoclonic seizures. In practice they aggravate both, so a teenager with juvenile myoclonic epilepsy started on carbamazepine seizes more, not less. Use broad-spectrum valproate, levetiracetam or lamotrigine for generalized epilepsy syndromes.

### What is the treatment algorithm for status epilepticus?

Status epilepticus means five minutes of continuous seizure or repeated seizures without recovery between them. Give a benzodiazepine first: IV lorazepam, or IM midazolam when there is no IV access. If seizures persist, move to a second-line IV agent, either fosphenytoin, levetiracetam or valproate. Refractory status needs anesthetic infusion with midazolam or propofol, intubation and continuous EEG. Check glucose immediately.

### Which antiepileptic drugs are safest in pregnancy?

Lamotrigine and levetiracetam are the preferred antiepileptics in pregnancy, and valproate is avoided because it carries the highest risk of neural tube defects and impaired cognitive outcomes. Every patient of childbearing potential on an antiepileptic should take daily folate. Do not stop therapy because a patient is pregnant, since an uncontrolled convulsion is more dangerous to the fetus than the drug.

### What are the classic phenytoin side effects tested on the USMLE?

Phenytoin causes gingival hyperplasia, hirsutism, drug-induced lupus, and cerebellar atrophy with ataxia and nystagmus, plus megaloblastic anemia from folate interference and fetal hydantoin syndrome. It follows zero-order kinetics, so a small dose increase can produce toxicity, and IV infusion can cause purple glove syndrome, which is why fosphenytoin is the preferred intravenous form.

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Canonical page: [Antiepileptic Drugs by Seizure Type](https://www.stepgenie.app/blog/seizure-classification-antiepileptic-drugs-usmle)
Topic hub: [Neurology](https://www.stepgenie.app/topics/neurology)