Key Facts

Epilepsy affects ~600,000 people in the UK (~1% prevalence). AEDs are the mainstay of treatment; ~70% of patients achieve seizure freedom with appropriate medication. Choosing the right drug for the seizure type and patient profile is critical.

Mechanisms of Action

• Sodium channel blockers: carbamazepine, lamotrigine, phenytoin, lacosamide — stabilise inactivated state of Na channels
• Calcium channel modulation: ethosuximide (T-type Ca channels — absence seizures), gabapentin/pregabalin (alpha-2-delta subunit)
• GABA enhancement: benzodiazepines, barbiturates, vigabatrin, tiagabine
• Glutamate inhibition: perampanel (AMPA antagonist)
• SV2A binding: levetiracetam, brivaracetam
• Multiple mechanisms: valproate (Na channels, T-type Ca channels, GABA enhancement, HDAC inhibition)

Pathophysiology

• Seizures: abnormal excessive synchronous neuronal activity
• AEDs reduce neuronal excitability through various mechanisms → raise seizure threshold
• Drug interactions: many AEDs are CYP inducers (carbamazepine, phenytoin, phenobarbital) or inhibitors (valproate) → affect concurrent medication

Drug Selection (NICE NG217)

Focal seizures:

• First-line: lamotrigine or carbamazepine
• Second-line: levetiracetam, oxcarbazepine, sodium valproate

Generalised tonic-clonic:

• First-line: sodium valproate (males, females not of childbearing potential) or lamotrigine (females of childbearing potential)
• Second-line: levetiracetam, clobazam

Absence:

• First-line: ethosuximide or sodium valproate
• Carbamazepine, phenytoin may WORSEN absences

Myoclonic:

• Sodium valproate first-line; levetiracetam alternative
• Carbamazepine may worsen myoclonus

Key Side Effects

• Valproate: teratogenic (NTDs ~7%, neurodevelopmental delay ~40%), weight gain, tremor, hair loss, hepatotoxicity, pancreatitis, thrombocytopenia
• Lamotrigine: rash (SJS/TEN ~0.1% — slow titration reduces risk), headache, insomnia
• Carbamazepine: diplopia, ataxia, hyponatraemia, rash (SJS — HLA-B*1502), enzyme induction, aplastic anaemia (rare)
• Phenytoin: gingival hyperplasia, hirsutism, coarsening of facial features, cerebellar atrophy (long-term), osteomalacia, zero-order kinetics → toxicity risk
• Levetiracetam: irritability, aggression, depression, drowsiness; few interactions

Red Flags

• Rash on lamotrigine/carbamazepine → stop and review (SJS/TEN risk)
• Hepatitis on valproate → stop; check LFTs urgently
• Phenytoin toxicity: nystagmus → ataxia → confusion → coma (dose-dependent, zero-order kinetics)
• Status epilepticus: seizure >5 minutes → emergency

Before Starting

• Baseline bloods: FBC, LFTs, U&Es, bone profile
• ECG: if cardiac history (some AEDs affect conduction)
• HLA-B*1502: before carbamazepine in SE Asian patients (SJS risk)
• Pregnancy test: in women of childbearing potential before valproate

Monitoring

• TDM: phenytoin (narrow TI, zero-order — target 10–20 mg/L); carbamazepine; occasionally lamotrigine (especially pregnancy)
• FBC: carbamazepine, valproate — risk of blood dyscrasias
• LFTs: valproate, carbamazepine
• U&Es, Na: carbamazepine (hyponatraemia — SIADH)
• Lamotrigine levels in pregnancy: monthly — levels fall ~50% due to increased clearance; dose increase usually needed

Special Tests

• EEG: confirm epilepsy diagnosis and classify
• MRI brain: first unprovoked seizure in adult (NICE)
• Vitamin D: long-term AEDs (especially enzyme inducers) → osteomalacia; supplement if deficient

General Principles

• Monotherapy: aim for single drug at optimal dose before adding second
• Slow titration: especially lamotrigine (reduce SJS risk); start low, increase slowly
• Consistent formulations: for phenytoin, carbamazepine, valproate — do NOT switch brands/generics without specialist advice (narrow TI)
• Driving: DVLA rules — must be seizure-free for 12 months (Group 1 licence) or 10 years (Group 2/HGV)

Status Epilepticus (NICE NG217)

1. Benzodiazepine: IV lorazepam 4 mg (repeat once at 10 min) or buccal midazolam 10 mg
2. Second-line (if seizure continues): IV phenytoin 15–20 mg/kg (with cardiac monitoring) OR IV levetiracetam 60 mg/kg (max 4.5 g) OR IV valproate 40 mg/kg
3. Refractory: rapid sequence induction and general anaesthesia (propofol, thiopental)

Pregnancy

• Pre-conception counselling: essential for all women with epilepsy
• Folic acid 5 mg/day: pre-conception through first trimester (all women on AEDs)
• Valproate: AVOID — MHRA PPP; switch to lamotrigine or levetiracetam BEFORE conception
• Lamotrigine: levels fall in pregnancy — monitor monthly, increase dose as needed
• Do NOT stop AEDs abruptly: seizure risk to mother and fetus

Referral Criteria

• Epilepsy specialist: all new diagnoses, treatment failure, drug-resistant epilepsy
• Epilepsy surgery centre: drug-resistant focal epilepsy (consider after failure of 2 appropriate AEDs)
• Pregnancy planning: pre-conception counselling with epilepsy specialist

• ~70% of patients achieve seizure freedom with AEDs
• Drug-resistant epilepsy (~30%): defined as failure of 2 appropriate AEDs at adequate doses
• Epilepsy surgery: can cure up to 60–70% of selected focal epilepsy patients
• SUDEP (sudden unexpected death in epilepsy): ~1 in 1,000 patients/year; risk reduced by seizure control and adherence
• Valproate in pregnancy: up to 40% neurodevelopmental problems — preventable with alternative AEDs
• Lamotrigine in pregnancy: good safety profile; dose adjustment needed due to increased clearance

AED Drug Interactions

AED Comparison