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Febrile vs. Afebrile Seizures in Children

Based on Nelson's Textbook of Pediatrics, 22nd Edition

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1. DEFINITIONS

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2. FEBRILE SEIZURES

2.1 Epidemiology

• Prevalence: 3–5% of children in Western countries; higher in Asia (up to 8–10% in Japan)
• Most common seizure type in children under 5 years
• Peak incidence: 18–24 months
• Age range: 3 months to 5 years (outside this range, look for other causes)
• Strong genetic predisposition: autosomal dominant with variable penetrance; genes involved include SCN1A, GABRG2, and chromosomes 8q13–q21, 19p

2.2 Pathophysiology

• Developing brain has lower seizure threshold at elevated temperatures
• Fever lowers the threshold for neuronal depolarization
• IL-1β and other pro-inflammatory cytokines released during fever may directly enhance neuronal excitability
• Seizure most commonly occurs during the rapid rise in temperature (first 24 hours of febrile illness), not at the peak
• Common precipitating infections: HHV-6 (roseola) is the most common identified virus; also otitis media, URIs, gastroenteritis, post-vaccination (especially MMR, DTaP)

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2.3 Classification: Simple vs. Complex Febrile Seizures

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2.4 Risk Factors for Recurrence of Febrile Seizures

• 0 risk factors: ~15% recurrence
• 1 risk factor: ~25–30% recurrence
• 2+ risk factors: ~50–60% recurrence

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2.5 Risk Factors for Developing Epilepsy after Febrile Seizures

• After simple febrile seizure: epilepsy risk ~1–1.5% (background population risk)
• After complex febrile seizure: epilepsy risk ~5–10%
• After febrile status epilepticus: risk higher, particularly for mesial temporal lobe epilepsy (hippocampal sclerosis — the FEBSTAT study link)

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2.6 Evaluation of Febrile Seizures

• Strongly consider if:
  • Age < 6–12 months (signs of meningitis may be absent)
  • Signs of meningismus or altered consciousness after postictal period
  • Complex febrile seizure with no obvious focus of infection
  • Child is ill-appearing, immunocompromised, or partially treated with antibiotics
• Not routinely indicated in a well-appearing child with simple febrile seizure aged >18 months with normal exam

• Not recommended after a first simple febrile seizure
• May be considered in complex febrile seizures or when epilepsy is suspected

• Not routinely indicated for simple febrile seizures
• Consider MRI in:
  • Focal febrile seizure
  • Prolonged febrile seizure (status epilepticus)
  • Abnormal neurological exam
  • Suspected structural etiology

• Not routinely indicated for simple febrile seizures
• May check glucose, electrolytes if clinically indicated (very young, malnourished, or prolonged seizure)

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2.7 Management of Febrile Seizures

• Most simple febrile seizures are self-limiting (< 5 minutes); no acute treatment usually needed
• If seizure > 5 minutes: Benzodiazepines (lorazepam IV/IM, diazepam rectal, midazolam buccal/intranasal)
• Identify and treat underlying cause of fever

• NOT recommended for simple febrile seizures
• Continuous AED prophylaxis (phenobarbital, valproate): effective but side effects outweigh benefits; not routinely used
• Intermittent oral diazepam at fever onset: reduces recurrence but side effects (sedation, ataxia) and impracticality limit use
• Antipyretics (acetaminophen, ibuprofen): reduce fever but do NOT prevent febrile seizures — not recommended as seizure prophylaxis
• Parental education and reassurance are key components

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3. AFEBRILE SEIZURES

3.1 Definition and Overview

• Provoked (acute symptomatic): CNS infection, trauma, metabolic disturbance, toxin — requires treatment of underlying cause
• Unprovoked: No identified acute cause; a single unprovoked seizure does not necessarily mean epilepsy
• Epilepsy: ≥2 unprovoked seizures > 24 hours apart, OR 1 unprovoked seizure with >60% risk of recurrence over 10 years

3.2 Classification (ILAE 2017 Framework)

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3.3 Important Childhood Epilepsy Syndromes (Afebrile)

A. Absence Epilepsy (Childhood Absence Epilepsy — CAE)

• Age: 4–10 years, peak 6–7 years; girls > boys
• Brief (5–20 sec) episodes of staring, unresponsiveness, eye fluttering; abrupt onset and offset
• No postictal confusion
• EEG: Classic 3 Hz generalized spike-and-wave discharges
• Hyperventilation provokes attacks
• Treatment: Ethosuximide (drug of choice), valproate, lamotrigine
• Prognosis: Remits in ~65–70% by adolescence

B. Juvenile Myoclonic Epilepsy (JME)

• Age: 12–18 years
• Morning myoclonic jerks (especially after awakening), generalized tonic-clonic, absence seizures
• Precipitated by sleep deprivation, alcohol, photic stimulation
• EEG: 4–6 Hz polyspike-and-wave
• Treatment: Valproate (first-line), levetiracetam, lamotrigine
• Lifelong treatment usually required (high relapse rate if stopped)

C. Benign Rolandic Epilepsy (BECTS — Self-Limited Epilepsy with Centrotemporal Spikes)

• Age: 3–13 years, peak 7–10 years; boys > girls
• Nocturnal focal seizures: hemifacial twitching, drooling, speech arrest, ± secondary generalization
• EEG: Centrotemporal (rolandic) spikes
• Usually no treatment needed; resolves by age 16
• Prognosis: Excellent — remits spontaneously

D. Infantile Spasms (West Syndrome)

• Age: Typically 3–12 months
• Sudden flexion or extension of trunk and extremities in clusters, usually on awakening
• EEG: Hypsarrhythmia (chaotic high-amplitude irregular spikes and slow waves)
• Causes: Structural (tuberous sclerosis, cortical dysplasia, Down syndrome), metabolic, unknown
• Treatment: ACTH or vigabatrin (especially for tuberous sclerosis complex)
• Prognosis: Poor — 70–90% have intellectual disability; may evolve to Lennox-Gastaut

E. Lennox-Gastaut Syndrome (LGS)

• Age: 1–8 years
• Multiple seizure types: tonic, atonic (drop attacks), atypical absence
• EEG: Slow (< 2.5 Hz) spike-and-wave + generalized paroxysmal fast activity during sleep
• Severe intellectual disability; refractory to treatment
• Treatment: Valproate, lamotrigine, rufinamide, clobazam, cannabidiol (Epidiolex), ketogenic diet

F. Dravet Syndrome (Severe Myoclonic Epilepsy of Infancy)

• Age: First year of life
• Prolonged febrile hemiconvulsions initially, then multiple seizure types
• SCN1A mutation (sodium channel)
• Cognitive regression over time
• Treatment: Valproate, clobazam, stiripentol; avoid sodium channel blockers (carbamazepine, phenytoin)

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3.4 Evaluation of First Unprovoked Afebrile Seizure

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3.5 Risk of Recurrence after First Unprovoked Afebrile Seizure

• Overall recurrence after first afebrile seizure: ~30–50% within 2 years
• Higher risk if:
  • Abnormal EEG (especially epileptiform discharges)
  • Remote symptomatic etiology (structural brain abnormality)
  • Prior neurological insult
  • Seizure occurring from sleep
  • Family history of epilepsy
• Lower risk if:
  • Normal EEG and MRI
  • Idiopathic/cryptogenic

3.6 Treatment Decision after First Afebrile Seizure

• Single seizure with normal EEG and MRI: Treatment generally not started; risk/benefit discussion
• Treatment recommended if:
  • Two or more unprovoked seizures (epilepsy)
  • Single seizure with high recurrence risk (abnormal EEG, structural lesion, epilepsy syndrome)
  • Status epilepticus

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4. HEAD-TO-HEAD COMPARISON: Febrile vs. Afebrile Seizures

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5. SPECIAL SITUATIONS

Febrile Status Epilepticus

• Febrile seizure lasting > 30 minutes or multiple seizures without recovery = febrile status epilepticus
• Accounts for ~5% of febrile seizures
• FEBSTAT Study: Documented acute hippocampal injury on MRI after febrile status; long-term risk of mesial temporal sclerosis and temporal lobe epilepsy
• Managed as per status epilepticus protocol: benzodiazepine → phenobarbital/levetiracetam/phenytoin

Generalized Epilepsy with Febrile Seizures Plus (GEFS+)

• Genetic epilepsy syndrome with febrile seizures persisting beyond age 6, plus afebrile generalized seizures
• SCN1A, SCN1B, GABRG2 mutations
• Spectrum disorder: ranges from simple febrile seizures to Dravet syndrome

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6. KEY TAKEAWAYS (Nelson's Perspective)

1. Simple febrile seizures are benign, self-limited, and require only parental education and fever management — no AEDs, no routine EEG/imaging.
2. Complex febrile seizures warrant more thorough evaluation and closer follow-up given higher epilepsy risk.
3. Afebrile seizures require systematic evaluation with EEG and often MRI to identify the epilepsy syndrome and guide treatment.
4. Fever does not cause epilepsy in most children — this must be communicated to parents.
5. Epilepsy syndrome diagnosis drives AED selection; wrong AED choice (e.g., carbamazepine in Dravet syndrome) can worsen seizures.
6. Prognosis varies widely — from the excellent prognosis of benign rolandic epilepsy to the severe outcome of Lennox-Gastaut syndrome.

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Sources: Nelson's Textbook of Pediatrics, 22nd Edition (chapters on Seizures, Febrile Seizures, and Epileptic Syndromes); Harrison's Principles of Internal Medicine, 21st Edition (p. 12037, 12040); ILAE 2017 Classification Framework; FEBSTAT Study findings.