NeurologyTier 1Disease (DEADMAN)

Epilepsy

Description

Definitions - get these exactly right

Seizure - transient signs/symptoms from abnormal excessive or synchronous neuronal activity
Epilepsy = any one of:

1. >=2 unprovoked seizures >24 h apart, OR

2. 1 unprovoked seizure + >=60% recurrence risk over 10 years (e.g. a structural lesion, or an epileptiform EEG), OR

3. An epilepsy syndrome

Resolved - past the applicable age for an age-dependent syndrome, or seizure-free for 10 years with the last 5 off medication
Provoked (acute symptomatic) seizure - within 7 days of an acute insult (stroke, trauma, metabolic, withdrawal). Not epilepsy, and usually not an indication for long-term treatment
Drug-resistant epilepsy - failure of 2 appropriately chosen, adequately dosed, tolerated antiseizure medication schedules
- *Triggers referral for surgical evaluation - not a third drug*

ILAE 2017 classification - seizure onset first

Focal onset	Generalised onset	Unknown onset
Aware vs impaired awareness	Motor: tonic-clonic, tonic, clonic, myoclonic, atonic, epileptic spasms	Classify when more information emerges
Motor (automatisms, clonic, hyperkinetic, tonic) or non-motor (autonomic, behaviour arrest, cognitive, emotional, sensory)	Non-motor (absence): typical, atypical, myoclonic, eyelid myoclonia
Focal to bilateral tonic-clonic

Then classify the epilepsy type (focal/generalised/combined/unknown), then the syndrome, and always ask about aetiology and comorbidity at every level

Localising features of focal seizures

Temporal (mesial/uncal) - rising epigastric sensation, olfactory or gustatory hallucination, deja vu/jamais vu, fear, oro-alimentary automatisms (lip smacking, chewing), behaviour arrest, post-ictal confusion and dysphasia (if dominant)
Frontal - brief, frequent, nocturnal, bizarre hyperkinetic with rapid recovery and minimal post-ictal state; often misdiagnosed as non-epileptic; Jacksonian march, Todd's paresis
Parietal - contralateral paraesthesia, distortion of body image
Occipital - simple coloured circular visual phenomena, forced eye deviation, ictal blindness (vs migraine aura: seconds not minutes, coloured and round not black-and-white zigzags)

Epidemiology

Prevalence ~0.5-1%; lifetime risk of a single seizure ~10%
Bimodal incidence - highest in the first year of life and over 60, and the elderly peak is now the larger
Cerebrovascular disease (stroke) is the commonest identifiable cause of new-onset epilepsy in the elderly
~250,000 Australians with epilepsy
~30% become drug-resistant - a figure essentially unchanged despite 20 new drugs

Aetiopathogenesis

ILAE aetiological categories - ask about all six in every patient

Structural - stroke (commonest in the elderly), hippocampal sclerosis, trauma, tumour, cortical dysplasia, cavernoma, AVM, hypoxic-ischaemic injury, neurocysticercosis (commonest cause worldwide)
Genetic - juvenile myoclonic epilepsy, childhood absence, GEFS+, SCN1A (Dravet), LGI1
Infectious - meningitis, encephalitis, HIV, TB, neurocysticercosis, cerebral malaria
Metabolic - porphyria, mitochondrial disease, pyridoxine dependency, uraemia
Immune - autoimmune encephalitis (NMDAR, LGI1, CASPR2), rasmussen encephalitis
- Faciobrachial dystonic seizures + hyponatraemia = LGI1 encephalitis - immunotherapy, not more ASM
Unknown - still ~30-40%

Provoking factors for acute symptomatic seizures

Alcohol withdrawal (peaks 6-48 h), benzodiazepine withdrawal, illicit stimulants
Drugs lowering the seizure threshold - tramadol, bupropion, clozapine, tricyclics, theophylline, imipenem, quinolones, high-dose penicillin
Metabolic - hypoglycaemia, hyponatraemia, hypocalcaemia, hypomagnesaemia, uraemia, hepatic failure
Eclampsia; PRES; hypertensive encephalopathy
Sleep deprivation, missed medication, intercurrent illness - the three commonest triggers in established epilepsy

Diagnosis

*Epilepsy is diagnosed on the history, and the history is the witness's history - obtain it directly, by phone if necessary*

Seizure vs syncope vs psychogenic non-epileptic seizure

	Seizure	Syncope	PNES
Trigger	Sleep deprivation, flashing light, none	Standing, pain, emotion, prolonged standing	Emotional, situational
Prodrome	Aura (seconds), stereotyped	Nausea, sweating, greying vision, warmth	Variable
During	Rigid then rhythmic clonic; eyes OPEN and deviated; cyanosis	Pale, limp, brief (<15 s) irregular myoclonic jerks are common	Eyes CLOSED and resisting opening; asynchronous, waxing-waning, pelvic thrusting, side-to-side head shaking
Duration	1-3 min	Seconds	Often prolonged, >5 min
Recovery	Post-ictal confusion 5-30 min, headache, myalgia	Rapid and complete	Variable; may be tearful, rapidly oriented
Signs	Lateral tongue bite, incontinence, injury	Incontinence also occurs - it does not discriminate	Tongue tip bite, weeping, memory for the event

Lateral tongue biting is highly specific for a generalised tonic-clonic seizure
Convulsive syncope is very common and is routinely misdiagnosed as epilepsy - ask what happened before they fell
PNES coexists with epilepsy in 10-20% - the presence of one does not exclude the other

Investigations

ECG in every first seizure - long QT, Brugada, heart block: an arrhythmia misdiagnosed as epilepsy is lethal
Bloods - glucose, UEC, calcium, magnesium, FBE, LFT, CK (rises after a GTC), beta-hCG, toxicology
- Lactate rises rapidly and normalises within ~1-2 h after a GTC - a useful early discriminator
- Prolactin (within 10-20 min, with a baseline) - supportive but insensitive, and useless in frontal seizures
EEG
- Supports the diagnosis and classifies the epilepsy; it does NOT make or exclude the diagnosis
- Single routine interictal EEG sensitivity ~30-50%; rises to ~80-90% with sleep-deprived and repeated recordings
- ~1-2% of normal people have epileptiform discharges - never treat an EEG
- 3 Hz generalised spike-and-wave = typical absence; generalised polyspike-and-wave = JME
- Video-EEG telemetry for diagnostic uncertainty, PNES, and pre-surgical work-up
MRI brain with an epilepsy protocol (thin coronal FLAIR through the hippocampi) - in all adult-onset epilepsy, focal features, or drug resistance
- CT is for the acute setting only - it misses hippocampal sclerosis and dysplasia
Lumbar puncture if fever, immunosuppression, or suspected encephalitis; autoimmune encephalitis antibodies in serum and CSF if subacute onset with cognitive or psychiatric change

Management

A. After a first seizure

Treat only if the recurrence risk is high: abnormal MRI, epileptiform EEG, nocturnal seizure, or focal onset
- Otherwise recurrence risk ~30-40% at 2 years; treatment reduces early recurrence but does not change long-term remission
Provoked seizures: correct the cause, do not start an ASM (alcohol withdrawal -> benzodiazepine, thiamine)
Driving, safety and work advice from the first consultation - see below

B. Choosing an antiseizure medication - by seizure type

Seizure type	First-line
Focal (+/- bilateral tonic-clonic)	Levetiracetam or lamotrigine; carbamazepine/oxcarbazepine, sodium valproate (men)
Generalised tonic-clonic	Levetiracetam or lamotrigine; valproate where permissible
Idiopathic (genetic) generalised epilepsy incl. JME	Valproate is the most effective drug - but see the restriction below. Levetiracetam or lamotrigine are the practical first-line in anyone of childbearing potential
Absence	Ethosuximide (first-line for absence alone), valproate, lamotrigine
Myoclonic	Valproate, levetiracetam, clonazepam, topiramate

*Sodium valproate must not be used in anyone of childbearing potential unless every other option is unsuitable and a pregnancy prevention programme is in place*
- Neural tube defects ~1-2%, major malformation ~10%, and neurodevelopmental impairment in up to 30-40% - dose-related
- This is a change in practice that has moved the practical first-line for generalised epilepsy to levetiracetam or lamotrigine in women and girls
*Carbamazepine, oxcarbazepine, phenytoin, gabapentin, pregabalin and vigabatrin AGGRAVATE myoclonic and absence seizures - a classic exam trap: do not give carbamazepine for JME*
Monotherapy at the maximum tolerated dose before adding a second drug; titrate slowly (lamotrigine especially - rash and SJS/TEN, and the dose must be halved with valproate and doubled with enzyme inducers)

C. Key adverse effects and interactions

Drug	Watch
Levetiracetam	Irritability, aggression, depression (ask, and ask the family); renal dose adjustment
Lamotrigine	Rash/SJS - titrate slowly; interacts with valproate (halve) and the COCP (oestrogen lowers levels ~50%)
Sodium valproate	Teratogenicity, weight gain, tremor, alopecia, hepatotoxicity, pancreatitis, hyperammonaemia, thrombocytopenia, PCOS
Carbamazepine	Enzyme INDUCER - fails the COCP, DOACs, warfarin; hyponatraemia (SIADH), rash, *HLA-B\15:02 -> SJS in Han Chinese, Thai and other Southeast Asian ancestry - test before prescribing**
Phenytoin	Zero-order kinetics - small dose change, large level change; gum hypertrophy, ataxia, neuropathy, osteomalacia, enzyme inducer
Topiramate	Cognitive slowing, paraesthesia, stones, glaucoma, weight loss, teratogenic (cleft)
Perampanel	Serious psychiatric and behavioural reactions
Enzyme inducers generally	Contraceptive failure, vitamin D deficiency and osteoporosis, drug interactions

D. Drug-resistant epilepsy - after 2 failed drugs

Refer to a comprehensive epilepsy centre. Do not simply add a third drug
Re-examine the diagnosis first - is it PNES? cardiac? is the classification wrong? is the drug wrong for the seizure type? is adherence the issue?
Video-EEG telemetry + high-resolution MRI +/- PET, SPECT, MEG, intracranial EEG
Resective surgery - anterior temporal lobectomy for mesial temporal sclerosis achieves seizure freedom in ~60-70%, far better than any further drug; the main problem is that referral is delayed by a median of ~20 years
Neuromodulation - vagus nerve stimulation, responsive neurostimulation, deep brain stimulation (anterior thalamic nucleus)
Ketogenic or modified Atkins diet; laser interstitial thermal therapy; corpus callosotomy for drop attacks
Cannabidiol - PBS/TGA access for Dravet and Lennox-Gastaut

E. Status epilepticus - a medical emergency

Definition: >=5 min of continuous seizure, or >=2 seizures without recovery between
0-5 min - ABC, oxygen, glucose, IV access, thiamine if alcohol; check BSL immediately
5-20 min - benzodiazepine: IV midazolam or diazepam, or IM/buccal midazolam 10 mg if no access. Under-dosing benzodiazepines is the commonest error
20-40 min - second-line IV agent: levetiracetam 60 mg/kg, sodium valproate 40 mg/kg, or phenytoin 20 mg/kg - all three are equivalent (ESETT); choose by comorbidity and availability
>40 min - refractory: intubation and general anaesthesia (propofol, midazolam or thiopentone infusion) with continuous EEG
Find the cause in parallel - CT, bloods, toxicology, LP, autoimmune encephalitis
Non-convulsive status: consider in any unexplained prolonged post-ictal state or altered conscious state - it needs an EEG

F. Everything else - the part that actually changes lives

Driving: *Austroads Assessing Fitness to Drive* - private licence: generally 12 months seizure-free (shorter in defined circumstances such as a provoked seizure or a medication change); commercial: 10 years seizure-free and off medication**
- Advise, document, and tell the patient it is their obligation to notify the licensing authority
SUDEP - discuss it explicitly; risk ~1 in 1,000 patient-years, higher in drug-resistant epilepsy
Pregnancy - preconception counselling in every patient of childbearing potential from the time of diagnosis
- Folic acid 5 mg daily before conception; levetiracetam or lamotrigine preferred; monitor levels - lamotrigine and levetiracetam clearance rises substantially in pregnancy
- Register with the Australian Pregnancy Register for antiseizure medication
- Breastfeeding is encouraged on almost all ASMs
Safety: showers not baths, supervised swimming, avoid heights and unguarded machinery, cooking safety
Bone health (enzyme inducers), mood and cognition screening, seizure diary, adherence
Epilepsy Action Australia / Epilepsy Foundation; seizure management plan for school or workplace

Associations

SUDEP risk factors - the established list

High frequency of generalised tonic-clonic seizures (the dominant risk factor)
Nocturnal seizures without supervision
Poor antiseizure medication adherence (and subtherapeutic levels)
Long duration of epilepsy
Also: young adult, male, drug-resistant epilepsy, polytherapy, intellectual disability, alcohol

Comorbidities

Depression and anxiety (~30%, and bidirectional), suicide risk 3x
Psychosis - ictal, post-ictal and interictal
Cognitive impairment, memory dysfunction (especially mesial temporal)
Migraine, ADHD, autism spectrum disorder
Osteoporosis and fracture - enzyme inducers, falls, vitamin D deficiency
Obstructive sleep apnoea - treating it improves seizure control
PCOS (valproate), sexual dysfunction, contraceptive failure
Stigma, unemployment, loss of licence, social isolation

Natural history & complications

~60-70% achieve sustained seizure freedom on medication
- ~50% respond to the first drug; ~13% to the second; <5% to any subsequent drug - the reason 2 failures defines drug resistance
~30% are drug-resistant; of these, surgery offers seizure freedom in well-selected cases
Many childhood syndromes remit (childhood absence ~65-70%); juvenile myoclonic epilepsy usually requires lifelong treatment (~90% relapse on withdrawal)

Withdrawing medication

Consider after >=2 years seizure-free, weighing:
- Against withdrawal: JME, abnormal MRI, abnormal EEG, focal epilepsy, long duration before control, history of status
- Practical: driving licence implications during and after withdrawal - discuss before starting the taper
Relapse risk ~30-40% at 2 years; taper over months

Complications

Injury - fractures, burns, drowning (bath and swimming deaths are the classic avoidable ones), road trauma
Status epilepticus - mortality ~10-20%, higher in refractory status
SUDEP
Todd's paresis (post-ictal focal weakness, resolves over hours - a stroke mimic)
Aspiration, rhabdomyolysis, posterior shoulder dislocation, vertebral compression fracture
Psychiatric and cognitive comorbidity; loss of employment and driving; stigma

Monitor

Seizure frequency and type (diary), adherence, triggers, sleep
Mood, suicidality, cognition - at every visit
Drug levels only where useful (phenytoin, pregnancy, suspected non-adherence, toxicity) - not routinely
FBE/LFT on valproate and carbamazepine; sodium on carbamazepine; vitamin D and bone density on enzyme inducers
Contraception, pregnancy plans and driving status - revisit at every review

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