Epilepsy and status epilepticus — seizure classification, AED selection and status protocol

Definition / Overview

• Epilepsy is defined as two or more unprovoked seizures occurring more than 24 hours apart, or one unprovoked seizure with a high probability of recurrence (e.g. abnormal EEG, structural lesion on neuroimaging).
• A provoked seizure occurs in the context of an identifiable and reversible trigger (e.g. hyponatraemia, hypoglycaemia, alcohol withdrawal, drug toxicity, CNS infection), these do not constitute epilepsy and generally do not warrant long-term antiepileptic drug (AED) therapy.
• Status epilepticus (SE) is defined classically as seizure activity lasting $\geq 30$ minutes, or recurrent seizures without return to baseline consciousness between episodes. In clinical practice, any seizure lasting $> 5$ minutes in adults (or $> 10$ minutes in children) should be treated as SE without waiting for the 30-minute threshold to be reached.
• Generalised convulsive status epilepticus (GCSE) is a neurological emergency carrying an all-cause mortality of approximately 30%.

Seizure Classification

Focal (Partial) Seizures

Seizures arising from a discrete cortical network in one hemisphere.

• An aura is itself a simple focal seizure, sensory, autonomic, or psychic symptoms arising from focal cortical activation.
• A prodrome (pre-seizure sensation, e.g. mood change hours before) differs from an aura and does not represent ictal activity.

Generalised Seizures

Involve both hemispheres from onset; no localising aura.

Unknown Onset

• Used when onset cannot be determined from available information.

Diagnosis & Investigation

History

• Characterise the episode: onset (focal vs. generalised), duration, post-ictal phase (supports seizure over syncope), tongue bite (lateral), urinary incontinence, witnesses.
• Distinguish from syncope: prodromal pre-syncope, brief tonic stiffening in syncope (convulsive syncope) can mimic seizure; however, rapid recovery and absence of post-ictal confusion favour syncope.
• Ask specifically about provoking factors, sleep deprivation, alcohol use, medication changes, family history, prior febrile convulsions, head trauma.

Key Investigations

• Note: 30-50% of patients with non-epileptic events ("pseudoseizures") also have true epileptic seizures, the two diagnoses are not mutually exclusive.
• Autoimmune encephalitis (e.g. anti-NMDAR, LGI1, CASPR2) should be considered in new-onset refractory seizures, particularly when associated with behavioural change, movement disorder, or autonomic instability.

When to Start an AED After a First Seizure

• Generally not indicated after a single unprovoked seizure, as approximately two-thirds will not recur.
• Initiate AED therapy after a first seizure when:
• Abnormal EEG (epileptiform activity)
• Structural lesion on MRI or CT
• Neurological deficit
• Strong family history of epilepsy
• Initiate AED therapy after a second unprovoked seizure, recurrence risk rises to approximately 75%.
• Provoked seizures: treat the underlying cause; AEDs not routinely indicated long-term.

Antiepileptic Drug Selection

Principles

• Start monotherapy and titrate to effect or tolerability before adding a second agent.
• Polytherapy should be reserved for failure of at least two adequate sequential monotherapy trials.
• Failure to achieve seizure freedom with two adequately trialled drugs defines drug-resistant epilepsy, refer for presurgical evaluation.
• Approximately 50% of patients achieve seizure freedom with the first AED; a further 10-15% achieve control with a second.

AED Selection by Seizure Type

Key Drug Pharmacology

Special Populations

• Women of childbearing potential: Minimise valproate use; lamotrigine or levetiracetam preferred; folic acid $5\,\text{mg}$ daily pre-conception; counsel on teratogenicity risk of polytherapy vs. monotherapy; monitor lamotrigine levels in pregnancy (clearance increases significantly).
• Older adults: Risk of falls, drug interactions, cognitive impairment, prefer levetiracetam, lamotrigine, or low-dose lacosamide; avoid phenobarbitone.
• Renal impairment: Levetiracetam, gabapentin, pregabalin require dose reduction.
• Hepatic impairment: Avoid valproate; prefer renally cleared agents.
• Alcohol-related seizures: Address withdrawal acutely with benzodiazepines; long-term AEDs not indicated if abstinence achieved.

Status Epilepticus: Emergency Protocol

Pathophysiology

• Sustained seizure activity leads to GABA receptor internalisation and progressive resistance to benzodiazepines over time, this is the mechanistic basis for escalating treatment urgency.
• Systemic consequences within 5-30 minutes of GCSE onset: hyperthermia, metabolic acidosis, hypoxia, hyperglycaemia, autonomic instability, rhabdomyolysis.
• Beyond 30-45 minutes, convulsive movements may become subtle (minor finger jerking, eye deviation) despite ongoing electrographic seizures, do not interpret clinical quietening as seizure cessation.
• Prolonged SE causes irreversible neuronal injury via glutamate excitotoxicity; brain injury from NCSE may evolve over hours to days.

Stepwise Management Algorithm

Immediate actions (all phases):

• Airway, breathing, circulation, position patient, high-flow oxygen, pulse oximetry
• IV access; finger-prick glucose
• Bloods: glucose, electrolytes, renal function, LFTs, FBC, AED levels, toxicology, blood gas
• Thiamine $100\,\text{mg}$ IV before dextrose if alcohol use or malnutrition suspected
• Correct hypoglycaemia, hyponatraemia, hypocalcaemia if identified

Phase 1, Impending/Early SE (5-30 minutes): Benzodiazepine

1. Lorazepam $0.1\,\text{mg/kg}$ IV (maximum $4\,\text{mg}$ per dose; may repeat once after 5 minutes), preferred first-line IV benzodiazepine
2. If no IV access: midazolam $0.2\,\text{mg/kg}$ IM (buccal or intranasal midazolam also acceptable in pre-hospital setting)
3. Diazepam $0.2\,\text{mg/kg}$ PR is an alternative if no other route available

Phase 2, Established SE (30-60 minutes): IV Antiepileptic Drug

Choose one:

• These agents have broadly similar efficacy in established SE; choice is guided by patient-specific factors (seizure type, comorbidities, prior AED use).

Phase 3, Refractory SE (30 minutes-48 hours): Anaesthetic Agents

Requires ICU admission, continuous EEG monitoring, and airway management.

1. Midazolam infusion $0.2\,\text{mg/kg}$ IV bolus then $0.2-0.6\,\text{mg/kg/h}$ infusion
2. Propofol $2\,\text{mg/kg}$ IV bolus then $2-10\,\text{mg/kg/h}$ infusion, risk of propofol infusion syndrome with prolonged high-dose use
3. Thiopentone (pentobarbital) $5\,\text{mg/kg}$ IV load then $1-5\,\text{mg/kg/h}$, reserve for most refractory cases; significant haemodynamic depression

Phase 4, Super-refractory SE ($> 48$ hours):

• Continue anaesthetic agents
• Consider: ketamine, isoflurane, ketogenic diet, immunomodulation (if autoimmune aetiology suspected), magnesium
• Seek expert neurological input; consider repeat neuroimaging, LP, autoimmune and paraneoplastic panel

Non-Convulsive Status Epilepticus (NCSE)

• Defined by electrographic seizure activity with absent or minimal motor features, accompanied by impaired consciousness or behavioural change.
• Suspected in any patient with unexplained persistent altered consciousness, EEG is essential.
• Approximately 20-30% of patients with GCSE who clinically settle will develop NCSE, perform EEG if patient does not return to baseline within 30-60 minutes of apparent seizure cessation.
• Also suspected when GCSE is treated with neuromuscular blockade, clinical examination cannot exclude ongoing seizures.
• Treatment is less immediately urgent than GCSE (systemic metabolic complications are less severe) but must be treated promptly to prevent neuronal injury.

Complications & Special Considerations

Post-ictal States

• Post-ictal confusion typically lasts minutes to hours; prolonged post-ictal state ($> 1$ hour) should prompt EEG to exclude NCSE.
• Todd's paralysis: transient focal neurological deficit (usually motor) lasting minutes to hours after a focal seizure, resolves spontaneously but must be distinguished from acute stroke (MRI diffusion-weighted imaging if diagnostic uncertainty).

Mortality and SUDEP

• Overall mortality in epilepsy is two to three times higher than the general population.
• Sudden unexpected death in epilepsy (SUDEP): poorly understood; likely involves brainstem-mediated cardiorespiratory effects of seizures. Higher risk in young patients with uncontrolled convulsive seizures, nocturnal seizures, and possible genetic cardiac channelopathy overlap.
• All patients with epilepsy should be counselled about SUDEP risk as part of shared decision-making.

Drug-Resistant Epilepsy

• Defined as failure of two adequately trialled AEDs (appropriate for seizure type, adequate dose, adequate duration).
• Referral for presurgical evaluation at a comprehensive epilepsy centre is warranted, includes high-density EEG, prolonged video-EEG, MRI with epilepsy protocol, neuropsychology, and where indicated, PET, SPECT, or invasive monitoring.
• Surgical resection (e.g. temporal lobectomy for mesial temporal sclerosis) offers seizure freedom in 60-70% of carefully selected patients.
• Neurostimulation options for non-surgical candidates: vagus nerve stimulation (VNS), responsive neurostimulation (RNS), deep brain stimulation (DBS), these reduce seizure frequency in most patients but seizure freedom is achieved in only a minority ($\sim 15\%$ with RNS).

Long-term Care & FRACP Viva Considerations

Lifestyle and Safety Counselling

• Driving: must not drive for a period following any seizure, specific requirements vary by state/territory (Australian standards specify seizure-free intervals for private and commercial licences). Advise patients to check jurisdiction-specific regulations.
• Water safety: no unsupervised swimming, no baths in deep standing water.
• Heights and machinery: avoid activities where loss of consciousness would cause harm to self or others.
• Alcohol: heavy use ($\geq 3$ standard drinks/day) lowers seizure threshold.
• Sleep deprivation and stress: common precipitants, particularly in JME.
• OCP interactions: enzyme-inducing AEDs (carbamazepine, phenytoin, phenobarbitone, oxcarbazepine, topiramate) reduce OCP efficacy, advise barrier contraception or use of non-enzyme-inducing AED.

Monitoring

• AED levels: useful for phenytoin (narrow therapeutic window, zero-order kinetics), carbamazepine, valproate, and phenobarbitone; less clinically useful for levetiracetam and lamotrigine (except in pregnancy).
• Routine bloods (FBC, renal, liver function) at initiation and periodically, valproate requires monitoring for hepatotoxicity and thrombocytopaenia; carbamazepine for hyponatraemia and blood dyscrasias.
• Bone health: enzyme-inducing AEDs accelerate vitamin D metabolism, monitor bone density in long-term use; supplement calcium and vitamin D.

Indigenous Health Equity

• Aboriginal and Torres Strait Islander peoples and Māori populations have higher rates of epilepsy associated with remote setting barriers to care, higher burden of traumatic brain injury, CNS infections, and metabolic disease.
• Culturally safe communication, involvement of family and community in shared decision-making, and addressing structural barriers (medication access, transport to specialist care) are essential components of equitable epilepsy management.

Key Viva Talking Points

• Differentiate provoked vs. unprovoked seizure, determines whether AED initiation is appropriate.
• Articulate the rationale for escalating SE treatment in phases, including the pharmacological basis for benzodiazepine refractoriness.
• Valproate in women of childbearing potential, when it is and is not appropriate, and the counselling required.
• Post-GCSE: always ask whether patient has returned to baseline, if not, request urgent EEG to exclude NCSE.
• Drug-resistant epilepsy referral pathway, do not continue adding AEDs indefinitely without surgical evaluation.

Sources

• Therapeutic Guidelines (eTG)
• Australian Medicines Handbook (AMH)