Epilepsy and Anti-epileptic Drugs

1. Introduction
2. Definitions
3. Classification of Seizures
4. Anti-Epileptic Drug Classes
   • Sodium Channel Blockers
   • Calcium Channel Blockers
   • GABA Potentiators
   • SV2A Modulators
   • Drugs with Multiple Mechanisms
5. Initiating and Stopping Anti-Epileptic Drugs
6. Interactions and Special Populations
7. Status Epilepticus
8. Driving and the DVLA
9. Summary
10. Drug Summary Table
11. Quiz

• Anti-epileptic drugs reduce neuronal excitability by one of four broad mechanisms: blocking sodium channels, blocking calcium channels, potentiating GABA (gamma-aminobutyric acid, the brain's main inhibitory neurotransmitter), or modulating synaptic vesicle release (levetiracetam binds SV2A, a protein on synaptic vesicles).
• First-line UK drugs (NICE guideline NG217): lamotrigine, levetiracetam or sodium valproate (valproate only within the restrictions below) for generalised tonic-clonic seizures; lamotrigine or levetiracetam for focal seizures; ethosuximide for absence seizures.
• Sodium valproate remains highly effective but is now restricted under 2024 guidance from the Medicines and Healthcare products Regulatory Agency (MHRA, the UK medicines regulator): new prescriptions in any patient under 55 (regardless of sex) require documented agreement from two specialists, working independently, that no suitable alternative exists. Female patients of childbearing potential additionally need a Pregnancy Prevention Programme (PPP, a set of safeguards that includes annual specialist review and a signed Risk Acknowledgement Form), and valproate is used only if other treatments have been unsuccessful.
• Status epilepticus is a medical emergency. Standard sequence: airway, breathing and circulation (ABC) support, IV access, a blood glucose check, and thiamine (vitamin B1) if indicated → IV lorazepam (or buccal midazolam, given into the cheek) → a second dose of the benzodiazepine if the seizure continues → IV levetiracetam, phenytoin or sodium valproate → phenobarbital or general anaesthesia, under expert guidance.

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 (treatment with a single drug). 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, or a rising epigastric sensation, meaning a feeling that rises from the upper abdomen).
• Epilepsy: an enduring predisposition to epileptic seizures. The practical diagnosis needs one of three things. First, at least two unprovoked seizures (with no temporary cause, such as low blood glucose) or reflex seizures (triggered by a stimulus, such as flashing lights), more than 24 hours apart. Second, one such seizure with an estimated recurrence risk of at least 60% over the next 10 years. Third, a diagnosis of an epilepsy syndrome (a recognised pattern of seizure type, EEG findings and age of onset).
• Status epilepticus: in its convulsive form (the form covered in this article), seizure activity lasting more than 5 minutes, or repeated seizures without recovery of consciousness between them. A medical emergency.

Classification of Seizures

The 2025 International League Against Epilepsy (ILAE) classification has four main classes: focal, generalised, unknown whether focal or generalised, and unclassified:

• Focal (formerly "partial"): originates in networks limited to one hemisphere (one half of the brain). Where assessable, classify consciousness as preserved or impaired using awareness and responsiveness:
  • Focal seizure with preserved consciousness (previously "focal aware"): awareness and responsiveness preserved.
  • Focal seizure with impaired consciousness (previously "focal impaired awareness"): awareness or responsiveness impaired; classically with automatisms (repetitive, purposeless movements such as lip-smacking and 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: originate within and rapidly engage networks distributed across both hemispheres; they do not require simultaneous involvement of the entire cortex:
  • 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 (stopping activity and not responding), classically in children. Characteristic 3 Hz "spike and wave" pattern on EEG (a sharp spike followed by a slow wave, repeating three times a second).
  • Myoclonic: brief shock-like jerks.
  • Atonic: sudden loss of muscle tone; "drop attacks".
  • Tonic: sustained increase in tone.
• Unknown whether focal or generalised: some seizure information is available, but does not establish whether the seizure is focal or generalised.
• Unclassified: the event is recognised as an epileptic seizure, but there is insufficient information to characterise it further.

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 (the brief period after opening when a channel cannot open again) of voltage-gated sodium channels (channels that open in response to a change in membrane voltage). This prevents 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 (unsteady, uncoordinated movement), diplopia (double vision), hyponatraemia (low blood sodium, due to the syndrome of inappropriate antidiuretic hormone secretion, SIADH), agranulocytosis (a severe fall in the white blood cells that fight infection), Stevens-Johnson syndrome (a severe skin and mucous membrane reaction, with higher risk in carriers of the HLA-B*1502 gene variant), and induction of CYP3A4. Induction means the drug speeds up the CYP3A4 liver enzyme, which reduces the efficacy of many other drugs, including the combined oral contraceptive pill (COCP).
• Lamotrigine: broad-spectrum, used in generalised, focal and absence seizures. Generally well tolerated. Notable side effect: Stevens-Johnson syndrome / toxic epidermal necrolysis (a more severe form of the same reaction, with widespread skin loss). The risk is highest with rapid dose escalation, so titration (stepwise dose increase) is slow. Lamotrigine is one of the safer AEDs in pregnancy: the MHRA review found no increased risk of major congenital malformations at maintenance doses.
• Phenytoin: older drug now mainly used in status epilepticus. Narrow therapeutic index (the toxic dose is close to the effective dose). Its metabolism becomes saturated within the therapeutic range, so the relationship between dose and plasma level is non-linear. Small dose increases produce disproportionately large rises in plasma level (covered in Pharmacokinetics). Side effects: gingival hyperplasia (gum overgrowth), hirsutism (excess hair growth), coarsening of facial features, ataxia, nystagmus (involuntary eye movements), megaloblastic anaemia (a large-cell anaemia from a lack of folate, which is vitamin B9, as phenytoin is a folate antagonist), and foetal hydantoin syndrome (a pattern of birth defects; phenytoin is teratogenic, meaning it can harm the developing baby).
• Sodium valproate: broad-spectrum, traditionally first-line for generalised seizures. Highly teratogenic (neural tube defects, which are malformations of the spine and brain such as spina bifida; foetal valproate syndrome, a pattern of birth defects and learning problems after exposure in the womb; and neurodevelopmental impairment, meaning delayed or impaired development of learning, speech or behaviour). It is also linked to male infertility and to a possible increased risk of neurodevelopmental conditions in children fathered by men who took it in the 3 months before conception. In 2024 the MHRA therefore restricted all new valproate prescriptions in patients under 55 (regardless of sex): they are started only if two specialists independently agree and document that no other effective and tolerated treatment exists, or that there are compelling reasons why the reproductive risks do not apply. Other side effects include weight gain, alopecia (hair loss), hepatotoxicity (liver damage), pancreatitis (inflammation of the pancreas), and tremor.

Calcium Channel Blockers

Drugs that block T-type calcium channels (low-threshold voltage-gated calcium channels) in thalamic relay neurons (cells that pass signals through the thalamus to the cortex) reduce the abnormal "spike-and-wave" oscillations of absence seizures.

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

GABA Potentiators

GABA (gamma-aminobutyric acid) is the brain's main inhibitory neurotransmitter. Enhancing activity at its GABA_A receptor hyperpolarises neurons (makes the inside of the cell more negative, so it fires less easily) and reduces excitability. There are several mechanisms:

• Benzodiazepines (lorazepam, midazolam, diazepam, clonazepam) bind a site on the GABA_A receptor that is separate from the GABA binding site, and increase the frequency of channel opening. Used in status epilepticus and as adjunctive (add-on) therapy alongside another anti-epileptic drug.
• 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 (the enzyme that breaks down GABA), raising GABA levels. Causes irreversible visual field defects (permanent loss of part of the area a person can see), so its use is limited. NICE recommends it as first-line treatment for infantile spasms (a rare epilepsy of infancy), usually with high-dose prednisolone, and lists it only as a third-line add-on option for focal seizures.
• Tiagabine: inhibits GABA reuptake (the uptake of GABA back into cells). Niche use.

SV2A Modulators

Levetiracetam (Keppra) binds the synaptic vesicle protein SV2A, modulating neurotransmitter release. Broad-spectrum, generally well tolerated, no significant drug interactions, and no effect on the CYP liver enzymes (cytochrome P450, which metabolise many drugs). It can be loaded intravenously, meaning a large first dose is given into a vein to reach an effective level quickly. It is a first-line UK drug for generalised tonic-clonic, focal and myoclonic seizures (NICE guideline NG217).

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

Drugs with Multiple Mechanisms

• Topiramate: sodium channel blockade, GABA potentiation, antagonism (blockade) of kainate receptors, a type of glutamate receptor. Side effects: weight loss, paraesthesia (pins and needles), kidney stones, cognitive slowing, glaucoma (raised pressure in the eye, which can damage vision). It is teratogenic: since June 2024 the MHRA has contraindicated it in pregnancy and in women of childbearing potential unless the conditions of a Pregnancy Prevention Programme are fulfilled.
• Gabapentin and pregabalin: bind the α₂δ subunit (an accessory part of the channel protein) of voltage-gated calcium channels, reducing neurotransmitter release. Neither is a first-line drug for epilepsy: NICE lists pregabalin only as a second-line add-on for focal seizures and no longer recommends gabapentin. Both are more widely prescribed for neuropathic pain (pain caused by nerve damage). Pregabalin and gabapentin are now controlled drugs (Schedule 3, a category with legal rules on prescribing and supply) in the UK because of misuse and addiction.
• Cannabidiol: used as an add-on to clobazam for seizures in Lennox-Gastaut syndrome and Dravet syndrome (rare, severe epilepsies that start in childhood). It is also used as an add-on for seizures in tuberous sclerosis complex (a genetic condition that causes benign tumours in several organs). Specialist use only.

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: lamotrigine, levetiracetam or sodium valproate (valproate only within the MHRA restrictions above).
Focal seizures: first-line: lamotrigine or levetiracetam.
Absence seizures: first-line: ethosuximide.
Myoclonic seizures: first-line: levetiracetam or sodium valproate (valproate only within the MHRA restrictions above).
Tonic / atonic seizures: first-line: a choice of lamotrigine or sodium valproate (valproate only within the MHRA restrictions above).

Stopping AEDs: consider after the patient has been seizure-free for at least 2 years. In the Medical Research Council (MRC) withdrawal study, about 59% of those who stopped were still seizure-free 2 years later, compared with 78% of those who continued. The risk of recurrence is higher in those whose epilepsy began in adolescence or adulthood and in those on polypharmacy (more than one drug). It is also higher in those with an abnormal recent EEG, structural brain lesions (visible areas of brain damage, such as a scar or tumour), or myoclonic / tonic-clonic seizures. Always reduce the dose gradually (taper). The Driver and Vehicle Licensing Agency (DVLA) advises against driving while medication is being withdrawn and for 6 months after the last dose.

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