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Epilepsy: A Comprehensive Overview

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1. DEFINITION

• At least two unprovoked seizures occur, more than 24 hours apart, OR
• A single unprovoked seizure occurs when the risk of recurrence is ≥60% (e.g., established structural brain abnormality, or clear epileptiform features on EEG)

• Population prevalence: 0.7%–0.8% (higher in low/middle-income countries)
• Lifetime risk of a single seizure: ~5%; lifetime risk of epilepsy: >3%
• Incidence is highest at the extremes of life — before age 20 or after age 60
• Approximately 500,000 people in the UK have epilepsy

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2. CLASSIFICATION OF EPILEPSY

A. By Seizure Onset

B. Epilepsy Types

1. Generalised epilepsy — all seizures originate at or rapidly engage bilateral brain networks (subcortical or cortical)
2. Focal epilepsy — all seizures arise from networks within one hemisphere
3. Combined generalised and focal epilepsy — multiple seizure types (e.g., Dravet syndrome, Lennox-Gastaut)
4. Unknown type

C. Generalised Seizure Subtypes

• Tonic–clonic (grand mal)
• Clonic
• Tonic
• Myoclonic
• Myoclonic–tonic–clonic
• Myoclonic–atonic
• Atonic
• Epileptic spasms

• Typical absence
• Atypical absence
• Myoclonic absence
• Eyelid myoclonia

D. Focal Seizure Subtypes

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3. PATHOPHYSIOLOGY

General Mechanism

• Inhibitory: GABA (gamma-aminobutyric acid) acts on ion channels to enhance chloride influx, reducing chances of action potential formation
• Excitatory: Glutamate and aspartate allow sodium and calcium influx, producing the opposite effect

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Focal Epilepsy — Pathophysiology

• Focal infection
• Tumour
• Hamartoma
• Trauma-related scarring
• Hippocampal sclerosis (the leading cause in adults)
• Cortical dysplasia, vascular malformations, etc.

• Remain localised → symptoms reflect the function of that cortical region
• Spread to temporal lobes → impairment of awareness (formerly "complex partial")
• Spread to both hemispheres → secondary generalized (focal-to-bilateral tonic–clonic)

• Occipital lobe → visual phenomena (lights, coloured scotomas)
• Temporal lobe → déjà vu, jamais vu, olfactory/gustatory hallucinations, automatisms
• Sensory strip → burning, tingling
• Motor strip → focal jerking (Jacksonian march)
• Frontal lobe → limb posturing, bizarre behaviour, hyperkinetic movements

• Hippocampal sclerosis (main cause of temporal lobe epilepsy; associated with childhood febrile convulsions; visible on MRI)
• Traumatic brain injury (risk significant with depressed skull fracture, penetrating injury, intracranial haemorrhage)
• Brain surgery (seizures in up to 17%)
• Brain tumours (cause 6% of adult-onset epilepsy)
• Vascular disorders — stroke (most common cause after age 60), cortical venous thrombosis, cavernomas, AVMs
• Developmental disorders — neuronal migration defects, cortical dysplasia, hamartomas
• Infections — encephalitis, cerebral abscess, neurocysticercosis, tuberculoma, HIV
• Autoimmune/inflammatory — anti-NMDA receptor encephalitis, anti-LGI-1, anti-VGKC encephalitis, MS, SLE, vasculitis

• Many single-gene epilepsy disorders involve mutations of voltage- or ligand-gated neuronal ion channels (channelopathies)
• Autosomal dominant nocturnal frontal lobe epilepsy — variants in neuronal nicotinic acetylcholine receptor gene
• Over 200 multisystemic genetic disorders include epilepsy (e.g., tuberous sclerosis, mitochondrial cytopathies)

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Generalised Epilepsy — Pathophysiology

• The brain is structurally normal
• Abnormalities of ion channels influencing neuronal firing, neurotransmitter release, and synaptic connections are the underlying molecular pathological substrates
• Likely polygenic with complex inheritance — almost all become apparent before age 35
• EEG shows spike and wave discharges

• Childhood absence epilepsy — absence seizures; spontaneous remission by age 18 usual
• Juvenile absence epilepsy (JAE) — less frequent absences than childhood form; ~80% develop GTCS; 80% seizure-free in adulthood
• Juvenile myoclonic epilepsy (JME) — myoclonic jerks + GTCS ± absences; 3–6 Hz generalized polyspike-wave on EEG; responds to treatment but requires lifelong therapy
• GTCS on awakening — GTCS, sometimes myoclonus; spike and wave on waking and sleep onset

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Combined Generalised and Focal Epilepsy

• Channelopathy caused by variants in the sodium channel gene SCN1A
• Presents in the first year of life with a mixture of generalised and focal onset seizures
• Seizures are intractable; an epileptic encephalopathy develops with cognitive and behavioural regression

• Multiple causes (various structural brain abnormalities or presumed genetic aetiologies)
• Results in multiple seizure types (particularly tonic seizures in sleep)
• Cognitive decline and diffuse slow spike-and-wave and paroxysms of fast activity on EEG

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Metabolic Causes — Pathophysiology

• Genetic metabolic disorders (e.g., mitochondrial Leigh syndrome, glucose transporter deficiency) cause epilepsy
• Transient metabolic abnormalities (hyponatraemia, hypoglycaemia, uraemia) cause acute symptomatic seizures; if severe enough to cause brain injury, epilepsy may follow
• Chronic alcohol use: causes epilepsy; repeated withdrawals predispose to ongoing seizure risk; alcohol-induced hypoglycaemia and head injury also contribute

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4. SIGNS AND SYMPTOMS

By Seizure Type

Generalised Tonic-Clonic Seizure (GTCS / Grand Mal)

Absence Seizures (Petit Mal)

• Always starts in childhood
• Loss of awareness with blank, vacant expression for <10 seconds
• Abrupt return to normal, as though nothing happened
• Slight fluttering of eyelids; no motor manifestations
• Can occur 20–30 times per day; often mistaken for daydreaming
• Accompanied by 3 Hz spike-and-wave on EEG

Myoclonic Seizures

• Brief, momentary jerking movements, predominantly arms
• More marked in the morning or on awakening
• Provoked by fatigue, alcohol, sleep deprivation
• May cause sudden involuntary twitch of finger or hand

Atonic Seizures

• Brief loss of muscle tone → heavy falls with or without loss of consciousness
• Only occur in the context of epilepsy syndromes involving other seizure types

Tonic Seizures

• Generalised increase in tone + loss of awareness
• Usually part of an epilepsy syndrome; unlikely to be isolated

Clonic Seizures

• Similar to tonic-clonic but no preceding tonic phase

Epileptic Spasms

• Mainly in infancy; unusual in adult practice
• Marked contractions of axial musculature, lasting a fraction of a second
• Recurring in clusters of 5–50, often on awakening
• Signify widespread cortical disturbance

Focal Aware Seizures (formerly simple partial)

• Awareness fully retained throughout; patient remembers entire event
• Motor: focal clonic/myoclonic movements; Jacksonian march
• Sensory: spreading paraesthesiae, burning, tingling
• Autonomic, cognitive, or emotional symptoms (aura)

Focal Impaired Awareness Seizures (formerly complex partial)

• Usually arise from temporal lobe (60%) or frontal lobe
• Preceding aura followed by complete or partial loss of awareness for 1–2 minutes
• Patient does not remember the episode
• Automatisms: lip-smacking, fidgeting, picking movements, walking in a circle, undressing
• Short period of post-ictal confusion may follow
• May evolve to bilateral tonic–clonic seizure

Frontal Lobe Seizures

• Bizarre behaviour patterns: limb posturing, sleepwalking, frenetic ill-directed motor activity, incoherent screaming
• Tonic posturing; forced head and eye deviation away from seizure onset
• "Figure of 4" or "fencing posture" (supplementary motor area)
• Abrupt onset; stereotyped; often nocturnal

Temporal Lobe Non-Motor Auras

• Cognitive: déjà vu, jamais vu
• Emotional: fear (may mimic panic attacks)
• Sensory: olfactory, gustatory, auditory hallucinations; vertigo
• Autonomic: abdominal rising sensation, nausea

Todd's Paralysis

• Local temporary paralysis of limbs following focal motor seizure
• Indicates spread of seizure activity along the motor homunculus

Epilepsia Partialis Continua

• Continuous focal jerking with retained awareness lasting at least an hour (sometimes days or years)
• Usually from contralateral motor cortex; face and hand most commonly involved
• Often associated with structural cause

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Trigger Factors

• Sleep deprivation
• Missed doses of AEDs
• Alcohol (particularly withdrawal)
• Recreational drug misuse
• Physical and mental exhaustion
• Flickering lights / TV / computer screens (GGE syndromes only)
• Intercurrent infections and metabolic disturbances
• Uncommon: loud noises, music, reading, hot baths

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5. INVESTIGATIONS

After a First Seizure

For Established Epilepsy

• Inter-ictal EEG is abnormal in only ~50% of patients with recurrent seizures → cannot exclude epilepsy
• Sensitivity increased to ~85% with prolonged recording including sleep
• False-negative rate: 20–40% even with provocation; false-positive rate: ~1%
• EEG abnormalities: focal cortical spikes (e.g., over temporal lobe) or generalised spike-and-wave (GGE)
• In status epilepticus: epileptic activity is continuous

• Epilepsy starting after age 16
• Seizures with focal clinical features
• EEG showing focal seizure source
• Difficult or deteriorating seizure control
• MRI is required (not just CT) for hippocampal sclerosis
• Not required if confident diagnosis of recognised GGE syndrome (e.g., JME)

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6. EXPECTED OUTCOMES / PROGNOSIS

• Recurrence rate after first seizure: ~40%; most within 1–2 months
• Recurrence rate after AED withdrawal: ~50%
• Generalised epilepsies and generalised seizures are more readily controlled than focal seizures
• Presence of a structural lesion reduces chances of seizure freedom
• JME: 90% remit with AEDs but relapse if AED withdrawn → requires lifelong treatment
• Childhood absence epilepsy: 40% develop GTCS; 80% remit in adulthood
• Anterior temporal lobectomy for hippocampal sclerosis: 50–70% achieve seizure freedom

• Features of GGE on EEG
• Abnormal neurological examination
• First seizure occurring in sleep
• Presence of structural brain lesions

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7. MANAGEMENT

A. Immediate/Acute Management (First Aid)

1. Move the person away from danger (fire, water, machinery, furniture)
2. After convulsions cease, turn into the recovery position (semi-prone)
3. Ensure airway is clear; do NOT insert anything in the mouth (tongue-biting occurs at onset and cannot be prevented)
4. If convulsions continue >5 minutes or recur without regaining consciousness → summon urgent medical attention (status epilepticus protocol)
5. Do not leave person alone until fully recovered (drowsiness/delirium can persist up to 1 hour)

B. Lifestyle / Non-Pharmacological Management

• Avoid activities placing self or others at risk during a seizure
• Only shallow baths or showers at home
• Avoid prolonged proximity to water (swimming, fishing, boating) without a companion
• Avoid dangerous sports (rock climbing)
• Leave bathroom doors unlocked

• Sleep deprivation, excess alcohol, recreational drugs
• Strobe/flickering lights (where photosensitivity confirmed on EEG)

• Single seizure: cease driving for 6 months
• Epilepsy (>1 seizure): cease driving immediately; licence restored when seizure-free for 1 year
• Vocational drivers (HGV/PSV): no licence if any seizure after age 5 until off medication and seizure-free >10 years
• Cease driving during AED withdrawal and for 6 months thereafter

• Epilepsy surgery (see below)
• Vagal nerve stimulation (VNS)
• Deep brain stimulation
• Ketogenic (low-carbohydrate) diet — may be useful in refractory cases

C. Pharmacological Management

Principles of AED Therapy

1. Start with one first-line drug at a low dose; gradually increase until seizures controlled or side-effects develop
2. Aim for monotherapy — 70% of patients achieve good control with a single AED
3. Optimise adherence (minimum number of doses per day)
4. If first drug fails → start second first-line drug, then gradually withdraw first
5. If second drug fails → start second-line drug in combination with preferred baseline drug
6. If combination fails → replace second-line drug with alternative second-line drug
7. If still failing → check adherence, reconsider diagnosis; consider non-drug treatments

Drug Choice by Epilepsy Type

• Carbamazepine, Oxcarbazepine/Eslicarbazepine, Gabapentin, Phenytoin, Vigabatrin, Tiagabine → may worsen generalised seizures and absences

Key Drug Notes

Contraception Considerations

• Enzyme-inducing AEDs (carbamazepine, phenytoin, barbiturates, some effects with lamotrigine and topiramate) increase risk of contraceptive failure → may need higher-dose OCP preparations
• Sodium valproate and levetiracetam have no interaction with hormonal contraception

Pregnancy Considerations

• Pre-conception counselling best practice
• Folic acid 5 mg daily for 2 months before conception
• Use single drug at lowest effective dose
• Carbamazepine and lamotrigine have lowest incidence of major fetal malformations
• Sodium valproate: up to 10% birth defects; up to 40% developmental/learning disorders in children exposed in utero → must not be used in women/girls able to have children unless pregnancy prevention programme in place
• Haemorrhagic disease of newborn risk with enzyme-inducing AEDs → give IM vitamin K 1 mg to infant at birth
• Monitor AED levels during pregnancy — lamotrigine and levetiracetam levels may fall early; carbamazepine may fall in third trimester

Withdrawing AED Therapy

• Consider after seizure-free for >2 years (many recommend 5 years)
• ~50% seizure recurrence rate after withdrawal
• Withdraw slowly (reducing dose gradually over weeks to months)
• Best prognosis for withdrawal: childhood-onset epilepsy, classical absence seizures
• JME: marked tendency to recur — generally requires lifelong treatment
• Focal epilepsy with identified structural lesion: likely to recur
• Must cease driving during withdrawal and for 6 months afterwards

D. Epilepsy Surgery

• 50–70% seizure freedom in selected patients with uncontrolled seizures from hippocampal sclerosis
• Requires intensive specialist assessment and investigation to identify seizure onset site and assess dispensability of target areas (vision, motor function)

• Vagal nerve stimulation (VNS)
• Deep brain stimulation
• Ketogenic diet

1. Re-evaluate the diagnosis
2. Assess concordance/adherence
3. Combine ASMs at maximum tolerated dose
4. Refer to specialist unit for epilepsy surgery consideration
5. Consider VNS and ketogenic diet

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8. EPILEPSY SYNDROMES (Summary Table)

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9. PATHOPHYSIOLOGY OF COMPLICATIONS

Sudden Unexpected Death in Epilepsy (SUDEP)

• Epilepsy is associated with a small but potentially modifiable risk of sudden death
• Explaining this risk should be done with care and sensitivity
• The aim is to motivate patients to optimise epilepsy control and minimise risk — e.g., avoid triggers, ensure treatment adherence

Status Epilepticus

• Defined as continuous seizure activity or repeated seizures without regaining consciousness
• Non-convulsive status epilepticus can present as delirium (especially in the elderly)
• In ICU settings, EEG monitoring is essential for diagnosis and treatment optimisation
• Management described separately (emergency protocols)

Cognitive and Developmental Complications

• Epileptic encephalopathy (Dravet, Lennox-Gastaut): seizures themselves cause cognitive and behavioural regression
• In utero valproate exposure: up to 40% of children have developmental disorders; IQ may be lower
• Adolescent epilepsy: seizures, AEDs, and psychological complications can hamper education

Bone Health / Osteoporosis

• Patients with epilepsy have higher risk of osteoporosis, apparently independently of the drug used
• Some centres advocate vitamin D supplementation in all epilepsy patients, especially women

Reproductive Complications

• Menstrual irregularities and reduced fertility are more common in women with epilepsy, also increased by sodium valproate

Drug Toxicity Complications

• Intoxication with most AEDs: unsteadiness, nystagmus, drowsiness; some agents may paradoxically provoke more seizures
• Skin rashes: especially with lamotrigine, carbamazepine, phenytoin → risk of Stevens-Johnson syndrome
• Idiosyncratic reactions: blood dyscrasias, hyponatraemia (carbamazepine, especially in elderly or those on diuretics)
• Enzyme induction (carbamazepine, phenytoin, barbiturates): multiple drug interactions including contraceptive failure
• Valproate teratogenicity: up to 10% major birth defects; up to 40% developmental disorders
• Haemorrhagic disease of the newborn: from enzyme-inducing AEDs in pregnancy

Psychosocial Complications

• Many people with epilepsy feel stigmatised and may become unnecessarily isolated from work and social life
• Driving restrictions significantly impact independence
• Career restrictions: firefighter, airline pilot, vocational driving prohibited
• Adolescence-specific: impact on school, family relationships, career choices, alcohol use, illicit drug use, sleep disturbance, oral contraception interactions

Non-Epileptic Attack Disorder (NEAD) — Complicating Diagnosis

• Attacks that resemble epileptic seizures but caused by psychological phenomena with no abnormal EEG
• May be very prolonged, mimicking status epilepticus
• Epileptic and non-epileptic attacks may coexist
• Three times more common in women
• Prevention requires psychotherapeutic rather than drug interventions

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Special Populations

Elderly (>60 years)

• Very common and increasing incidence
• Cerebrovascular disease is the cause in 30–50% of patients over 50
• Non-convulsive status epilepticus can present as delirium
• Carbamazepine-induced hyponatraemia increases significantly with age
• AED regimens: keep simple; careful attention to drug interactions
• Neurodegenerative disease/dementia should be considered

Adolescents

• Seizures, AEDs, and psychological complications hamper education
• Parents may adopt overly protective roles
• Alcohol affects sleep; excess associated with poor AED adherence
• Sleep disturbance worsened by social activities and computer games

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