Pediatric Neurology - Seizure
A Comprehensive Guide for Medical Students
Author: YK Shim Division of Pediatric Neurology, Department of Pediatrics, Korea University College of Medicine Last Updated: 2025
Table of Contents
- Introduction
- Seizure Fundamentals
- ILAE Classification of Epilepsy
- Electroencephalography (EEG)
- Seizures in the Genetic Era
- Medical Evaluation and Diagnostic Workup
- Physical Examination and Phenotyping
- Precision Medicine in Epilepsy
- Clinical Pearls and Pitfalls
- Summary: Approach to Pediatric Neurologic Diseases
- Learning Objectives and Self-Assessment
- References and Further Reading
1. Introduction
Pediatric neurology encompasses disorders of the nervous system in children, from neonates to adolescents. The developing brain presents unique challenges and opportunities for diagnosis and treatment.
Why This Matters
┌─────────────────────────────────────────────────────────────────┐
│ PEDIATRIC EPILEPSY IMPACT │
├─────────────────────────────────────────────────────────────────┤
│ │
│ 📊 PREVALENCE 🧠 IMPACT 🎯 OPPORTUNITY │
│ ───────────── ────────── ───────────── │
│ 0.5-1% of Affects Early diagnosis │
│ children development enables targeted │
│ worldwide & quality therapy │
│ of life │
│ │
└─────────────────────────────────────────────────────────────────┘
2. Seizure Fundamentals
2.1 Core Definitions
╔═══════════════════════════════════════════════════════════════════════════════╗
║ KEY DEFINITIONS ║
╠═══════════════════════════════════════════════════════════════════════════════╣
║ ║
║ SEIZURE ║
║ ════════ ║
║ Transient signs/symptoms due to abnormal excessive ║
║ or synchronous neuronal activity in the brain ║
║ ║
║ EPILEPSY ║
║ ════════ ║
║ ≥2 unprovoked seizures >24h apart ║
║ OR ║
║ 1 seizure + recurrence risk ≥60% ║
║ ║
║ STATUS EPILEPTICUS ║
║ ══════════════════ ║
║ Seizure lasting >5 minutes OR multiple seizures ║
║ without full recovery between them ║
║ ║
╚═══════════════════════════════════════════════════════════════════════════════╝
2.2 Seizure Semiology: What to Observe
┌─────────────────────────────────────────────────────────────────────────────┐
│ SEIZURE OBSERVATION TIMELINE │
├─────────────────────────────────────────────────────────────────────────────┤
│ │
│ PRE-ICTAL ICTAL PHASE POST-ICTAL │
│ ────────── ─────────── ────────── │
│ │
│ ┌─────────┐ ┌───────────┐ ┌──────────┐ │
│ │ WARNING │ ───▶ │ SEIZURE │ ───▶ │ RECOVERY │ │
│ │ (Aura) │ │ ACTIVITY │ │ PHASE │ │
│ └─────────┘ └───────────┘ └──────────┘ │
│ │
│ • Behavior • Where did it • Confusion? │
│ • Activity start? • Weakness? │
│ • Triggers • Progression? • Duration? │
│ • Awareness? • Sleep? │
│ • Duration? │
│ │
└─────────────────────────────────────────────────────────────────────────────┘
2.3 Seizure History Checklist
| Question | Why It Matters |
|---|---|
| What was the patient doing before? | Identify triggers |
| Was there any warning (aura)? | Suggests focal onset |
| Where did movements start? | Localization |
| What was the sequence? | Seizure propagation |
| Was there loss of awareness? | Focal vs. generalized |
| How long did each phase last? | Severity assessment |
| What was the postictal state? | Todd’s paralysis, confusion |
| Any triggers? | Fever, sleep deprivation, photic |
3. ILAE Classification of Epilepsy
3.1 Three Levels of Diagnosis (ILAE 2017)
flowchart TD
A[🔍 LEVEL 1: SEIZURE TYPE] --> B[📋 LEVEL 2: EPILEPSY TYPE]
B --> C[🏥 LEVEL 3: EPILEPSY SYNDROME]
A --> A1[Focal]
A --> A2[Generalized]
A --> A3[Unknown]
B --> B1[Focal Epilepsy]
B --> B2[Generalized Epilepsy]
B --> B3[Combined]
B --> B4[Unknown]
C --> C1[Specific Syndrome<br/>e.g., Dravet, CAE]
style A fill:#e1f5fe
style B fill:#fff3e0
style C fill:#e8f5e9
3.2 Seizure Classification Overview (ILAE 2017/2025)
┌───────────────────────────────────────────────────────────────────────────────┐
│ ILAE SEIZURE CLASSIFICATION │
├───────────────────────────────────────────────────────────────────────────────┤
│ │
│ SEIZURE ONSET │
│ ┌────────────┼────────────┐ │
│ ▼ ▼ ▼ │
│ ┌─────────┐ ┌──────────┐ ┌─────────┐ │
│ │ FOCAL │ │GENERALIZED│ │ UNKNOWN │ │
│ └────┬────┘ └─────┬────┘ └─────────┘ │
│ │ │ │
│ ┌────────┴────────┐ │ │
│ ▼ ▼ ▼ │
│ ┌─────────┐ ┌─────────────────────────────────┐ │
│ │AWARENESS│ │ MOTOR │ │
│ ├─────────┤ │ • Tonic-clonic • Myoclonic │ │
│ │Retained │ │ • Tonic • Atonic │ │
│ │Impaired │ │ • Clonic • Spasms │ │
│ └─────────┘ └─────────────────────────────────┘ │
│ │ │
│ ▼ ┌─────────────────────────────────┐ │
│ ┌─────────┐ │ NON-MOTOR │ │
│ │ ONSET │ │ • Typical absence │ │
│ ├─────────┤ │ • Atypical absence │ │
│ │Motor │ │ • Myoclonic absence │ │
│ │Non-motor│ │ • Eyelid myoclonia │ │
│ └─────────┘ └─────────────────────────────────┘ │
│ │
└───────────────────────────────────────────────────────────────────────────────┘
3.3 Focal Seizure Features
| Feature | Options | Clinical Significance |
|---|---|---|
| Awareness | Retained / Impaired | Replaces “simple” vs “complex” |
| Motor Onset | Automatisms, Atonic, Clonic, Tonic, Hyperkinetic, Myoclonic, Spasms | Helps localize |
| Non-Motor Onset | Autonomic, Behavior arrest, Cognitive, Emotional, Sensory | Suggests specific regions |
| Progression | Focal to bilateral tonic-clonic | Previously “secondary generalized” |
3.4 Epilepsy Syndromes by Age
┌─────────────────────────────────────────────────────────────────────────────────┐
│ EPILEPSY SYNDROMES BY AGE OF ONSET │
├─────────────────────────────────────────────────────────────────────────────────┤
│ │
│ NEONATES & INFANTS (0-2 years) │
│ ═══════════════════════════════ │
│ ┌─────────────────────────────────────────────────────────────────────────┐ │
│ │ • Self-limited neonatal epilepsy 🟢 Good prognosis │ │
│ │ • Self-limited familial neonatal epilepsy 🟢 Good prognosis │ │
│ │ • Early infantile DEE (Ohtahara) 🔴 Severe │ │
│ │ • Epilepsy of infancy with migrating 🔴 Severe │ │
│ │ focal seizures (EIMFS) │ │
│ │ • Infantile spasms (West syndrome) 🟠 Variable │ │
│ │ • Dravet syndrome 🔴 Severe │ │
│ └─────────────────────────────────────────────────────────────────────────┘ │
│ │
│ CHILDHOOD (2-12 years) │
│ ═══════════════════════ │
│ ┌─────────────────────────────────────────────────────────────────────────┐ │
│ │ Self-Limited Focal: │ │
│ │ • SLECTS (Rolandic) 🟢 Excellent prognosis │ │
│ │ • Panayiotopoulos syndrome 🟢 Excellent prognosis │ │
│ │ • Childhood occipital visual epilepsy 🟢 Good prognosis │ │
│ │ │ │
│ │ Generalized: │ │
│ │ • Childhood absence epilepsy (CAE) 🟢 Good (70% remission) │ │
│ │ • Epilepsy with myoclonic absences 🟠 Variable │ │
│ │ • Epilepsy with eyelid myoclonia 🟠 Often lifelong │ │
│ │ │ │
│ │ DEE: │ │
│ │ • Lennox-Gastaut syndrome 🔴 Severe, refractory │ │
│ │ • ESES/CSWS 🟠 Cognitive impact │ │
│ └─────────────────────────────────────────────────────────────────────────┘ │
│ │
│ ADOLESCENCE (12-18 years) │
│ ═════════════════════════ │
│ ┌─────────────────────────────────────────────────────────────────────────┐ │
│ │ • Juvenile absence epilepsy (JAE) 🟠 Often lifelong treatment │ │
│ │ • Juvenile myoclonic epilepsy (JME) 🟠 Lifelong treatment needed │ │
│ │ • Epilepsy with GTC alone 🟠 Variable │ │
│ └─────────────────────────────────────────────────────────────────────────┘ │
│ │
│ Legend: 🟢 Good/Excellent 🟠 Variable/Moderate 🔴 Severe/Poor │
│ │
└─────────────────────────────────────────────────────────────────────────────────┘
4. Electroencephalography (EEG)
4.1 EEG Electrode Placement (10-20 System)
INTERNATIONAL 10-20 SYSTEM
══════════════════════════
Nasion
│
┌───────────┼───────────┐
Fp1 Fpz Fp2
│ ╲ │ ╱ │
F7────F3────Fz────F4────F8
│ │ │ │ │
T3────C3────Cz────C4────T4
│ │ │ │ │
T5────P3────Pz────P4────T6
│ ╱ │ ╲ │
O1─────────Oz─────────O2
│
Inion
┌──────────────────────────────────────────────┐
│ Fp = Frontopolar F = Frontal │
│ T = Temporal C = Central │
│ P = Parietal O = Occipital │
│ z = Midline Odd = Left Even = Right│
└──────────────────────────────────────────────┘
4.2 Age-Dependent PDR Development
POSTERIOR DOMINANT RHYTHM (PDR) MATURATION
═══════════════════════════════════════════
Frequency (Hz)
│
11 ┤ ══════ Adult
10 ┤ ●━━━━━●
9 ┤ ●━━━━━┘
8 ┤ ●━━━━━┘
7 ┤ ●━━━━━┘
6 ┤ ●━━━━━┘
5 ┤ ●━━━━━┘
4 ┤●━━━━━┘
3 ┤
2 ┤
1 ┤
└──┬─────┬─────┬─────┬─────┬─────┬─────┬─────┬──▶ Age
3mo 6mo 1yr 2yr 3yr 5yr 8yr 10yr
┌─────────────────────────────────────────────────────────────┐
│ CLINICAL PEARL: PDR should be at least [Age in years + 2] │
│ Example: 5-year-old should have PDR ≥ 7 Hz │
└─────────────────────────────────────────────────────────────┘
4.3 Normal vs Abnormal EEG Patterns
┌─────────────────────────────────────────────────────────────────────────────────┐
│ EEG PATTERN RECOGNITION │
├─────────────────────────────────────────────────────────────────────────────────┤
│ │
│ ✅ NORMAL VARIANTS (Don't over-interpret!) │
│ ═══════════════════════════════════════════ │
│ │
│ Pattern Appearance Age Range │
│ ─────────────────────────────────────────────────────────── │
│ Posterior slow of youth ∿∿∿ Delta waves Children < 12 yrs │
│ posterior │
│ │
│ Mu rhythm ⌒⌒⌒ Arch-shaped Any age │
│ 8-10 Hz, central │
│ │
│ Lambda waves ∧ Sharp Visual scanning │
│ occipital │
│ │
│ Hypnagogic hypersynchrony ≋≋≋ High amp Children │
│ theta, drowsy │
│ │
│ POSTS ⋏ Positive Adolescents │
│ occipital │
│ │
├─────────────────────────────────────────────────────────────────────────────────┤
│ │
│ ⚠️ EPILEPTIFORM PATTERNS │
│ ════════════════════════ │
│ │
│ Pattern Appearance Associated Syndrome │
│ ─────────────────────────────────────────────────────────────────── │
│ Centrotemporal spikes ╱╲ SLECTS (Rolandic) │
│ C3/C4, T3/T4 │
│ │
│ 3 Hz spike-wave ╱╲_╱╲_╱╲ Childhood absence │
│ Generalized │
│ │
│ Hypsarrhythmia ≋∧≋∧≋∧ West syndrome │
│ Chaotic, high amp │
│ │
│ Slow spike-wave (<2.5 Hz) ╱╲__╱╲__ Lennox-Gastaut │
│ Generalized │
│ │
│ Polyspike-wave ╱╲╱╲╱╲_ JME │
│ Multiple spikes │
│ │
│ Burst-suppression ∧∧∧____∧∧∧____ Early infantile DEE │
│ Bursts + flat │
│ │
└─────────────────────────────────────────────────────────────────────────────────┘
4.4 EEG Patterns and Associated Syndromes
| EEG Pattern | Visual | Syndrome | Key Features |
|---|---|---|---|
| 3 Hz Spike-Wave | ∧_∧_∧_ |
Childhood Absence | Abrupt onset/offset, hyperventilation activates |
| Centrotemporal Spikes | _∧_ |
SLECTS/Rolandic | Sleep-activated, horizontal dipole |
| Hypsarrhythmia | ≋∧≋ |
Infantile Spasms | Chaotic, asynchronous, high amplitude |
| Slow Spike-Wave | ∧__∧__ |
Lennox-Gastaut | <2.5 Hz, runs during sleep |
| Burst-Suppression | ∧∧∧___ |
Early DEE | Bursts alternating with flat periods |
| Photoparoxysmal | ∧∧∧ |
JME, Dravet | Triggered by photic stimulation |
4.5 Detailed EEG Pattern Descriptions
📚 Visual Learning Resources: For actual EEG waveform images, refer to the open-access resources listed in Section 4.7
4.5.1 Normal Background Activity by Age
Neonatal EEG (Term Infant)
Characteristics:
- Discontinuous pattern transitioning to continuous by 44 weeks
- Trace alternant in quiet sleep (bursts 3-8 sec, interburst 4-8 sec)
- Anterior slow dysrhythmia (frontal delta)
- Multifocal sharp transients (normal in neonates)
- Brush rhythms (beta-delta complexes) - premature marker
Infant EEG (3-12 months)
Characteristics:
- PDR emerges at 3-4 Hz, gradually increases
- Central theta activity during wakefulness
- Sleep spindles develop around 6-8 weeks
- Vertex waves and K-complexes by 5-6 months
- Hypnagogic hypersynchrony - HIGH AMPLITUDE theta during drowsiness (NORMAL!)
Childhood EEG (1-10 years)
Characteristics:
- PDR: [Age + 2] Hz rule (e.g., 5 yr old = 7 Hz minimum)
- Posterior slow waves of youth (delta mixed with alpha) - NORMAL
- Prominent drowsy patterns
- Abundant sleep architecture
- Hyperventilation response: 3 Hz slowing for up to 1 min after = NORMAL
4.5.2 Epileptiform Patterns - Detailed Descriptions
3 Hz Spike-and-Wave (Childhood Absence Epilepsy)
┌─────────────────────────────────────────────────────────────────┐
│ MORPHOLOGY │
│ ══════════ │
│ │
│ Spike Slow wave Spike Slow wave │
│ ╱╲ ╭──╮ ╱╲ ╭──╮ │
│ ╱ ╲ ╱ ╲ ╱ ╲ ╱ ╲ │
│ ╱ ╲──╯ ╰──────╱ ╲──╯ ╰───── │
│ │
│ |←─── 333 msec ───→| (= 3 Hz) │
│ │
│ KEY FEATURES: │
│ • Frequency: 2.5-4 Hz (typically 3 Hz) │
│ • Amplitude: 200-400 µV │
│ • Distribution: GENERALIZED, BIFRONTAL maximum │
│ • Duration: 4-20 seconds (often 10 sec) │
│ • Onset/Offset: ABRUPT (like turning a switch) │
│ • Activation: Hyperventilation, drowsiness │
│ • Inhibition: Eye opening, alerting, sleep │
│ • Background: NORMAL between discharges │
│ │
│ ⚠️ RED FLAGS suggesting NOT typical CAE: │
│ • Asymmetry or focal features │
│ • Abnormal background │
│ • Polyspikes at onset │
│ • Very slow (<2.5 Hz) frequency │
└─────────────────────────────────────────────────────────────────┘
Centrotemporal Spikes (SLECTS/Rolandic Epilepsy)
┌─────────────────────────────────────────────────────────────────┐
│ MORPHOLOGY │
│ ══════════ │
│ │
│ Channel C3-P3: ╱╲ │
│ ╱ ╲____ ← Negative spike │
│ │
│ Channel C4-P4: ╱╲ │
│ ___╱ ╲ ← Positive deflection │
│ (horizontal dipole!) │
│ │
│ KEY FEATURES: │
│ • Location: C3/C4, T3/T4 (centrotemporal region) │
│ • Morphology: HIGH amplitude, blunt spike with slow wave │
│ • Amplitude: Often >100-200 µV │
│ • HORIZONTAL DIPOLE: negative at C, positive at F │
│ • State: DRAMATICALLY increased in sleep (10x) │
│ • May be unilateral OR bilateral (independent) │
│ • Background: NORMAL │
│ │
│ 💡 CLINICAL PEARL: │
│ Spikes may persist 1-2 years AFTER clinical seizures stop │
│ Do NOT chase the EEG - treat the patient! │
└─────────────────────────────────────────────────────────────────┘
Hypsarrhythmia (Infantile Spasms/West Syndrome)
┌─────────────────────────────────────────────────────────────────┐
│ MORPHOLOGY │
│ ══════════ │
│ │
│ ∧ ∿ ╱╲ ∧∧ ≋ ∧ │
│ ╱ ╲ ╱ ∿ ╱ ╲ ∿ ╱ ╲ ╱ ≋ ╱ ╲ ∿ │
│ ╱ ∨ ╲╱ ╲∿ ╲_╱ ╲_╱ ≋_╱ ╲_╱ ∿ │
│ ∿∿ ∧ ╱╲ │
│ CHAOTIC, HIGH AMPLITUDE, ASYNCHRONOUS │
│ │
│ KEY FEATURES: │
│ • Amplitude: Very HIGH (>200-300 µV, often 500-1000 µV) │
│ • Mixture: Spikes + sharp waves + slow waves │
│ • Pattern: CHAOTIC, disorganized │
│ • Synchrony: ASYNCHRONOUS (hemispheres not in sync) │
│ • Continuous vs Modified: True vs some organization │
│ • During spasm: May see electrodecrement or fast rhythm │
│ • Background: SEVERELY abnormal (NO normal activity) │
│ │
│ VARIANTS: │
│ • Modified hypsarrhythmia: Some synchrony/organization │
│ • Asymmetric: Suggests focal/structural etiology │
│ │
│ 🚨 URGENCY: Recognize and treat promptly! │
│ Delayed treatment = worse developmental outcome │
└─────────────────────────────────────────────────────────────────┘
Slow Spike-and-Wave (Lennox-Gastaut Syndrome)
┌─────────────────────────────────────────────────────────────────┐
│ MORPHOLOGY │
│ ══════════ │
│ │
│ Spike Slow wave (prolonged) │
│ ╱╲ ╭────────╮ │
│ ╱ ╲ ╱ ╲ │
│ ╱ ╲──╯ ╰──────── │
│ │
│ |←───── 400-600 msec ─────→| (= 1.5-2.5 Hz) │
│ │
│ KEY FEATURES: │
│ • Frequency: 1.5-2.5 Hz (SLOW compared to CAE) │
│ • Distribution: Generalized, often frontal maximum │
│ • Runs: LONG runs during NREM sleep │
│ • Background: ABNORMAL (slow, disorganized) │
│ • Evolution: Often evolves from prior hypsarrhythmia │
│ │
│ SLEEP ACTIVATION: │
│ • Generalized paroxysmal fast activity (GPFA) │
│ • 10-25 Hz, most prominent in frontal regions │
│ • Highly characteristic of LGS │
│ │
│ ⚠️ VS CHILDHOOD ABSENCE: │
│ LGS: <2.5 Hz, abnormal background, polyspikes │
│ CAE: ~3 Hz, normal background, no polyspikes │
└─────────────────────────────────────────────────────────────────┘
Burst-Suppression Pattern (Early Infantile DEE)
┌─────────────────────────────────────────────────────────────────┐
│ MORPHOLOGY │
│ ══════════ │
│ │
│ Burst (1-3 sec) Suppression (3-10 sec) │
│ ∧∧∧∨∧∧∧∨ _________________________ │
│ High amp Flat or <10 µV │
│ Mixed freq │
│ │
│ KEY FEATURES: │
│ • Burst: High amplitude (150-350 µV), mixed frequencies │
│ • Suppression: Very low (<10-25 µV), near-isoelectric │
│ • Periodicity: 3-20 second cycle │
│ • Reactivity: ABSENT to stimuli │
│ • Synchrony: May be synchronous or asynchronous │
│ │
│ SEEN IN: │
│ • Ohtahara syndrome (EIEE) │
│ • Early myoclonic encephalopathy │
│ • Severe hypoxic-ischemic encephalopathy │
│ • STXBP1, KCNQ2, SCN2A mutations │
│ │
│ PROGNOSIS: Generally poor, indicates severe brain dysfunction │
└─────────────────────────────────────────────────────────────────┘
4.6 EEG Interpretation Pearls
┌─────────────────────────────────────────────────────────────────┐
│ 🎯 EEG INTERPRETATION PEARLS │
├─────────────────────────────────────────────────────────────────┤
│ │
│ 1. ALWAYS assess background FIRST │
│ • Normal background = better prognosis │
│ • Abnormal background = structural/metabolic concern │
│ │
│ 2. AGE MATTERS │
│ • PDR formula: Age + 2 = minimum Hz │
│ • Neonatal patterns are DIFFERENT from older children │
│ • Trace alternant is NORMAL in neonates │
│ │
│ 3. STATE MATTERS │
│ • Many epileptiform patterns INCREASE in sleep │
│ • Always record sleep if possible │
│ • SLECTS: 10x more spikes in sleep │
│ │
│ 4. DON'T OVER-READ │
│ • Posterior slow of youth = NORMAL │
│ • Hypnagogic hypersynchrony = NORMAL │
│ • Wicket spikes = NORMAL variant │
│ • Rhythmic mid-temporal theta (RMTD) = NORMAL │
│ │
│ 5. CLINICAL CORRELATION IS KEY │
│ • EEG alone does NOT diagnose epilepsy │
│ • Normal EEG does NOT exclude epilepsy │
│ • Spikes without seizures ≠ epilepsy │
│ │
└─────────────────────────────────────────────────────────────────┘
4.7 Open-Access EEG Educational Resources
⚖️ Note: The following resources are freely available for educational purposes. Always verify current licensing terms before using images in your own materials.
Free Online EEG Atlases and Databases
| Resource | Description | Access |
|---|---|---|
| American Epilepsy Society EEG Atlas | Comprehensive introductory text and atlas covering normal and abnormal findings in adults, children, and infants. CC BY-NC-SA 4.0 licensed. | NCBI Bookshelf |
| NCBI - Developmental EEG Chapter | Detailed coverage of premature, neonatal, infant, and childhood EEG patterns | NCBI Bookshelf |
| NCBI - EEG in Epilepsies | Epileptiform patterns and interpretation | NCBI Bookshelf |
| Wikimedia Commons EEG Category | Various EEG images under Creative Commons licenses | Wikimedia Commons |
EEG Data Repositories (For Research/Advanced Learning)
| Database | Description | Access |
|---|---|---|
| Child Mind Institute MIPDB | Pediatric EEG database, CC BY-NC-SA | CMI EEG |
| SCCN/UCSD EEG Data | Publicly available EEG datasets | SCCN Database |
| PhysioNet | EEG datasets under neuroelectric tag | PhysioNet |
| OpenNeuro | Open sharing of neuroimaging data including EEG | OpenNeuro |
| GitHub EEG Datasets List | Curated list of public EEG datasets | GitHub - meagmohit/EEG-Datasets |
Recommended Learning Sequence
┌─────────────────────────────────────────────────────────────────┐
│ 📚 SUGGESTED EEG LEARNING PATHWAY │
├─────────────────────────────────────────────────────────────────┤
│ │
│ STEP 1: Read the AES EEG Atlas (NCBI) │
│ → Understand normal patterns first │
│ │
│ STEP 2: Study developmental EEG chapter │
│ → Learn age-dependent variations │
│ │
│ STEP 3: Review epileptiform patterns chapter │
│ → Associate patterns with syndromes │
│ │
│ STEP 4: Practice with real data │
│ → Child Mind Institute database │
│ → OpenNeuro pediatric datasets │
│ │
│ STEP 5: Clinical correlation │
│ → Always link EEG to clinical presentation │
│ │
└─────────────────────────────────────────────────────────────────┘
5. Seizures in the Genetic Era
5.1 Genetic Architecture of Epilepsy
┌─────────────────────────────────────────────────────────────────────────────────┐
│ GENETIC ARCHITECTURE OF EPILEPSY │
├─────────────────────────────────────────────────────────────────────────────────┤
│ │
│ 40% of epilepsies have │
│ significant genetic component │
│ │
│ EFFECT SIZE │
│ ▲ │
│ │ ┌─────────────────────────────────────────────────────────────┐ │
│ HIGH │ │ RARE VARIANTS │ │
│ │ │ • De novo mutations 🧬 SCN1A, KCNQ2, STXBP1 │ │
│ │ │ • Single gene disorders 🧬 Found by WES/WGS │ │
│ │ │ • Large effect 🧬 Often DEEs │ │
│ │ └─────────────────────────────────────────────────────────────┘ │
│ │ │
│ │ THE MISSING │
│ │ HERITABILITY │
│ │ GAP │
│ │ │
│ │ ┌─────────────────────────────────────────────────────────────┐ │
│ LOW │ │ COMMON VARIANTS │ │
│ │ │ • Found by GWAS 🧬 Polygenic risk │ │
│ │ │ • Small individual effect 🧬 IGE/GGE associations │ │
│ │ │ • Cumulative effect 🧬 Population risk │ │
│ │ └─────────────────────────────────────────────────────────────┘ │
│ │ │
│ └───────────────────────────────────────────────────────────────────▶ │
│ ALLELE FREQUENCY │
│ Rare ◄──────────────────► Common │
│ │
└─────────────────────────────────────────────────────────────────────────────────┘
5.2 Major Epilepsy Genes
┌─────────────────────────────────────────────────────────────────────────────────┐
│ MAJOR EPILEPSY GENES │
├─────────────────────────────────────────────────────────────────────────────────┤
│ │
│ 🔴 SODIUM CHANNELS │
│ ════════════════════════════════════════════════════════════════ │
│ ┌────────┬──────────┬─────────────────────────┬───────────────────┐ │
│ │ Gene │ Channel │ Phenotype │ Prevalence │ │
│ ├────────┼──────────┼─────────────────────────┼───────────────────┤ │
│ │ SCN1A │ Nav1.1 │ Dravet, GEFS+ │ 1:12,200 births │ │
│ │ SCN2A │ Nav1.2 │ Early DEE, BFNIS │ -- │ │
│ │ SCN8A │ Nav1.6 │ Early DEE │ -- │ │
│ └────────┴──────────┴─────────────────────────┴───────────────────┘ │
│ │
│ 🔵 POTASSIUM CHANNELS │
│ ════════════════════════════════════════════════════════════════ │
│ ┌────────┬──────────┬─────────────────────────┬───────────────────┐ │
│ │ Gene │ Channel │ Phenotype │ Prevalence │ │
│ ├────────┼──────────┼─────────────────────────┼───────────────────┤ │
│ │ KCNQ2 │ Kv7.2 │ BFNE, KCNQ2-DEE │ 1:17,000 births │ │
│ │ KCNT1 │ KNa1.1 │ EIMFS, ADNFLE │ -- │ │
│ │ KCNA2 │ Kv1.2 │ DEE, episodic ataxia │ -- │ │
│ └────────┴──────────┴─────────────────────────┴───────────────────┘ │
│ │
│ 🟢 SYNAPTIC FUNCTION │
│ ════════════════════════════════════════════════════════════════ │
│ ┌────────┬───────────────────┬───────────────────────────────────┐ │
│ │ Gene │ Function │ Phenotype │ │
│ ├────────┼───────────────────┼───────────────────────────────────┤ │
│ │ STXBP1 │ Vesicle release │ Ohtahara, West, DEE │ │
│ │ SYNGAP1│ Synaptic plasticity│ ID + epilepsy │ │
│ │ CDKL5 │ Kinase signaling │ CDKL5-DEE, atypical Rett │ │
│ │ PCDH19 │ Cell adhesion │ Clustering epilepsy (♀) │ │
│ └────────┴───────────────────┴───────────────────────────────────┘ │
│ │
│ 🟡 OTHER IMPORTANT GENES │
│ ════════════════════════════════════════════════════════════════ │
│ ┌────────┬───────────────────┬───────────────────────────────────┐ │
│ │ Gene │ Function │ Phenotype │ │
│ ├────────┼───────────────────┼───────────────────────────────────┤ │
│ │ PRRT2 │ Synaptic protein │ PKD, BFIE (1:9,970 - most common!)│ │
│ │ SLC2A1 │ Glucose transport │ GLUT1 deficiency (1:24,300) │ │
│ │ TSC1/2 │ mTOR pathway │ Tuberous sclerosis │ │
│ │ DEPDC5 │ mTOR pathway │ FFEVF, focal epilepsy │ │
│ └────────┴───────────────────┴───────────────────────────────────┘ │
│ │
└─────────────────────────────────────────────────────────────────────────────────┘
5.3 Developmental and Epileptic Encephalopathies (DEEs)
graph TD
subgraph DEE["DEVELOPMENTAL & EPILEPTIC ENCEPHALOPATHIES (DEEs)"]
A[Over 800 genes identified] --> B[Both epilepsy AND development affected]
B --> C{Age of Onset}
C -->|Neonatal| D[KCNQ2<br/>STXBP1<br/>SCN2A]
C -->|Early Infantile| E[SCN1A<br/>CDKL5<br/>SCN8A]
C -->|Infantile| F[ARX<br/>PCDH19<br/>SLC2A1]
D --> G[Burst-Suppression Pattern]
E --> H[Variable EEG]
F --> I[Hypsarrhythmia possible]
end
style DEE fill:#fff5f5
style D fill:#ffebee
style E fill:#fff3e0
style F fill:#e8f5e9
6. Medical Evaluation and Diagnostic Workup
6.1 First Seizure Evaluation Algorithm
flowchart TD
A[🚨 FIRST UNPROVOKED SEIZURE] --> B{Child returned<br/>to baseline?}
B -->|No| C[🔴 RED FLAGS]
B -->|Yes| D{Risk factors<br/>present?}
C --> C1[• Prolonged postictal >30min]
C --> C2[• Focal neurological deficit]
C --> C3[• Signs of elevated ICP]
C --> C4[• History of trauma]
C --> C5[• Age < 6 months]
C --> C6[• Immunocompromised]
C1 & C2 & C3 & C4 & C5 & C6 --> E[🏥 EMERGENT IMAGING<br/>CT → MRI]
D -->|Yes| F[Outpatient workup<br/>within 24-48h]
D -->|No| G[Outpatient workup<br/>within 1-2 weeks]
F --> H[📋 COMPLETE WORKUP]
G --> H
H --> H1[EEG - routine or sleep-deprived]
H --> H2[MRI brain - epilepsy protocol]
H --> H3[Labs if indicated]
H --> H4[Consider genetics]
style A fill:#ffcdd2
style C fill:#ffebee
style E fill:#ef5350,color:#fff
style H fill:#e8f5e9
6.2 Diagnostic Workup Summary
┌─────────────────────────────────────────────────────────────────────────────────┐
│ FIRST SEIZURE WORKUP CHECKLIST │
├─────────────────────────────────────────────────────────────────────────────────┤
│ │
│ 📋 IMMEDIATE (Emergency Department) │
│ ════════════════════════════════════ │
│ □ Glucose (bedside + lab confirmation) │
│ □ Electrolytes (Na, Ca, Mg) if metabolic cause suspected │
│ □ CBC if infection suspected │
│ □ Toxicology screen if altered mental status │
│ □ CT head ONLY if red flags present │
│ │
│ 📋 OUTPATIENT (Within 1-2 weeks) │
│ ═══════════════════════════════════ │
│ □ EEG (routine; sleep-deprived if initial normal) │
│ □ MRI brain with epilepsy protocol │
│ □ Detailed developmental assessment │
│ │
│ 📋 EXTENDED WORKUP (If indicated) │
│ ═══════════════════════════════════ │
│ □ Video-EEG monitoring │
│ □ Genetic testing (panel, WES, WGS) │
│ □ Metabolic studies (lactate, amino acids, etc.) │
│ □ LP with CSF studies │
│ │
└─────────────────────────────────────────────────────────────────────────────────┘
6.3 When to Order Genetic Testing
flowchart LR
A[Consider Genetic Testing] --> B{Clinical Features}
B --> C[Early onset<br/>< 2 years]
B --> D[Refractory to<br/>2+ ASMs]
B --> E[Developmental<br/>regression]
B --> F[Family history<br/>of epilepsy]
B --> G[Dysmorphic<br/>features]
B --> H[Specific EEG<br/>patterns]
C & D & E & F & G & H --> I{Testing Strategy}
I --> J[Chromosomal<br/>Microarray]
I --> K[Epilepsy Gene<br/>Panel]
I --> L[Whole Exome<br/>Sequencing]
I --> M[Whole Genome<br/>Sequencing]
J --> N[CNVs, Aneuploidy]
K --> O[Known epilepsy genes]
L --> P[Coding regions]
M --> Q[Complete genome]
style A fill:#e3f2fd
style I fill:#fff3e0
6.4 Genetic Testing Algorithm
┌─────────────────────────────────────────────────────────────────────────────────┐
│ GENETIC TESTING DECISION PATHWAY │
├─────────────────────────────────────────────────────────────────────────────────┤
│ │
│ STEP 1: Chromosomal Microarray │
│ ═══════════════════════════════ │
│ │ │
│ ▼ │
│ ┌────────────────────────────────┐ │
│ │ Detects CNVs, deletions, │ │
│ │ duplications, aneuploidy │ │
│ │ Yield: ~5-10% in epilepsy │ │
│ └────────────────────────────────┘ │
│ │ │
│ Normal │ │
│ ▼ │
│ STEP 2: Gene Panel or WES │
│ ═══════════════════════════ │
│ │ │
│ ┌──────────────────────┴──────────────────────┐ │
│ ▼ ▼ │
│ ┌──────────────────────────┐ ┌──────────────────────────┐ │
│ │ SPECIFIC PHENOTYPE │ │ UNKNOWN ETIOLOGY │ │
│ │ → Gene Panel │ │ → WES (Trio preferred) │ │
│ │ • Faster turnaround │ │ • Broader coverage │ │
│ │ • Less VUS │ │ • Higher yield (~30%) │ │
│ │ • Lower cost │ │ • More VUS │ │
│ └──────────────────────────┘ └──────────────────────────┘ │
│ │ │
│ Normal │ │
│ ▼ │
│ STEP 3: Advanced Testing │
│ ════════════════════════ │
│ │ │
│ ┌──────────────────────┼──────────────────────┐ │
│ ▼ ▼ ▼ │
│ ┌─────────────────┐ ┌─────────────────┐ ┌─────────────────┐ │
│ │ WGS │ │ RNA-seq │ │ Functional │ │
│ │ (non-coding) │ │ (splicing) │ │ Studies │ │
│ └─────────────────┘ └─────────────────┘ └─────────────────┘ │
│ │
│ ═══════════════════════════════════════════════════════════════════ │
│ 💡 CLINICAL IMPACT: Finding the cause leads to management changes │
│ in 36% of DEE patients! │
│ ═══════════════════════════════════════════════════════════════════ │
│ │
└─────────────────────────────────────────────────────────────────────────────────┘
7. Physical Examination and Phenotyping
7.1 Systematic Phenotyping Approach
┌─────────────────────────────────────────────────────────────────────────────────┐
│ COMPREHENSIVE PHENOTYPING CHECKLIST │
├─────────────────────────────────────────────────────────────────────────────────┤
│ │
│ 📏 GROWTH PARAMETERS │
│ ═════════════════════ │
│ □ Head circumference → Plot on growth chart │
│ • Microcephaly: < -2 SD (consider MECP2, FOXG1, genetic syndromes) │
│ • Macrocephaly: > +2 SD (consider PTEN, megalencephaly syndromes) │
│ □ Height and weight → Failure to thrive? Overgrowth? │
│ □ Growth trajectory → Crossing percentiles? │
│ │
│ 👤 CRANIOFACIAL EXAMINATION │
│ ═══════════════════════════ │
│ ┌─────────────┬───────────────────────────────────────────────────────┐ │
│ │ Region │ Features to Assess │ │
│ ├─────────────┼───────────────────────────────────────────────────────┤ │
│ │ Skull │ Shape, fontanelles (open/closed), sutures │ │
│ │ Forehead │ Prominent? Sloping? Bossing? │ │
│ │ Eyes │ Spacing (hyper/hypotelorism), slant, epicanthus │ │
│ │ Nose │ Bridge (depressed/prominent), tip, nares │ │
│ │ Ears │ Position (low-set?), rotation, size, pits/tags │ │
│ │ Mouth │ Philtrum length, lip thickness, palate │ │
│ │ Chin │ Micro/retrognathia, prognathism │ │
│ └─────────────┴───────────────────────────────────────────────────────┘ │
│ │
│ 🖐️ EXTREMITIES │
│ ═══════════════ │
│ □ Digits: Count, syndactyly, polydactyly, clinodactyly │
│ □ Palms: Single transverse crease, dermatoglyphics │
│ □ Limbs: Proportions, contractures, tone │
│ │
└─────────────────────────────────────────────────────────────────────────────────┘
7.2 Neurocutaneous Markers
┌─────────────────────────────────────────────────────────────────────────────────┐
│ NEUROCUTANEOUS FINDINGS │
├─────────────────────────────────────────────────────────────────────────────────┤
│ │
│ TUBEROUS SCLEROSIS COMPLEX (TSC1/TSC2) │
│ ══════════════════════════════════════ │
│ │
│ ┌──────────────────┐ ┌──────────────────┐ ┌──────────────────┐ │
│ │ ASH-LEAF SPOTS │ │ SHAGREEN PATCH │ │ ANGIOFIBROMAS │ │
│ │ (╭───────╮) │ │ ┌──────────┐ │ │ • • • │ │
│ │ │░░░░░░░│ │ │ │▓▓▓▓▓▓▓▓▓▓│ │ │ • • • • │ │
│ │ │░░░░░░░│ │ │ │▓▓▓▓▓▓▓▓▓▓│ │ │ • • • │ │
│ │ ╰───────╯ │ │ └──────────┘ │ │ (nose, cheeks) │ │
│ │ Hypopigmented │ │ Connective │ │ Facial papules │ │
│ │ Wood's lamp (+) │ │ tissue nevus │ │ appear age 3-5 │ │
│ └──────────────────┘ └──────────────────┘ └──────────────────┘ │
│ │
│ NEUROFIBROMATOSIS TYPE 1 (NF1) │
│ ═══════════════════════════════ │
│ │
│ ┌──────────────────┐ ┌──────────────────┐ ┌──────────────────┐ │
│ │ CAFÉ-AU-LAIT │ │ AXILLARY/INGUINAL│ │ LISCH NODULES │ │
│ │ ┌───────┐ │ │ FRECKLING │ │ ◉ │ │
│ │ │░░░░░░░│ │ │ · · · · · │ │ (iris) │ │
│ │ └───────┘ │ │ · · · · · │ │ │ │
│ │ ≥6 spots │ │ Crowe sign │ │ Slit lamp exam │ │
│ │ >5mm prepubertal│ │ │ │ │ │
│ │ >15mm adult │ │ │ │ │ │
│ └──────────────────┘ └──────────────────┘ └──────────────────┘ │
│ │
│ STURGE-WEBER SYNDROME │
│ ═════════════════════ │
│ │
│ ┌──────────────────────────────────────────┐ │
│ │ PORT-WINE STAIN (V1 distribution) │ │
│ │ │ │
│ │ ╭──────╮ │ │
│ │ ╱▓▓▓▓▓▓▓▓╲ ← Trigeminal V1 │ │
│ │ │▓▓▓▓▓▓▓▓▓▓│ │ │
│ │ │ ◉ ◉ │ │ │
│ │ │ ▽ │ │ │
│ │ │ ─── │ │ │
│ │ ╲________╱ │ │
│ │ │ │
│ │ Associated with: leptomeningeal │ │
│ │ angioma, glaucoma, seizures │ │
│ └──────────────────────────────────────────┘ │
│ │
└─────────────────────────────────────────────────────────────────────────────────┘
7.3 HPO and Standardized Terminology
┌─────────────────────────────────────────────────────────────────────────────────┐
│ PHENOTYPE DOCUMENTATION RESOURCES │
├─────────────────────────────────────────────────────────────────────────────────┤
│ │
│ 🌐 HUMAN PHENOTYPE ONTOLOGY (HPO) │
│ ══════════════════════════════════ │
│ Website: https://hpo.jax.org │
│ │
│ ┌─────────────────────────────────────────────────────────────────────────┐ │
│ │ HPO HIERARCHY EXAMPLE │ │
│ │ │ │
│ │ Abnormality of the nervous system (HP:0000707) │ │
│ │ │ │ │
│ │ ├── Abnormal CNS morphology │ │
│ │ │ │ │ │
│ │ │ └── Cerebral cortical dysplasia │ │
│ │ │ │ │
│ │ └── Seizure (HP:0001250) │ │
│ │ │ │ │
│ │ ├── Focal seizure │ │
│ │ │ ├── Focal aware seizure │ │
│ │ │ └── Focal impaired awareness seizure │ │
│ │ │ │ │
│ │ └── Generalized seizure │ │
│ │ ├── Absence seizure │ │
│ │ └── Tonic-clonic seizure │ │
│ │ │ │
│ └─────────────────────────────────────────────────────────────────────────┘ │
│ │
│ 📚 NIH ELEMENTS OF MORPHOLOGY │
│ ══════════════════════════════ │
│ Website: https://elementsofmorphology.nih.gov │
│ │
│ • Standardized definitions with photographs │
│ • Anatomical terminology for dysmorphic features │
│ • Essential for consistent phenotype documentation │
│ │
└─────────────────────────────────────────────────────────────────────────────────┘
8. Precision Medicine in Epilepsy
8.1 Gene-Specific Treatment Overview
flowchart TD
subgraph PRECISION["🎯 PRECISION MEDICINE IN EPILEPSY"]
A[Genetic Diagnosis] --> B{Gene Identified}
B -->|SCN1A| C[🔴 DRAVET SYNDROME]
B -->|KCNQ2| D[🟢 KCNQ2-EPILEPSY]
B -->|SLC2A1| E[🟡 GLUT1 DEFICIENCY]
B -->|TSC1/2| F[🟣 TUBEROUS SCLEROSIS]
C --> C1[❌ AVOID Na+ blockers]
C --> C2[✓ Valproate, Clobazam]
C --> C3[✓ Stiripentol, CBD, Fenfluramine]
D --> D1[✓ Na+ blockers EFFECTIVE]
D --> D2[✓ Carbamazepine, Phenytoin]
E --> E1[✓ KETOGENIC DIET]
E --> E2[⚠️ Limited ASM efficacy]
F --> F1[✓ mTOR inhibitors]
F --> F2[✓ Everolimus, Sirolimus]
end
style PRECISION fill:#f5f5f5
style C fill:#ffebee
style D fill:#e8f5e9
style E fill:#fff8e1
style F fill:#f3e5f5
8.2 SCN1A/Dravet Syndrome - Critical Safety Information
╔═══════════════════════════════════════════════════════════════════════════════╗
║ ║
║ ⚠️⚠️⚠️ DRAVET SYNDROME (SCN1A) - MEDICATION ALERT ⚠️⚠️⚠️ ║
║ ║
╠═══════════════════════════════════════════════════════════════════════════════╣
║ ║
║ ❌ MEDICATIONS TO AVOID (Can worsen seizures & cause status epilepticus!) ║
║ ═══════════════════════════════════════════════════════════════════════ ║
║ ║
║ SODIUM CHANNEL BLOCKERS: ║
║ ┌─────────────────────────────────────────────────────────────────────┐ ║
║ │ • Phenytoin (Dilantin) • Lacosamide (Vimpat) │ ║
║ │ • Fosphenytoin (Cerebyx) • Rufinamide (Banzel) │ ║
║ │ • Carbamazepine (Tegretol) • Eslicarbazepine │ ║
║ │ • Oxcarbazepine (Trileptal) │ ║
║ │ • Lamotrigine (Lamictal) │ ║
║ └─────────────────────────────────────────────────────────────────────┘ ║
║ ║
║ OTHER MEDICATIONS TO AVOID: ║
║ ┌─────────────────────────────────────────────────────────────────────┐ ║
║ │ • Vigabatrin (Sabril) • Pregabalin (Lyrica) │ ║
║ │ • Tiagabine (Gabitril) • Gabapentin │ ║
║ └─────────────────────────────────────────────────────────────────────┘ ║
║ ║
║ ✅ RECOMMENDED TREATMENTS ║
║ ════════════════════════ ║
║ ║
║ FIRST-LINE: ║
║ ┌─────────────────────────────────────────────────────────────────────┐ ║
║ │ • Valproate (Depakote) + Clobazam (Onfi) │ ║
║ └─────────────────────────────────────────────────────────────────────┘ ║
║ ║
║ ADD-ON OPTIONS: ║
║ ┌─────────────────────────────────────────────────────────────────────┐ ║
║ │ • Stiripentol (Diacomit) • Topiramate │ ║
║ │ • Cannabidiol (Epidiolex) • Ketogenic diet │ ║
║ │ • Fenfluramine (Fintepla) │ ║
║ └─────────────────────────────────────────────────────────────────────┘ ║
║ ║
║ 🚨 IN STATUS EPILEPTICUS: ║
║ ┌─────────────────────────────────────────────────────────────────────┐ ║
║ │ ✓ USE: Benzodiazepines (Lorazepam, Midazolam, Diazepam) │ ║
║ │ ✓ USE: Valproate IV │ ║
║ │ ✗ AVOID: Phenytoin/Fosphenytoin (even in emergency!) │ ║
║ │ ✗ AVOID: Lacosamide │ ║
║ └─────────────────────────────────────────────────────────────────────┘ ║
║ ║
╚═══════════════════════════════════════════════════════════════════════════════╝
8.3 Treatment Comparison: SCN1A vs KCNQ2
┌─────────────────────────────────────────────────────────────────────────────────┐
│ OPPOSITE TREATMENT STRATEGIES: SCN1A vs KCNQ2 │
├─────────────────────────────────────────────────────────────────────────────────┤
│ │
│ SCN1A KCNQ2 │
│ (Dravet Syndrome) (KCNQ2 Epilepsy) │
│ │
│ Mechanism: Loss of Nav1.1 Mechanism: Loss of Kv7.2 │
│ function in (or Gain of function) │
│ inhibitory neurons │
│ │
│ │ │ │
│ ▼ ▼ │
│ ┌────────────────────────┐ ┌────────────────────────┐ │
│ │ Na+ CHANNEL │ │ Na+ CHANNEL │ │
│ │ BLOCKERS │ │ BLOCKERS │ │
│ │ │ │ │ │
│ │ ❌ CONTRAINDICATED │ │ ✅ FIRST-LINE │ │
│ │ │ │ │ │
│ │ • Worsen seizures │ │ • Often effective │ │
│ │ • Can cause SE │ │ • CBZ, OXC, PHT │ │
│ │ • May be fatal │ │ • Early response │ │
│ └────────────────────────┘ └────────────────────────┘ │
│ │
│ ┌─────────────────────────────────────────────────────────────────────────┐ │
│ │ 💡 CLINICAL PEARL: Genetic diagnosis BEFORE medication selection │ │
│ │ can prevent harm and improve outcomes! │ │
│ └─────────────────────────────────────────────────────────────────────────┘ │
│ │
└─────────────────────────────────────────────────────────────────────────────────┘
8.4 Emerging Therapies
┌─────────────────────────────────────────────────────────────────────────────────┐
│ EMERGING PRECISION THERAPIES │
├─────────────────────────────────────────────────────────────────────────────────┤
│ │
│ 🧬 ANTISENSE OLIGONUCLEOTIDES (ASO) │
│ ═══════════════════════════════════ │
│ ┌─────────────────────────────────────────────────────────────────────────┐ │
│ │ Target: SCN1A (Dravet syndrome) │ │
│ │ Mechanism: Upregulate SCN1A expression via TANGO approach │ │
│ │ Status: Phase 3 clinical trials (Zorevunersen) │ │
│ │ │ │
│ │ Normal mRNA → [ASO blocks inhibitor] → ↑ Nav1.1 protein │ │
│ └─────────────────────────────────────────────────────────────────────────┘ │
│ │
│ 🦠 GENE THERAPY │
│ ═══════════════ │
│ ┌─────────────────────────────────────────────────────────────────────────┐ │
│ │ ETX101 (Encoded Therapeutics) │ │
│ │ • AAV-delivered gene therapy for Dravet │ │
│ │ • Targets SCN1A expression in inhibitory neurons │ │
│ │ • Status: Phase 1/2 trials │ │
│ │ │ │
│ │ AAV vector → [Delivery to neurons] → ↑ SCN1A expression │ │
│ └─────────────────────────────────────────────────────────────────────────┘ │
│ │
│ ✂️ GENE EDITING (CRISPR) │
│ ════════════════════════ │
│ ┌─────────────────────────────────────────────────────────────────────────┐ │
│ │ Approach: dCas9-mediated promoter activation │ │
│ │ Target: Upregulate SCN1A expression │ │
│ │ Status: Preclinical (mouse models successful) │ │
│ │ │ │
│ │ Challenges: │ │
│ │ • CNS delivery │ │
│ │ • Potential immune response to Cas9 │ │
│ │ • Off-target effects │ │
│ └─────────────────────────────────────────────────────────────────────────┘ │
│ │
│ 💊 SMALL MOLECULE MODULATORS │
│ ════════════════════════════ │
│ ┌─────────────────────────────────────────────────────────────────────────┐ │
│ │ • Ezogabine (KCNQ2): Compassionate use │ │
│ │ • Quinidine (KCNT1): Limited efficacy │ │
│ │ • mTOR inhibitors (TSC): FDA approved (Everolimus) │ │
│ └─────────────────────────────────────────────────────────────────────────┘ │
│ │
└─────────────────────────────────────────────────────────────────────────────────┘
9. Clinical Pearls and Pitfalls
9.1 Diagnostic Pearls
┌─────────────────────────────────────────────────────────────────────────────────┐
│ 💎 DIAGNOSTIC PEARLS │
├─────────────────────────────────────────────────────────────────────────────────┤
│ │
│ 🔥 "Fever + prolonged seizure in infant → Think SCN1A" │
│ ───────────────────────────────────────────────────── │
│ First febrile seizure that is prolonged (>15 min), hemiclonic, │
│ or followed by more seizures = HIGH suspicion for Dravet │
│ → Order SCN1A testing early, AVOID sodium channel blockers │
│ │
│ 📊 "Burst-suppression in neonate → Think STXBP1, KCNQ2, SCN2A" │
│ ────────────────────────────────────────────────────────────── │
│ Severe early-onset DEE with burst-suppression pattern │
│ → Urgent genetic panel, consider sodium channel blockers for KCNQ2 │
│ │
│ ♀️ "Seizures only in females + variable severity → Think PCDH19" │
│ ──────────────────────────────────────────────────────────────── │
│ Seizure clusters, often fever-related, males are unaffected carriers │
│ → X-linked inheritance with cellular mosaicism │
│ │
│ 🍬 "Low CSF glucose + normal blood glucose → Think GLUT1" │
│ ───────────────────────────────────────────────────────── │
│ CSF:blood glucose ratio <0.4, movement disorder, developmental delay │
│ → SLC2A1 testing, ketogenic diet is treatment of choice │
│ │
│ 🌙 "Seizures only from sleep + centrotemporal spikes → Think SLECTS" │
│ ──────────────────────────────────────────────────────────────────── │
│ Benign rolandic epilepsy, speech arrest, drooling │
│ → Usually no imaging needed, excellent prognosis, often no treatment │
│ │
│ 👀 "Staring spells + 3Hz spike-wave + hyperventilation trigger → Think CAE" │
│ ─────────────────────────────────────────────────────────────────────── │
│ Brief (<30 sec) absence seizures, multiple per day │
│ → First-line: Ethosuximide or Valproate, 70% remission by adolescence │
│ │
└─────────────────────────────────────────────────────────────────────────────────┘
9.2 Common Pitfalls to Avoid
┌─────────────────────────────────────────────────────────────────────────────────┐
│ ⚠️ COMMON PITFALLS │
├─────────────────────────────────────────────────────────────────────────────────┤
│ │
│ ❌ PITFALL 1: Starting sodium channel blocker without genetic diagnosis │
│ ═══════════════════════════════════════════════════════════════════ │
│ │
│ Scenario: Infant with febrile seizures started on phenytoin │
│ Later diagnosed with Dravet syndrome │
│ │
│ Result: Seizure worsening, status epilepticus │
│ │
│ Prevention: • Consider genetics early in refractory infant epilepsy │
│ • Use valproate/clobazam as first-line if Dravet suspected │
│ │
│ ❌ PITFALL 2: Misinterpreting normal EEG variants as epileptiform │
│ ═══════════════════════════════════════════════════════════════════ │
│ │
│ Common mistakes: │
│ • Posterior slow waves of youth → Called "occipital spikes" │
│ • Hypnagogic hypersynchrony → Called "generalized slowing" │
│ • Wicket spikes → Called "temporal sharp waves" │
│ │
│ Prevention: • Know age-appropriate normal variants │
│ • Correlate with clinical history │
│ │
│ ❌ PITFALL 3: Skipping developmental history │
│ ═══════════════════════════════════════════════════════════════════ │
│ │
│ Missed: Developmental regression preceding seizure onset │
│ (Key feature of DEE, metabolic disorders) │
│ │
│ Prevention: • Always document developmental milestones │
│ • Ask about skill loss, plateau │
│ │
│ ❌ PITFALL 4: Inadequate family history │
│ ═══════════════════════════════════════════════════════════════════ │
│ │
│ Missed: • Autosomal dominant epilepsy syndromes │
│ • Consanguinity (recessive disorders) │
│ • Febrile seizures in relatives (GEFS+, Dravet) │
│ │
│ Prevention: • Three-generation pedigree │
│ • Ask about seizures, developmental delay, early deaths │
│ │
└─────────────────────────────────────────────────────────────────────────────────┘
10. Summary: Approach to Pediatric Neurologic Diseases
10.1 Etiology Framework
┌─────────────────────────────────────────────────────────────────────────────────┐
│ ETIOLOGY OF PEDIATRIC NEUROLOGIC DISEASES │
├─────────────────────────────────────────────────────────────────────────────────┤
│ │
│ ┌─────────────────┐ │
│ │ PEDIATRIC │ │
│ │ NEUROLOGIC │ │
│ │ DISEASES │ │
│ └────────┬────────┘ │
│ │ │
│ ┌───────────────┬───────────┼───────────┬───────────────┐ │
│ ▼ ▼ ▼ ▼ ▼ │
│ ┌──────────┐ ┌──────────┐ ┌──────────┐ ┌──────────┐ ┌──────────┐ │
│ │ 🧬 │ │ ⚗️ │ │ 🦠 │ │ 🌍 │ │ 🏥 │ │
│ │ GENETIC │ │METABOLIC │ │INFECTIOUS│ │ENVIRON- │ │STRUCTURAL│ │
│ │ │ │ │ │ │ │ MENTAL │ │ │ │
│ └────┬─────┘ └────┬─────┘ └────┬─────┘ └────┬─────┘ └────┬─────┘ │
│ │ │ │ │ │ │
│ ▼ ▼ ▼ ▼ ▼ │
│ • Monogenic • IEM • Meningitis • HIE • Malformations │
│ • Chromosomal • Mito • Encephalitis• Toxins • Tumors │
│ • Complex • Storage • TORCH • Trauma • Vascular │
│ │
└─────────────────────────────────────────────────────────────────────────────────┘
10.2 Clinical Approach Summary
flowchart TD
A[👶 Child with Neurological Concern] --> B[📋 COMPREHENSIVE HISTORY]
B --> B1[Prenatal: exposures, infections]
B --> B2[Perinatal: complications, APGAR]
B --> B3[Development: milestones, regression]
B --> B4[Seizure: detailed semiology]
B --> B5[Family: 3-generation pedigree]
B1 & B2 & B3 & B4 & B5 --> C[🔍 PHYSICAL EXAMINATION]
C --> C1[Growth parameters]
C --> C2[Dysmorphic features]
C --> C3[Skin: neurocutaneous]
C --> C4[Neurological exam]
C --> C5[Developmental assessment]
C1 & C2 & C3 & C4 & C5 --> D[🧪 INVESTIGATIONS]
D --> D1[EEG]
D --> D2[MRI brain]
D --> D3[Genetic testing]
D --> D4[Metabolic workup]
D1 & D2 & D3 & D4 --> E[📊 DIAGNOSIS]
E --> E1[Classify seizure type]
E --> E2[Determine epilepsy type]
E --> E3[Identify syndrome]
E --> E4[Find etiology]
E1 & E2 & E3 & E4 --> F[💊 MANAGEMENT]
F --> F1[Gene-specific treatment]
F --> F2[Avoid contraindicated drugs]
F --> F3[Consider non-pharmacologic]
F --> F4[Genetic counseling]
style A fill:#e3f2fd
style B fill:#fff3e0
style C fill:#e8f5e9
style D fill:#fce4ec
style E fill:#f3e5f5
style F fill:#e0f7fa
11. Learning Objectives and Self-Assessment
11.1 Learning Objectives Checklist
After completing this lecture, students should be able to:
| # | Objective | Self-Check |
|---|---|---|
| 1 | Define seizure, epilepsy, and status epilepticus | □ |
| 2 | Apply the ILAE 2017/2022 classification system | □ |
| 3 | Interpret age-appropriate EEG findings | □ |
| 4 | List major epilepsy genes and their phenotypes | □ |
| 5 | Outline the diagnostic workup for first seizure | □ |
| 6 | Perform systematic phenotyping using HPO terminology | □ |
| 7 | Recognize when genetic testing is indicated | □ |
| 8 | Identify gene-specific treatment considerations | □ |
| 9 | Avoid medications contraindicated in specific genetic epilepsies | □ |
| 10 | Counsel families on epilepsy prognosis and management | □ |
11.2 Self-Assessment Questions
Question 1: A 6-month-old presents with recurrent prolonged seizures triggered by fever. Genetic testing reveals an SCN1A pathogenic variant. Which medication should be AVOIDED?
**Answer**: Sodium channel blockers should be **AVOIDED**: - Phenytoin/Fosphenytoin - Carbamazepine - Oxcarbazepine - Lamotrigine - Lacosamide These drugs block sodium channels and can worsen seizures in Dravet syndrome because SCN1A mutations already cause loss of Nav1.1 function in inhibitory neurons. **First-line treatment**: Valproate + ClobazamQuestion 2: What is the expected posterior dominant rhythm frequency for a healthy 3-year-old?
**Answer**: **7-8 Hz** PDR maturation follows this pattern: - 6 months: 4-5 Hz - 1 year: 5-6 Hz - 2 years: 6-7 Hz - **3 years: 7-8 Hz** - 8 years: 8-9 Hz - 10 years: 9-10 Hz (adult-like) Clinical pearl: PDR should be approximately [age in years + 2-3] HzQuestion 3: A neonate presents with tonic seizures on day 3 of life. EEG shows burst-suppression. Which genes should be prioritized for testing?
**Answer**: Priority genes for neonatal-onset DEE with burst-suppression: 1. **STXBP1** - Most common cause of Ohtahara syndrome 2. **KCNQ2** - Early neonatal onset, may respond to sodium channel blockers 3. **SCN2A** - Variable phenotype 4. **KCNT1** - EIMFS 5. **ARX** (in males) - X-linked Consider urgent epilepsy gene panel or rapid trio whole exome sequencing.Question 4: When is emergent neuroimaging indicated after a first unprovoked seizure?
**Answer**: Emergent imaging (CT initially, MRI when stable) is indicated for: **RED FLAGS:** - Prolonged postictal state (>30 minutes) - Persistent focal neurological deficit - Signs of elevated intracranial pressure - History of significant head trauma - Immunocompromised state - Concern for child abuse - Age < 6 months with symptomatic seizure - New focal findings on examination **NOT required if:** - Child returned to baseline - Non-focal examination - Recognized benign epilepsy syndrome - Simple febrile seizureQuestion 5: What is the first-line treatment for KCNQ2-related epilepsy, and why does this differ from Dravet syndrome?
**Answer**: **KCNQ2 first-line**: Sodium channel blockers (Carbamazepine, Oxcarbazepine, Phenytoin) **Why the opposite of Dravet?** | Feature | SCN1A (Dravet) | KCNQ2 | |---------|---------------|-------| | Affected channel | Nav1.1 (sodium) | Kv7.2 (potassium) | | Mutation effect | Loss of function in inhibitory neurons | Loss or gain of function | | Na+ blockers | Worsen seizures | Often effective | | Mechanism | Further reduces inhibitory neuron function | Different pathophysiology | This illustrates why genetic diagnosis BEFORE medication selection is critical for precision medicine in epilepsy.Question 6: A 5-year-old girl has absence seizures provoked by hyperventilation, with 3 Hz generalized spike-wave on EEG. What is the diagnosis and prognosis?
**Answer**: **Diagnosis**: Childhood Absence Epilepsy (CAE) **Key features**: - Age 4-8 years - Brief (5-15 second) staring spells - Multiple episodes daily - Triggered by hyperventilation - 3 Hz generalized spike-wave **Prognosis**: GOOD - ~70% achieve remission by adolescence - Some develop JME or GTC seizures **Treatment**: - First-line: Ethosuximide (absence only) or Valproate (if GTC risk) - Avoid: Carbamazepine, Phenytoin (can worsen absence)12. References and Further Reading
Key References
- ILAE Classification
- ILAE Definition & Classification Portal
- Specchio N, et al. Epilepsia 2022 - Childhood epilepsy syndromes
- Updated Classification of Epileptic Seizures (2025)
- Pediatric EEG
- Genetic Epilepsies
- McTague A, et al. Lancet Neurology 2016 - Genetic landscape of epileptic encephalopathies
- Precision medicine in KCNQ2 epilepsy
- Phenotyping Resources
- Clinical Guidelines
Online Resources
| Resource | URL | Description |
|---|---|---|
| ILAE | ilae.org | Classification, guidelines |
| HPO | hpo.jax.org | Phenotype terminology |
| OMIM | omim.org | Gene-disease relationships |
| GeneReviews | ncbi.nlm.nih.gov/books/NBK1116/ | Clinical genetic summaries |
| ClinVar | ncbi.nlm.nih.gov/clinvar/ | Variant interpretation |
Suggested Textbooks
- Swaiman’s Pediatric Neurology (6th edition)
- Pediatric Epilepsy (Pellock, Nordli, Sankar, Wheless)
- Atlas of Pediatric EEG (Blume, Kaibara, Young)
Version History
| Version | Date | Changes |
|---|---|---|
| 1.0 | 2023-10-23 | Initial student lecture |
| 2.0 | 2025-01 | Comprehensive update: ILAE 2022/2025, genetic content, precision medicine |
| 2.1 | 2025-01 | Enhanced visual materials: diagrams, flowcharts, Mermaid charts |
Acknowledgments
This lecture material is prepared for medical student education by YK Shim, Division of Pediatric Neurology, Department of Pediatrics, Korea University College of Medicine.
This document is intended for educational purposes. Clinical decisions should be based on individual patient assessment and current guidelines.
License: CC BY-NC-SA 4.0