Epilepsy and Anti-epileptic Drugs

Core

Introduction

Epilepsy affects around 1 in 100 people in the UK. With modern anti-epileptic drugs (AEDs), around two-thirds of patients achieve sustained seizure-freedom, mostly on monotherapy. Failure of two well-tolerated agents at adequate doses is the working definition of drug-resistant epilepsy, in which combinations are tried but seizure-freedom rates are markedly lower. The pre-clinical curriculum focuses on the principles of how AEDs work, the standard first-line agents for the major seizure types, and the management of status epilepticus.

Definitions

• Seizure: a sudden, abnormal discharge of cortical electrical activity producing sensory disturbance, motor activity, altered consciousness, or autonomic features.
• Convulsion: the involuntary muscle contraction component of some (but not all) seizures.
• Aura: a sensory or psychic experience preceding or constituting the early phase of a seizure (e.g. strange smell, déjà vu, rising epigastric sensation).
• Epilepsy: a tendency to recurrent unprovoked seizures (in practice, two or more separated by at least 24 hours, or one with a substantially raised recurrence risk).
• Status epilepticus: seizure activity lasting more than 5 minutes, or repeated seizures without recovery of consciousness between them. A medical emergency.

Classification of Seizures

The current International League Against Epilepsy (ILAE) classification distinguishes three groups by where the seizure starts:

• Focal (formerly "partial"): arises from one part of one hemisphere. Subdivided by awareness:
  • Focal aware (formerly "simple partial"): consciousness preserved.
  • Focal impaired awareness (formerly "complex partial"): consciousness impaired; classically with automatisms (lip-smacking, plucking at clothes).
  • Focal to bilateral tonic-clonic: focal onset spreading to involve both hemispheres.
  Focal seizures are most often temporal lobe in origin (auditory hallucinations, déjà vu, fear, automatisms), with frontal lobe second most common.
• Generalised: involve both hemispheres from onset:
  • Tonic-clonic: the classic "grand mal"; tonic stiffening followed by clonic jerking, with loss of consciousness.
  • Absence: "petit mal"; brief loss of awareness with staring and behavioural arrest, classically in children. Characteristic 3 Hz "spike and wave" on EEG.
  • Myoclonic: brief shock-like jerks.
  • Atonic: sudden loss of muscle tone; "drop attacks".
  • Tonic: sustained increase in tone.
• Unknown onset: classification not possible from available information.

Anti-Epileptic Drug Classes

AEDs reduce neuronal excitability. Most fall into one of four mechanistic groups:

Sodium Channel Blockers

These drugs prolong the inactivated state of voltage-gated sodium channels, preventing rapid repetitive neuronal firing.

• Carbamazepine: classically first-line for focal seizures (now displaced by lamotrigine and levetiracetam in NICE guidance). Side effects include drowsiness, ataxia, diplopia, hyponatraemia (SIADH), agranulocytosis, Stevens-Johnson syndrome (especially in HLA-B*1502 carriers), and induction of CYP3A4 (reducing the efficacy of many other drugs including the COCP).
• Lamotrigine: broad-spectrum, used in generalised, focal and absence seizures. Generally well tolerated. Notable side effect: Stevens-Johnson syndrome / toxic epidermal necrolysis, especially with rapid dose escalation; titration is slow. Lamotrigine is one of the better-tolerated AEDs in pregnancy.
• Phenytoin: older drug now mainly used in status epilepticus. Narrow therapeutic index, exhibits zero-order kinetics at therapeutic doses (small dose increases produce disproportionately large rises in plasma level; covered in Pharmacokinetics). Side effects: gingival hyperplasia, hirsutism, coarsening of facial features, ataxia, nystagmus, megaloblastic anaemia (folate antagonism), foetal hydantoin syndrome (teratogenic).
• Sodium valproate: broad-spectrum, traditionally first-line for generalised seizures. Highly teratogenic (neural tube defects, foetal valproate syndrome, neurodevelopmental impairment) and recently linked to risks in male reproductive health, leading the MHRA in 2024 to restrict all new valproate prescriptions in patients under 55 (regardless of sex) to those in whom no alternative is suitable, supported by two-specialist review. Other side effects include weight gain, alopecia ("valproate" hair loss), hepatotoxicity, pancreatitis, and tremor.

Calcium Channel Blockers

Drugs that block T-type calcium channels in thalamic relay neurons reduce the abnormal "spike-and-wave" oscillations of absence seizures.

• Ethosuximide: first-line for childhood absence seizures. Side effects: GI upset, drowsiness.
• Sodium valproate: also has some calcium channel activity, contributing to its broad-spectrum efficacy.

GABA Potentiators

Enhancing GABA_A activity hyperpolarises neurons and reduces excitability. Several mechanisms:

• Benzodiazepines (lorazepam, midazolam, diazepam, clonazepam) bind a separate site on the GABA_A receptor and increase the frequency of channel opening. Used in status epilepticus and as adjunctive therapy.
• Barbiturates (phenobarbital) bind GABA_A and prolong the duration of channel opening. Largely historical now because of sedation, dependence, and CYP induction.
• Vigabatrin: irreversibly inhibits GABA-transaminase, raising GABA levels. Causes irreversible visual field defects, restricting use to refractory disease (especially infantile spasms).
• Tiagabine: inhibits GABA reuptake. Niche use.

SV2A Modulators

Levetiracetam (Keppra) binds the synaptic vesicle protein SV2A, modulating neurotransmitter release. Broad-spectrum, generally well tolerated, no significant drug interactions, no CYP effects, and can be loaded intravenously. Has rapidly become a first-line UK drug for generalised tonic-clonic and focal seizures (NICE 2022).

Side effects: behavioural change (irritability, low mood, occasionally aggression), drowsiness.

Drugs with Multiple Mechanisms

• Topiramate: sodium channel blockade, GABA potentiation, kainate receptor antagonism. Side effects: weight loss, paraesthesia, kidney stones, cognitive slowing, glaucoma. Teratogenic.
• Gabapentin and pregabalin: bind the α₂δ subunit of voltage-gated calcium channels, reducing neurotransmitter release. Mainly used for focal seizures; more widely prescribed for neuropathic pain. Pregabalin and gabapentin are now controlled drugs (Schedule 3) in the UK because of misuse and addiction.
• Cannabidiol: recently licensed for Lennox-Gastaut and Dravet syndromes.

Initiating and Stopping Anti-Epileptic Drugs

The principles of NICE guidance:

• Start monotherapy at low dose and titrate up to seizure control or maximum tolerated dose.
• If the first drug fails, switch to a different monotherapy before considering combination.
• Combination therapy is reserved for patients in whom two attempts at monotherapy have failed.
• Choose drug by seizure type:

Generalised tonic-clonic: first-line: levetiracetam or lamotrigine.
Focal seizures: first-line: lamotrigine or levetiracetam.
Absence seizures: first-line: ethosuximide.
Myoclonic seizures: first-line: levetiracetam.
Tonic / atonic seizures: first-line: lamotrigine; specialist alternatives include sodium valproate (only with two-specialist sign-off in patients under 55, per MHRA 2024).

Stopping AEDs: consider after the patient has been seizure-free for at least 2 years. Around 60% remain seizure-free after withdrawal; the risk of recurrence is higher in those with childhood-onset epilepsy, polypharmacy, abnormal recent EEG, structural brain lesions, or myoclonic / tonic-clonic seizures. Always taper gradually. The DVLA requires no driving for 6 months after stopping medication.

Interactions and Special Populations

Liver enzyme effects:

• Inducers: phenytoin, carbamazepine, phenobarbital, primidone, topiramate (at higher doses).
• Inhibitors: sodium valproate.

The most clinically important inducer interaction is reduced efficacy of the combined oral contraceptive pill: women on an enzyme-inducing AED need an alternative or additional contraceptive method.

Pregnancy:

• Sodium valproate: teratogenic (neural tube defects, foetal valproate syndrome) and associated with neurodevelopmental impairment in around 30-40% of exposed children. Now subject to the MHRA Pregnancy Prevention Programme (PPP): not prescribed to anyone of childbearing potential except in tightly defined circumstances with annual specialist review and a signed risk-acknowledgement form.
• Phenytoin, carbamazepine, topiramate: all teratogenic, although less than valproate.
• Lamotrigine, levetiracetam: lower risk; preferred where possible during pregnancy.
• Folic acid 5 mg daily is recommended pre-conceptually and through the first trimester for any woman of childbearing age on AEDs.

Status Epilepticus

Status epilepticus is convulsive seizure activity lasting more than 5 minutes or repeated seizures without recovery between them. Mortality is 10-20% if seizures continue beyond 60 minutes; the urgency of treatment increases progressively.

Standard stepwise UK management:

Status epilepticus: standard sequence

0-5 min: ABC, recovery position, oxygen, IV access, blood glucose, blood gas, U&E, calcium, magnesium, anti-epileptic levels.
5-10 min: Lorazepam 4 mg IV (or buccal midazolam 10 mg / rectal diazepam if no IV access).
10-20 min: Repeat lorazepam dose.
20-40 min (refractory): Levetiracetam, sodium valproate, or phenytoin IV (NICE 2022 places these as equivalent options).
40-60 min (super-refractory): General anaesthesia: thiopental, propofol or midazolam infusion in ICU, with intubation.

Always give thiamine if there is any suspicion of alcohol misuse or malnutrition, and check blood glucose immediately to exclude hypoglycaemia.

Driving and the DVLA

Patients with epilepsy must inform the DVLA. Standard UK rules (paraphrased):

• Group 1 (car/motorcycle): must be seizure-free for 1 year before resuming driving. Six months off after a single unprovoked seizure (with no high-risk features). Six months off after stopping AEDs.
• Group 2 (HGV/PSV): stricter: must be 10 years seizure-free without medication.

This is one of the most common things doctors are asked about by epilepsy patients and is regularly tested in the UK Prescribing Safety Assessment.

Summary

• AEDs work by blocking sodium channels (lamotrigine, carbamazepine, phenytoin, valproate), blocking T-type calcium channels (ethosuximide), potentiating GABA (benzodiazepines, phenobarbital, vigabatrin), or modulating SV2A (levetiracetam).
• NICE 2022 first-line: levetiracetam or lamotrigine for tonic-clonic and focal; ethosuximide for absence; levetiracetam for myoclonic.
• Sodium valproate is highly effective but strictly avoided in girls and women of childbearing potential (Pregnancy Prevention Programme).
• Carbamazepine, phenytoin and phenobarbital are CYP inducers: reduce COCP efficacy and many other drugs.
• Lamotrigine requires slow titration to avoid Stevens-Johnson syndrome.
• Status epilepticus: ABC + IV access + glucose / thiamine → lorazepam IV (repeat once) → levetiracetam / valproate / phenytoin IV → general anaesthesia in ICU.
• DVLA: 1 year seizure-free before resuming driving (Group 1); 10 years without medication (Group 2).

Drug Summary Table

Reviewed by: Dr. Marcus Judge

Quiz

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