Epilepsy - Comprehensive Medical Student Review

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1. Definition

1. At least two unprovoked (or reflex) seizures occurring >24 hours apart
2. One unprovoked seizure with a probability of further seizures ≥60% over the next 10 years (e.g., after a single seizure with a structural lesion on MRI, or epileptiform EEG)
3. Diagnosis of an epilepsy syndrome

Key distinction: A seizure is a single event of abnormal excessive hypersynchronous neuronal activity. Epilepsy is the underlying disease predisposing to recurrent seizures. Provoked seizures (e.g., alcohol withdrawal, hypoglycemia, hyponatremia) are not epilepsy.

• Bradley and Daroff's Neurology in Clinical Practice

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2. Pathophysiology

The Paroxysmal Depolarizing Shift (PDS)

• AMPA- and NMDA-type glutamate receptor-channels (excitatory input)
• Voltage-gated Ca²⁺ channels (gCa) amplifying depolarization
• Followed by hyperpolarization via: GABA-A receptors (Cl⁻), GABA-B receptors (K⁺), and Ca²⁺-activated K⁺ channels (gK)

Seizure Spread

• Focal seizure: Starts in a focus, spreads via intrahemispheric fibers (1), to homotopic contralateral cortex via corpus callosum (2), and to subcortical centers (3)
• Secondary generalization: Thalamic involvement (4) propagates activity to both hemispheres simultaneously
• Primary generalized seizure: Both hemispheres activated simultaneously from onset via thalamocortical circuits (Panel B above)

Imbalance Summary (Exam High-Yield)

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3. ILAE Classification (2017) - Three Levels

Level 1: SEIZURE TYPE
        ↓
Level 2: EPILEPSY TYPE  
        ↓
Level 3: EPILEPSY SYNDROME
        + ETIOLOGY (at every level)
        + COMORBIDITIES

Level 1 - Seizure Types

A. Focal-Onset Seizures (arise from one hemisphere)

• Focal aware (previously "simple partial") - consciousness preserved
• Focal impaired awareness (previously "complex partial") - consciousness impaired
• Focal to bilateral tonic-clonic (previously "secondarily generalized")

B. Generalized-Onset Seizures (both hemispheres from onset)

C. Unknown Onset

Level 2 - Epilepsy Types

• Focal epilepsy
• Generalized epilepsy
• Combined generalized and focal (e.g., Dravet syndrome)
• Unknown

Level 3 - Common Epilepsy Syndromes (High-Yield)

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4. Etiology

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5. Clinical Assessment & Diagnosis

History (most important diagnostic tool)

• Full description of the episode (from witness): onset, progression, duration
• Pre-ictal aura (points to focal onset)
• Ictal features: automatisms, motor activity, eye deviation, head turn
• Post-ictal: confusion (Todd's paralysis, aphasia), duration
• Provoking factors, sleep deprivation, alcohol, medications
• Family history, birth history, febrile seizures

EEG (Electroencephalogram)

• Interictal EEG: Spike-and-wave discharges between seizures
  • 3 Hz generalized spike-wave = absence epilepsy
  • Centrotemporal spikes = BECTS
  • Hypsarrhythmia = West syndrome
  • Focal temporal spikes = TLE
• Ictal EEG: Rhythmic activity corresponding to clinical seizure
• EEG is normal in 50% of patients with epilepsy on a routine interictal recording
• Sleep deprivation, hyperventilation, and photic stimulation are activation procedures
• EEG bands: delta (0.5-4 Hz), theta (4-7 Hz), alpha (8-13 Hz), beta (13-30 Hz)

Neuroimaging

• MRI brain (preferred over CT): Structural causes (hippocampal sclerosis, tumors, dysplasia)
• FLAIR and T2 sequences most sensitive for cortical abnormalities
• CT head: Used acutely to exclude hemorrhage/mass

Initial Investigations for New-Onset Seizures

• Blood glucose, electrolytes (Na⁺, Ca²⁺, Mg²⁺), renal/liver function, FBC
• Toxicology screen
• EEG
• MRI brain
• LP if encephalitis/meningitis suspected

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6. Antiseizure Medications (ASMs) - High-Yield Table

Drug Selection Principles (High-Yield)

• Absence epilepsy: Ethosuximide (1st-line pure absence), Valproate (if GTC also present)
• Focal epilepsy: Carbamazepine or Lamotrigine (1st-line)
• JME: Valproate (most effective), Lamotrigine, Levetiracetam
• Dravet syndrome: AVOID Na⁺ channel blockers (phenytoin, carbamazepine, lamotrigine - they worsen); use valproate, clobazam, topiramate
• Infantile spasms (West syndrome): ACTH or prednisolone (1st-line); vigabatrin (especially in TSC)
• Women of childbearing age: Avoid valproate if possible (teratogenicity); lamotrigine preferred

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7. Management Principles

When to Start Treatment

• After two unprovoked seizures - start ASM
• After one seizure with high recurrence risk (structural lesion, epileptiform EEG, epilepsy syndrome)
• After one seizure alone - treatment not automatically required

Monotherapy First

• Start with a single ASM at low dose and titrate
• Failure of two appropriately chosen and dosed ASMs defines drug-resistant epilepsy (~30% of patients)

Drug-Resistant Epilepsy

• Surgical evaluation is the 1st-line treatment for drug-resistant focal epilepsy
• Most common surgery: Anterior temporal lobectomy (for mesial TLE)
• Other surgical options: Corpus callosotomy (drop attacks), hemispherectomy
• Neuromodulation: Vagus nerve stimulation (VNS), responsive neurostimulation (RNS), deep brain stimulation (DBS - anterior nucleus of thalamus)
• Ketogenic diet: High-fat, low-carbohydrate; especially useful in pediatric drug-resistant epilepsy

Stopping ASMs

• Typically considered after 2 years seizure-free
• EEG guides decision - normal EEG = better prognosis
• Gradual taper over weeks-months
• Discuss driving implications

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8. Status Epilepticus (SE)

Convulsive SE lasting >30 min carries mortality up to 20%.

Most Common Cause

• Non-compliance with ASM (most common cause of tonic-clonic SE)

Management Protocol (Time-Critical)

0-5 min:  ABCs, IV access, O2, glucose, vitals, bloods
          Benzodiazepine (FIRST-LINE):
          - IV Lorazepam 0.1 mg/kg (drug of FIRST choice in hospital)
          - IM Midazolam (out-of-hospital or no IV access)
          - Rectal Diazepam (community)

5-20 min: If seizure continues → SECOND-LINE:
          - IV Levetiracetam, OR
          - IV Valproate, OR
          - IV Phenytoin/Fosphenytoin

20-40 min: If refractory SE → THIRD-LINE:
           - Anaesthetic doses: Propofol, Thiopental, Midazolam infusion
           - ICU admission, EEG monitoring

Super-refractory SE (>24h despite anaesthesia):
           - Ketamine, Ketogenic diet, Immunotherapy

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9. Special Situations

Epilepsy in Pregnancy

• Discuss contraception - enzyme-inducing ASMs (phenytoin, carbamazepine, phenobarbital) reduce efficacy of oral contraceptives
• Valproate has highest teratogenic risk (10x neural tube defects, neurodevelopmental effects) - avoid if possible
• Lamotrigine and levetiracetam are preferred in pregnancy
• Folic acid supplementation (5 mg/day) for all women on ASMs planning pregnancy
• AAN/AES 2024 Practice Guideline (PMID: 38748979): confirms teratogenesis risk hierarchy and recommends shared decision-making

Sudden Unexpected Death in Epilepsy (SUDEP)

• Leading cause of epilepsy-related death
• Rate: ~1 in 1000 person-years; higher in drug-resistant epilepsy
• Mechanism: Postictal cardiorespiratory failure, possibly postictal generalized EEG suppression
• Risk reduction: Better seizure control, avoid nocturnal seizures, use of safety pillows

Non-Epileptic Attack Disorder (NEAD / PNES)

• Psychogenic non-epileptic seizures (PNES) - must be distinguished from epilepsy
• Often present with motor seizures but no EEG correlate
• Video-EEG monitoring is the gold standard for diagnosis

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10. Exam High-Yield Summary

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