Decision support only — not a substitute for a neurologist, the ILAE/NICE guidelines, eTG, or the Austroads driving standards. The recurring theme of chronic epilepsy care: classify the seizure and syndrome before choosing a drug, because the wrong drug can make some generalised epilepsies worse; and the drug is only part of it — driving, pregnancy, bone health, mood and SUDEP all need active management. Status epilepticus is recapped at the end (§10). Verify all doses.
1 First seizure — is it epilepsy, and do you start a drug?
Was it a seizure, and was it provoked?
- MimicsSyncope (convulsive syncope is common), psychogenic non-epileptic seizures, TIA, migraine, parasomnia — a careful witness history outperforms any test.
- ProvokedAcute symptomatic seizure (hyponatraemia, hypoglycaemia, alcohol withdrawal, drugs, sepsis, acute brain injury) → treat the cause, not "epilepsy".
- Work-upEEG (supports classification, doesn't exclude), MRI brain (structural cause), bloods; consider ECG for the syncope question.
When to start an ASM
- DefinitionEpilepsy = ≥2 unprovoked seizures >24 h apart, OR one unprovoked seizure with a ≥60% recurrence risk (epileptiform EEG, structural lesion), OR an epilepsy syndrome.
- After oneTreating a first unprovoked seizure cuts short-term recurrence but doesn't change long-term remission — a shared decision weighing recurrence risk, occupation and driving MESS.
- ThenStart one drug, titrate slowly to the lowest effective dose, and classify before choosing (§2).
2 Choosing the drug — by seizure type & syndrome
The single most consequential step. Broad-spectrum agents (valproate, lamotrigine, levetiracetam) cover most types; sodium-channel blockers and gabapentinoids can worsen generalised, absence and myoclonic seizures. SANAD II is the head-to-head evidence: lamotrigine stays first-line for focal, valproate is the most effective for generalised.
| Seizure type | First-line | Alternatives / add-on | Avoid — can worsen |
|---|
| Focal (± bilateral tonic-clonic) |
Lamotrigine or levetiracetam SANAD II |
Carbamazepine, oxcarbazepine, lacosamide, brivaracetam, zonisamide, perampanel, cenobamate, eslicarbazepine |
— |
| Generalised tonic-clonic (idiopathic) |
Valproate (most effective) SANAD II; lamotrigine or levetiracetam if valproate unsuitable |
Perampanel, topiramate, clobazam |
Carbamazepine, oxcarbazepine, phenytoin, gabapentin, pregabalin |
| Absence |
Ethosuximide (fewer attentional effects than valproate) Glauser NEJM; valproate |
Lamotrigine (less effective) |
Carbamazepine, oxcarbazepine, phenytoin, gabapentin, vigabatrin |
| Myoclonic / JME |
Levetiracetam or valproate |
Lamotrigine (may worsen myoclonus in some), clobazam, clonazepam, brivaracetam, topiramate |
Carbamazepine, oxcarbazepine, phenytoin, gabapentin, pregabalin |
Practice-vs-evidence gap worth naming: levetiracetam is prescribed far more than SANAD II supports — it was not non-inferior to lamotrigine for focal epilepsy, nor to valproate for generalised. Its appeal is convenience and pregnancy safety, not superior seizure control.
3 The anti-seizure medications
| Agent | Mechanism | Key adverse effects | Interactions / notes |
|---|
| Lamotrigine |
Na-channel; broad-spectrum |
SJS/TEN if titrated fast — slow titration mandatory |
Valproate doubles levels → halve dose; oestrogen (COC) lowers levels; good in pregnancy |
| Levetiracetam |
SV2A |
Irritability, mood/aggression, depression |
No enzyme interactions; renal dose; IV available; easy to load |
| Valproate |
Multiple; broad-spectrum |
Weight gain, tremor, hair loss, hepatotoxicity, pancreatitis, hyperammonaemia |
Highest teratogenicity + neurodevelopmental harm (§5); enzyme inhibitor |
| Carbamazepine |
Na-channel |
Hyponatraemia, rash (HLA-B*15:02 → SJS), diplopia, ataxia |
Strong enzyme inducer; auto-induction; worsens generalised seizures |
| Oxcarbazepine / eslicarbazepine |
Na-channel |
Hyponatraemia (more than carbamazepine) |
Milder inducer; worsens generalised seizures |
| Phenytoin |
Na-channel |
Non-linear kinetics, gum hyperplasia, ataxia, neuropathy, cerebellar |
Strong inducer; levels needed (free level if low albumin); mostly acute/status now |
| Lacosamide |
Na-channel (slow inactivation) |
Dizziness, PR prolongation |
Focal + generalised tonic-clonic; IV available; minimal interactions |
| Brivaracetam |
SV2A (high affinity) |
Fewer behavioural effects than levetiracetam |
Focal; IV available |
| Perampanel |
AMPA antagonist |
Behavioural/psychiatric (aggression — boxed warning), dizziness |
Once daily nocte; focal + generalised tonic-clonic |
| Topiramate |
Multiple |
Cognitive slowing, word-finding, weight loss, renal stones, glaucoma; teratogenic (cleft) |
Broad-spectrum; also migraine |
| Cenobamate |
Na-channel + GABA-A |
DRESS if titrated fast — very slow titration; QT shortening |
Potent for drug-resistant focal; high seizure-freedom rates; interactions |
| Ethosuximide |
T-type Ca-channel |
GI upset, rarely blood dyscrasias |
Absence only — no effect on tonic-clonic |
| Cannabidiol |
Multiple |
Sedation, LFT rise (esp. with valproate) |
Dravet, Lennox-Gastaut, tuberous sclerosis |
4 Principles of long-term drug therapy
Getting to seizure freedom
- MonotherapyStart one drug, titrate to the lowest effective dose; ~50% controlled on the first agent, another ~15% on a second.
- Switch vs addIf the first drug fails for efficacy, substitute (cross-titrate); add-on/rational polytherapy once monotherapies fail.
- Diminishing returnsSeizure-freedom odds fall steeply after two appropriate drugs fail — that's the trigger to reconsider the diagnosis and refer (§6).
Monitoring & adherence
- LevelsNot routine. Use for phenytoin (non-linear), suspected non-adherence or toxicity, and pregnancy (lamotrigine/levetiracetam clearance rises).
- AdherenceMissed doses are the commonest cause of breakthrough seizures — ask before escalating.
- TitrationLamotrigine and cenobamate need slow titration for skin/hypersensitivity risk.
5 People who can become pregnant — and valproate
Valproate — the hard line
- Risk~10% major malformations (dose-dependent) plus reduced IQ and higher autism/ADHD rates even without malformation.
- RuleAvoid in anyone who could become pregnant unless no effective alternative and a pregnancy-prevention programme is in place (TGA/eTG). Counsel and document.
- MenA precautionary signal about possible risk to offspring via fathers (MHRA) is under regulatory review — worth flagging when counselling.
Planning & pregnancy
- PreferredLamotrigine and levetiracetam have the most reassuring pregnancy data; aim for monotherapy at the lowest effective dose.
- FolateHigh-dose folate pre-conception and first trimester.
- In pregnancyLamotrigine and levetiracetam clearance rises — monitor levels, expect dose increases; register in a pregnancy ASM registry.
- ContraceptionEnzyme inducers reduce hormonal contraceptive efficacy; the COC lowers lamotrigine levels — plan for both.
6 Drug-resistant epilepsy — refer, don't just add drugs
ILAE definition: failure of two tolerated, appropriately chosen and used ASM schedules (mono or combination) to achieve sustained seizure freedom. Around a third of epilepsy is drug-resistant, and the surgical-referral gap is a genuine failure of care — patients reach a surgical centre a median of roughly two decades after onset.
What to do
- ReassessConfirm the diagnosis (is it epilepsy? are these psychogenic events?), the classification, and adherence before labelling "resistant".
- Refer earlyAfter two drugs fail, refer to a comprehensive epilepsy centre for pre-surgical evaluation — don't cycle through a third, fourth, fifth drug for years.
- SurgeryResective surgery beats continued medication in suitable focal (esp. temporal lobe) epilepsy Wiebe NEJM ERSET; laser ablation is a less-invasive option.
When surgery isn't an option
- NeuromodulationVNS (established), responsive neurostimulation (RNS), and deep brain stimulation of the anterior thalamic nucleus SANTE — palliative, reduce frequency rather than cure.
- DietKetogenic diet, especially in children and specific syndromes.
- Newer ASMsCenobamate has notable seizure-freedom rates in drug-resistant focal epilepsy.
7 SUDEP & safety counselling
Sudden unexpected death in epilepsy
- Scale~1 in 1000 patient-years overall; substantially higher in drug-resistant epilepsy.
- Risk factorsFrequent generalised tonic-clonic seizures (the dominant one), nocturnal seizures, poor adherence, drug resistance.
- Reduce itOptimise seizure control (especially GTCS), adherence, and consider nocturnal supervision/monitoring. Guidelines say discuss SUDEP openly — patients want to know.
Everyday safety
- WaterShowers over baths; never swim alone.
- TriggersSleep deprivation, alcohol, missed doses; photosensitivity in a minority.
- RescueA seizure-action plan; midazolam (buccal/intranasal) for prolonged seizures in the community.
8 Comorbidities, bone health & interactions
Enzyme induction
- CulpritsCarbamazepine, phenytoin, phenobarbital (topiramate/oxcarbazepine partial).
- ConsequencesContraceptive failure, reduced DOAC/warfarin/statin/immunosuppressant levels.
- CleanerLevetiracetam, brivaracetam, lamotrigine, lacosamide, gabapentinoids — few interactions.
Bone & metabolic
- BoneLong-term enzyme inducers (and valproate) → reduced bone density; check vitamin D, supplement, consider DXA.
- WeightValproate/pregabalin gain; topiramate/zonisamide loss.
Mood & cognition
- ScreenDepression and anxiety are common and under-treated; ASMs carry a class suicidality warning.
- OffendersLevetiracetam and perampanel for irritability/aggression; topiramate for cognitive slowing.
9 Driving & stopping treatment
Driving (Australia — Austroads)
- FrameworkGoverned by Assessing Fitness to Drive. Private licence: a non-driving period after a first seizure (commonly 6 months) then conditional; recurrent epilepsy needs a defined seizure-free period.
- CommercialMuch stricter — long seizure-free periods, often off medication.
- DutyThe patient must notify the driver licensing authority (VicRoads in Victoria); advise and document. Confirm current AFTD criteria — they are category-specific.
Withdrawing an ASM
- WhenConsider after ≥2 years seizure-free, as a shared decision.
- Relapse~40% relapse; higher with an abnormal EEG, structural cause, or JME (usually lifelong).
- HowTaper slowly; there are driving restrictions during withdrawal and for a period after — factor this in.
10 Status epilepticus — the acute recap
0–5 min
Resuscitate (ABC, O₂, glucose, IV access). A seizure ≥5 min is status — treat, don't wait.
5–20 min
Benzodiazepine — IV lorazepam, or IM midazolam / buccal if no access. Give an adequate dose; under-dosing is the classic error. Repeat once.
20–40 min
IV levetiracetam, valproate, or phenytoin — the three are equivalent as second-line ESETT. Pick by patient (avoid valproate in pregnancy; phenytoin needs cardiac monitoring).
>40 min
Refractory status → anaesthesia (propofol/midazolam/thiopentone), intubation, continuous EEG, ICU. Hunt the cause throughout.
Don't miss: hypoglycaemia and hyponatraemia, eclampsia (magnesium, not the usual ladder), non-convulsive status (fluctuating consciousness → EEG), and pseudostatus (psychogenic). Give thiamine before glucose in possible alcohol dependence.
Guidelines & definitions. ILAE operational definition of epilepsy (Fisher 2014) and drug-resistant epilepsy (Kwan 2010); NICE NG217 (epilepsies in children, young people and adults; updated Jan 2025); eTG (Neurology); Austroads "Assessing Fitness to Drive"; TGA valproate safety advice.
Trials & reviews. SANAD I (Lancet 2007) & SANAD II (Lancet 2021 — lamotrigine for focal; valproate for generalised); Glauser childhood absence (NEJM 2010 — ethosuximide/valproate > lamotrigine); Kwan, Schachter, Brodie, "Drug-Resistant Epilepsy" (NEJM 2011); Wiebe RCT of surgery for temporal-lobe epilepsy (NEJM 2001); ERSET early surgery (JAMA 2012); SANTE (anterior-thalamic DBS); ESETT (NEJM 2019 — levetiracetam/valproate/phenytoin equivalent in established status); MESS (early vs deferred treatment after a first seizure).
Caveats. Drug choice is syndrome-specific — misclassifying a generalised epilepsy and prescribing a sodium-channel blocker can worsen it. Valproate teratogenicity restrictions are firm for anyone who could become pregnant; the male-fertility signal is precautionary and evolving. Driving periods are category-specific — use the current Austroads standard, not the round numbers here. Verify all doses and PBS status. Companion to the neurology set (stroke, migraine, Parkinson's, MS).