Epilepsy and Epileptic Syndromes - A Comprehensive Overview

1. Definitions

1. At least two unprovoked (or reflex) seizures occurring more than 24 hours apart
2. One unprovoked seizure with a probability of further seizures similar to the general recurrence risk (≥60%) after two unprovoked seizures, occurring over the next 10 years
3. Diagnosis of an epilepsy syndrome

2. Classification Framework

Level 1: Seizure Type
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Level 2: Epilepsy Type
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Level 3: Epilepsy Syndrome + Etiology

3. Classification of Seizure Types (ILAE 2017)

A. Focal Onset Seizures

• Motor: clonic, tonic, myoclonic, epileptic spasms, hyperkinetic, automatisms
• Non-motor: sensory (tingling, visual), autonomic (flushing, epigastric rising), cognitive (déjà vu, forced thinking), emotional (fear, laughter), behavior arrest

• Temporal lobe: Rising epigastric aura, fear, déjà vu/jamais vu, oroalimentary automatisms (lip smacking, chewing), postictal aphasia if dominant hemisphere
• Frontal lobe: Often nocturnal, brief, prominent motor features, asymmetric tonic posturing, hyperkinetic movements, minimal postictal confusion
• Parietal lobe: Somatosensory aura (tingling, numbness) with sensory march, distorted body image
• Occipital lobe: Elementary visual hallucinations (flashing colored lights, geometric shapes), forced blinking, nystagmoid eye movements

B. Generalized Onset Seizures

C. Unknown Onset

• Tonic-clonic (onset unwitnessed)
• Behavior arrest
• Epileptic spasms

4. Distribution of Seizure Types by Age

• Absence and myoclonic seizures predominate in childhood/adolescence
• Complex partial (focal with dyscognitive features) seizures peak in older individuals
• Generalized tonic-clonic seizures are prominent in the 15-34 age group

5. Classification of Epilepsies by Type (ILAE 2017)

1. Focal epilepsy - seizures arise consistently from one hemisphere
2. Generalized epilepsy - bilateral networks involved from the start
3. Combined generalized and focal epilepsy - patient has both seizure types
4. Unknown epilepsy - type cannot be determined

6. Etiology (ILAE 2017 Framework)

7. Major Epileptic Syndromes

Neonatal Period

• Onset: first 3 months of life
• Seizures: tonic spasms in clusters; brief
• EEG: burst-suppression pattern (alternating high-amplitude bursts and electrical silence)
• Etiology: structural brain malformations
• Prognosis: very poor; often evolves to West syndrome

• Self-limited focal clonic or apneic seizures in first week
• KCNQ2/KCNQ3 mutations in familial form
• Prognosis: good; seizures typically remit

Infancy

• Age of onset: 3-12 months (peak 4-6 months)
• Triad: Epileptic spasms + hypsarrhythmia on EEG + developmental regression
• Spasms: brief flexion/extension of trunk and limbs, in clusters on awakening
• EEG - Hypsarrhythmia: chaotic, high-voltage, disorganized background with multifocal spikes

• Treatment: ACTH (first-line), vigabatrin (especially in tuberous sclerosis), high-dose steroids
• Prognosis: ~50% evolve to Lennox-Gastaut syndrome

• Onset: 5-8 months; often febrile, prolonged hemiclonic seizures
• SCN1A mutations (loss-of-function) in ~80%
• Multiple seizure types develop: focal, myoclonic, absence, tonic-clonic
• Sodium channel blockers (carbamazepine, lamotrigine) may WORSEN seizures - CONTRAINDICATED
• Treatment: valproate, clobazam, stiripentol, cannabidiol (Epidiolex)

Childhood

• Age: 4-10 years; female predominance
• Multiple daily absence seizures (20-200/day); 5-20 seconds; no postictal period
• EEG: 3-Hz generalized spike-and-wave activity
• Hyperventilation reliably provokes attacks
• Treatment: ethosuximide (first-line), valproate, lamotrigine
• 60-70% achieve seizure remission by adolescence

• Age: 7-10 years; male slight predominance
• Focal sensorimotor seizures: facial twitching, hypersalivation, speech arrest, hemifacial clonic activity; often nocturnal
• EEG: characteristic high-amplitude centrotemporal sharp waves with sleep activation

• Prognosis: remits by age 16 in virtually all; often no treatment needed

• Age: 3-10 years (peak 3-5 years)
• Triad: Multiple seizure types (tonic, atonic/drop attacks, atypical absences) + slow spike-and-wave (<2.5 Hz) + cognitive dysfunction
• EEG: slow spike-and-wave in waking; bursts of fast paroxysmal activity (~10 Hz) in sleep
• May evolve from West syndrome
• Drug-resistant; treatment: valproate, lamotrigine, rufinamide, clobazam, cannabidiol, felbamate
• Prognosis: poor; chronic course, cognitive deterioration

• Myoclonic jerks immediately followed by atonic component causing falls
• EEG: polyspike-wave and irregular slow spike-wave
• Treatment: valproate, ethosuximide; ketogenic diet highly effective

• Age: mean 7 years; male predominance
• Myoclonic absences: impaired consciousness + very prominent myoclonus of upper extremities, lasting 10-60 seconds; recurring multiple times/day
• EEG: 3-Hz generalized rhythmic spike-and-wave
• Resistant to monotherapy; dual therapy (valproate + ethosuximide) often required

• Cognitive decline associated with continuous spike-and-wave in slow-wave sleep
• Seizures often easily controlled; neuropsychological decline is the main problem

• Onset: 2-8 years (peak 5-7 years)
• Acquired verbal agnosia/aphasia in a child with previously normal language
• EEG: continuous spike-wave during slow sleep, especially over temporal regions
• Related to CSWS; seizures often controlled but language may not recover fully

• Age: 3-6 years
• Prolonged autonomic seizures: vomiting, eye deviation, pallor, loss of consciousness
• EEG: occipital and multifocal spike-waves
• Excellent prognosis; usually self-limited

Adolescence and Adulthood

• Onset: 10-17 years
• Less frequent absences than CAE; often accompanied by GTC seizures
• Responds to valproate and lamotrigine
• Usually persists into adulthood (unlike CAE)

• Onset: 12-18 years
• Classic triad: Morning myoclonic jerks (on awakening) + GTC seizures + sometimes absence seizures
• Triggered by sleep deprivation, alcohol, photostimulation
• EEG: 4-6 Hz polyspike-and-slow-wave discharges
• Treatment: valproate (most effective), levetiracetam, lamotrigine
• Lifelong treatment usually needed (80-90% relapse if medication withdrawn)

• CHRNA4 and CHRNB2 mutations (nicotinic acetylcholine receptor)
• Clusters of brief nocturnal hypermotor/hyperkinetic seizures
• Often misdiagnosed as parasomnias
• Responds well to carbamazepine

• Unverricht-Lundborg disease (cystatin B gene; most common PME)
• Lafora disease (progressive, fatal; polyglucosan bodies in neurons)
• MERRF (mitochondrial; myopathy, ragged-red fibers)
• Neuronal ceroid lipofuscinoses
• Sialidoses

• Most common epilepsy in adults; most common surgically remediable epilepsy
• Rising epigastric aura → fear → déjà vu → automatisms (oroalimentary, manual)
• Substrate: hippocampal sclerosis (most common structural cause)
• MRI: hippocampal atrophy and T2 signal increase
• Treatment: carbamazepine or oxcarbazepine (first-line); surgery highly effective (~70% seizure-free)

• Photosensitive epilepsy (most common: flashing lights)
• Reading epilepsy
• Hot-water epilepsy
• Musicogenic epilepsy

8. Pathophysiology

Cellular and Network Mechanisms

9. Epidemiology

• Prevalence: approximately 1-2% of the population worldwide
• Incidence: 40-70 per 100,000 per year; bimodal (peaks in infancy/childhood and >65 years)
• Lifetime risk of at least one seizure: ~10%; lifetime risk of epilepsy: ~3%
• Drug-resistant epilepsy (failure of ≥2 appropriate ASMs): affects ~30% of patients

• Prior CNS infection (meningitis/encephalitis)
• Head trauma (especially penetrating; Vietnam Head Injury Study showed 53% post-traumatic epilepsy at 15 years)
• Stroke and cerebrovascular disease (leading cause in elderly)
• Febrile seizures complicated (prolonged, focal, or multiple)
• Family history
• Cortical malformations

10. Diagnostic Evaluation

History (Most Important)

• Detailed ictal semiology from patient AND witness
• Age of onset, seizure frequency, duration, postictal features
• Precipitants, sleep relationship, diurnal pattern
• Birth history, developmental milestones, family history

EEG

• Standard interictal EEG: sensitivity ~50% for a single routine study; increases to ~90% after three studies
• Activation procedures: hyperventilation (provokes absence), photic stimulation, sleep deprivation
• Prolonged video-EEG monitoring: gold standard for ictal characterization and surgical planning
• Interictal epileptiform discharges (IEDs): spikes, sharp waves, spike-and-wave complexes

Neuroimaging

• MRI is the imaging of choice: high-resolution 3T with epilepsy protocol (thin cuts, coronal hippocampal T2/FLAIR, T1 volumetrics)
• CT: used acutely to rule out hemorrhage, tumors, calcifications (neurocysticercosis)
• PET (FDG): interictal hypometabolism at seizure focus; used pre-surgically
• SPECT (ictal/interictal subtraction = SISCOM): identifies ictal hyperperfusion zone

Laboratory

• Glucose, electrolytes (Na, Ca, Mg), renal/hepatic function, CBC
• Specific: lactate/pyruvate (mitochondrial disease), amino acids, CSF analysis
• Genetic testing: gene panels for suspected genetic epilepsies

11. Differential Diagnosis

12. Treatment

Principles

• First-line: antiseizure medication (ASM) monotherapy
• Treat underlying cause if identified
• Avoid precipitants: sleep deprivation, alcohol, fever, specific triggers
• Goal: seizure freedom without unacceptable side effects

When to Start ASMs

• After two unprovoked seizures
• After one unprovoked seizure if recurrence risk ≥60% (structural lesion, epileptiform EEG, nocturnal seizure, Todd's palsy)

Antiseizure Medications by Seizure/Syndrome Type

• Dravet syndrome (SCN1A loss-of-function)
• Lennox-Gastaut syndrome (may worsen absence/atonic seizures)
• Generalized epilepsies with absence (carbamazepine, vigabatrin)

Drug-Resistant Epilepsy

• Epilepsy surgery (most effective for drug-resistant focal epilepsy: ~70% seizure-free after temporal lobectomy)
• Vagus nerve stimulation (VNS): reduces seizure frequency by 50% in ~50% of patients
• Responsive neurostimulation (RNS): closed-loop brain stimulation at seizure onset zone
• Deep brain stimulation (DBS): anterior nucleus of thalamus
• Ketogenic diet: high-fat, low-carbohydrate diet; especially effective in children; mechanism involves KATP channel activation and reduced glutamate synthesis
• Radiosurgery (Gamma Knife): for mesial TLE, hypothalamic hamartoma

13. Special Situations

Status Epilepticus (SE)

• Convulsive SE: Continuous seizure >5 minutes or repeated seizures without recovery
• Initial management: benzodiazepines (IV lorazepam 0.1 mg/kg, or IM midazolam)
• Second-line if refractory: IV levetiracetam, valproate, fosphenytoin
• Refractory SE (RSE): anesthetic agents (propofol, midazolam infusion, barbiturate coma)
• Non-convulsive SE (NCSE): altered consciousness + seizure activity on EEG; requires EEG monitoring for diagnosis

Women with Epilepsy

• Catamenial epilepsy: seizure exacerbation perimenstrually (progesterone withdrawal)
• Valproate is teratogenic (neural tube defects, cognitive effects in offspring); avoid in women of childbearing age unless no alternatives
• Enzyme-inducing ASMs (carbamazepine, phenytoin) reduce contraceptive efficacy
• Folic acid supplementation pre-conception (5 mg/day) for all women on ASMs

Febrile Seizures

• Affect 2-5% of children aged 6 months-5 years
• Simple: <15 min, generalized, single in 24h - excellent prognosis
• Complex: >15 min, or focal, or recurs within 24h - increased epilepsy risk
• Febrile Seizures Plus (FS+): febrile seizures extending beyond usual age; may evolve to GEFS+

14. Comorbidities

• Depression: prevalence ~36% (vs. 11% in healthy controls); bidirectional relationship with epilepsy
• Anxiety: elevated risk; especially temporal lobe epilepsy
• ADHD: more than twice as prevalent
• Cognitive impairment: particularly in early-onset or drug-resistant epilepsy
• Migraine: risk ratio 2.4x compared to controls
• Sleep disorders: excessive daytime sleepiness common
• Sudden Unexpected Death in Epilepsy (SUDEP): occurs in ~1/1000 person-years in epilepsy; risk factors include nocturnal GTC seizures, frequent seizures, prone sleeping position

Summary: Key Epileptic Syndromes at a Glance