Seizures and Antiepileptic Drugs — ILAE Classification, Drug of Choice, Status Epilepticus and Adverse Effects

A seizure is a paroxysmal electrical discharge of neurons that changes function or behaviour. It may be provoked (hypoglycaemia, hyponatraemia, hypocalcaemia, alcohol withdrawal, meningitis, head injury) or unprovoked. A seizure counts as unprovoked when there is no provoking cause or it happens more than 7 days after an acute brain insult such as stroke or haemorrhage.

The ILAE 2014 practical definition says a person has epilepsy if any one of these applies: (1) at least two unprovoked (or reflex) seizures more than 24 hours apart; (2) one unprovoked seizure plus a recurrence risk of at least 60% over the next 10 years; or (3) diagnosis of an epilepsy syndrome.

Status epilepticus was once defined as a seizure lasting 30 minutes. The ILAE 2015 definition uses two time points for convulsive status: t1 = 5 minutes (treat — the seizure is unlikely to stop on its own) and t2 = 30 minutes (risk of long-term neuronal injury begins). In practice, a seizure lasting 5 minutes or more, or repeated seizures without recovery in between, is status epilepticus.

The 2017 ILAE operational classification first asks where the seizure starts: focal onset, generalized onset or unknown onset. Focal seizures are then described by awareness (aware or impaired awareness) and by whether the first feature is motor or non-motor. Generalized seizures are split into motor and non-motor (absence).

• New focal seizure types: automatisms, behaviour arrest, hyperkinetic, autonomic, cognitive and emotional.
• Either onset: atonic, clonic, epileptic spasms, myoclonic and tonic seizures can be focal or generalized.
• New generalized types: absence with eyelid myoclonia, myoclonic absence, myoclonic-atonic and myoclonic-tonic-clonic.
• Unknown onset seizures can still be described by their features (for example, unknown-onset tonic-clonic).

Antiseizure drugs are broadly broad-spectrum (work for many seizure types — valproate, levetiracetam, lamotrigine, topiramate, zonisamide, clobazam) or narrow-spectrum (mainly focal seizures — carbamazepine, oxcarbazepine, phenytoin, lacosamide, gabapentin, pregabalin, vigabatrin). When the seizure type is uncertain, a broad-spectrum drug is the safer first choice.

The temporal lobes are the commonest site of epileptogenicity, and mesial temporal structures account for nearly 80% of temporal lobe epilepsy. It is a focal epilepsy: an aura (rising epigastric sensation, nausea, olfactory or gustatory hallucination, déjà vu, fear), then behavioural arrest with a blank stare and oral and alimentary automatisms (lip-smacking, chewing) with ipsilateral hand automatisms and contralateral dystonic posturing. The commonest pathology in drug-resistant cases is hippocampal sclerosis.

Enzyme effects matter for interactions. Carbamazepine, phenytoin and phenobarbital induce CYP enzymes, so they lower levels of oral contraceptives and many other drugs. Valproate inhibits CYP enzymes and prolongs the half-life of lamotrigine. Levetiracetam is cleared without the hepatic CYP system and needs no slow titration.

Phenytoin kinetics: below about 10 mg/L elimination is first-order, but the enzymes saturate and elimination becomes zero-order at higher levels, so a small dose increase can cause a big rise in level. The therapeutic range is 10–20 mcg/mL; toxicity starts with nystagmus, then ataxia, slurred speech and coma.

Treat airway, breathing and circulation at the same time as giving drugs. The aim is to stop the seizure as fast as possible while supporting the patient.

1. Stabilise (0–5 min): position the airway, give oxygen, monitor, get IV access and check bedside glucose; if thiamine deficiency is possible give thiamine before dextrose.
2. First line — benzodiazepine: lorazepam 0.1 mg/kg IV (no faster than 2 mg/min) or diazepam 0.15 mg/kg IV; repeat once after 3–5 minutes if needed. Without IV access use IM, buccal, nasal or rectal routes — IM midazolam is better than IV lorazepam when no IV line is available (AES, Level A).
3. Second line — one IV antiseizure drug: fosphenytoin 20 mg PE/kg, phenytoin 20 mg/kg (no faster than 50 mg/min), levetiracetam 40–60 mg/kg (max 4,500 mg) or valproate about 30 mg/kg.
4. Refractory status (seizures continue after benzodiazepine and a second drug): continuous infusion of midazolam, propofol, thiopental or pentobarbital in the ICU with EEG monitoring.
5. Find the cause: CT head, electrolytes (Na, Ca, Mg), glucose, renal function, drug levels and toxicology, and lumbar puncture when infection is possible.

Valproate is the most teratogenic antiseizure drug. It raises the risk of neural tube defects (spina bifida, anencephaly) about tenfold — roughly 1–2% versus 0.1–0.2% in the general population — and also causes craniofacial, heart, limb defects and hypospadias. Exposure in the womb lowers IQ and increases autism spectrum disorder and ADHD risk in a dose-dependent way.

• Do not switch a well-controlled woman abruptly in pregnancy — breakthrough seizures are dangerous; use the lowest effective dose of a single drug.
• Folic acid is advised for every woman of child-bearing age on antiseizure drugs, ideally before conception.
• If status epilepticus occurs in the first trimester, lorazepam is still the first drug and levetiracetam is a good second-line choice.
• Enzyme inducers (carbamazepine, phenytoin) make hormonal contraception fail — counsel about reliable contraception.

Before starting carbamazepine, screen for HLA-B*1502 (and HLA-A*3101) where available, check a pregnancy test and a baseline blood count. Valproate must be avoided in urea cycle disorders (risk of hyperammonaemic encephalopathy) and liver failure.

• 'Status = 30 minutes' is the old definition; treatment starts at 5 minutes.
• Carbamazepine or phenytoin for absence or myoclonic seizures — wrong; they can aggravate both.
• Vigabatrin vs ACTH: ACTH is first line for infantile spasms overall; vigabatrin wins only in tuberous sclerosis.
• First unprovoked seizure in an adult who is back to normal does not always need long-term drugs — two unprovoked seizures (or one with ≥ 60% recurrence risk) define epilepsy.
• Hyponatraemia points to carbamazepine/oxcarbazepine; gum hypertrophy to phenytoin; weight loss and kidney stones to topiramate; visual field loss to vigabatrin.
• Juvenile myoclonic epilepsy — morning myoclonic jerks within an hour of waking, often photosensitive, 3–6 Hz polyspike-and-wave; valproate is the drug of choice but think twice in young women.

Related reading: Glasgow Coma Scale for the post-ictal patient, neurocysticercosis as a common cause of focal seizures in India, and pre-eclampsia and eclampsia for magnesium sulfate.