What are the differential diagnoses for seizures in infants under 12 months of age?

Differential Diagnoses for Seizures in Infants

The differential diagnosis for seizures in infants under 12 months must distinguish between true epileptic seizures and non-epileptic paroxysmal events (NEPE), with the most common etiologies varying dramatically by age: in neonates (0-29 days), hypoxic-ischemic injury accounts for 46-65% of cases, followed by intracranial hemorrhage and stroke (10-12%), while in older infants (1-12 months), febrile seizures become the leading cause (35%), followed by epilepsy (21%) and infections (13%). 1, 2

Age-Specific Differential Diagnoses

Neonatal Period (0-29 Days)

Acute Symptomatic Causes (95% of cases):

• Hypoxic-ischemic encephalopathy (HIE): 46-65% of neonatal seizures, with 90% occurring within first 2 days of life 1
• Intracranial hemorrhage: 10-12% of cases 1
• Perinatal ischemic stroke: 10-12% of cases 1
• Central nervous system infections: More likely if seizures occur beyond day 7 1
• Metabolic disorders: Including hypoglycemia, hypocalcemia, hyponatremia
• Genetic disorders and malformations of cortical development: More likely if seizures occur beyond day 7 1

Neonatal-Onset Epilepsies (rare, <5%):

• Vitamin B6-dependent epilepsy: Consider if seizures are refractory to standard antiseizure medications 3
• Channelopathies: Including self-limited neonatal epilepsy and KCNQ2 encephalopathy 3

Older Infants (1-12 Months)

True Epileptic Seizures:

• Febrile seizures: 35% of new-onset seizures, occurring between 6 months-5 years with fever ≥38°C 1, 2
• Epilepsy syndromes: 21% of cases 2
• Meningitis/encephalitis: 13% of cases 2
• Metabolic causes: 12% of cases 2
• Structural brain malformations: 4% of cases 2
• Cerebral palsy: 3% of cases 2

Non-Epileptic Paroxysmal Events (NEPE):

These are critically important to recognize as they are frequently misdiagnosed as epilepsy. In one study, 13 of 22 infants referred for suspected epilepsy actually had NEPE 4. Common patterns include:

• Breath-holding spells: Most frequent NEPE (55.1%), strongly associated with crying as trigger (97.5%), and anemia (23.4% of cases) 5
• Jitteriness: 10.6% of NEPE 5
• Shuddering attacks: 9.3% of NEPE 5
• Benign myoclonus of infancy
• Masturbation-like movements 4
• Stereotypic eye blinking or head movements 4

Critical Diagnostic Approach

EEG Confirmation is Essential

Only focal clonic and focal tonic seizures can be diagnosed by clinical observation alone; all other seizure types require EEG or amplitude-integrated EEG (aEEG) confirmation. 3 This is critical because:

• Clinical diagnosis alone leads to treating non-seizure events and underestimating true seizure burden 3
• In infants with suspected NEPE, EEG was abnormal in only 8.8% of cases, indicating limited diagnostic yield 5
• Even experienced clinicians (neonatologists and pediatric neurologists) correctly identified paroxysmal events in only 67% of cases without EEG 6

Age-Based Diagnostic Algorithm

For Neonates (0-29 days):

1. Timing matters: Seizures within 48 hours → think HIE; seizures after day 7 → consider infection, genetic disorders, or malformations 1
2. Imaging priority: MRI with diffusion-weighted imaging is superior to ultrasound (identifies etiology in additional 11.9% of cases and provides prognostic information) 1
3. Consider vitamin B6-dependent epilepsy if seizures are refractory to phenobarbital and second-line agents 3

For Older Infants (1-12 months):

1. Fever present: If generalized seizure <15 minutes without recurrence in 24 hours = simple febrile seizure (no imaging indicated) 1
2. No fever, first seizure: Assess for triggers (crying → breath-holding spells), check hemoglobin (anemia predicts breath-holding spells, AOR 2.65) 5
3. Age 13-18 months with crying-triggered events: High likelihood of breath-holding spells (AOR 3.95) 5
4. Developmental delay present: 11% of infants with new-onset seizures have developmental delay; increases likelihood of structural or genetic etiology 2

Common Pitfalls to Avoid

Do not assume all paroxysmal events are epileptic. NEPE may persist for 2 weeks to 7 months but resolve spontaneously without treatment 4. Key distinguishing features:

• Normal interictal EEGs (require at least 4 recordings for NEPE) 4
• Normal development throughout observation period 4
• Specific triggers (crying for breath-holding spells) 5
• Resolution without antiseizure medication 4

Do not order imaging for simple febrile seizures. There is no indication for MRI or CT in children with simple febrile seizures 1. Even when abnormalities are found on MRI (11.4% in one study), they do not change management 1.

Do not delay vitamin B6 trial in refractory neonatal seizures. Treatment with pyridoxine (and subsequently pyridoxal phosphate if unsuccessful) should not be delayed for diagnostic testing, as therapeutic trials can be started without affecting diagnostic results 3. Partial or transient response to standard antiseizure medications does not rule out vitamin B6-dependent epilepsy 3.