What are the differential diagnoses and initial work‑up for a neonate or infant presenting with early‑onset epilepsy?

Early-Onset Epilepsy: Differential Diagnoses and Initial Work-Up

Immediate Priorities and Stabilization

In neonates and infants presenting with early-onset seizures, immediately secure airway, breathing, and circulation while performing point-of-care glucose testing to exclude hypoglycemia, as this is a rapidly reversible cause that must not be missed. 1, 2

• Continuously monitor heart rate, blood pressure, temperature, and oxygen saturation 1
• Establish IV/IO access immediately for medication administration and metabolic correction 1
• Correct hypoglycemia with D10%-containing isotonic IV solution at maintenance rate if present 1

Age-Specific Differential Diagnoses

Neonatal Period (0-29 days)

Hypoxic-ischemic encephalopathy dominates as the cause of neonatal seizures, accounting for 46-65% of cases, with 90% presenting within the first 2 days of life. 3, 1, 2

Primary etiologies by frequency:

• Hypoxic-ischemic injury (46-65%): Strongly suspect if seizures occur within first 48 hours after documented perinatal asphyxia 3, 1, 2
• Intracranial hemorrhage and perinatal ischemic stroke (10-12% combined): Consider with birth trauma, low hematocrit, or coagulopathy 3, 1
• Metabolic derangements: Hypoglycemia, hypocalcemia, hypomagnesemia, hyponatremia 1, 2
• Infection: Meningitis, encephalitis, sepsis—more likely if seizures occur beyond day 7 3, 1
• Genetic epilepsies: Channelopathies (KCNQ2, KCNQ3, SCN2A, SCN8A), synaptopathies (STXBP1), inborn errors of metabolism, particularly if seizures persist beyond first week 3, 4, 5
• Malformations of cortical development: More likely with late-onset seizures (>7 days) 3

Infancy (1-12 months)

West syndrome is the most common epilepsy syndrome in infancy with an incidence of 41 per 100,000, followed by benign familial or nonfamilial infantile epilepsy at 22 per 100,000. 6

Key differential categories:

• Structural-metabolic causes (35%): Brain malformations, tuberous sclerosis complex, neurodegenerative disorders 7, 6
• Genetic epilepsies (17%): Increasingly recognized with next-generation sequencing, including CDKL5, ARX, KCNT1 mutations 4, 7, 5, 6
• Unknown etiology (48%): Despite comprehensive workup 6

Systematic Initial Work-Up

Essential Laboratory Studies

Immediately obtain electrolytes (sodium, calcium, magnesium), blood gas analysis, complete blood count, and blood culture if infection suspected. 1, 2

• Correct hypocalcemia and hypomagnesemia BEFORE initiating anticonvulsants, as these metabolic derangements can perpetuate seizures 1, 2
• Consider toxicologic screening if any question of drug exposure 8
• Perform lumbar puncture if: clinical signs of meningism present, after complex convulsion, child unduly drowsy/irritable/systemically ill, or age <12-18 months (especially <12 months) 8, 2
• Critical pitfall: Do NOT perform lumbar puncture in comatose infants without experienced physician evaluation due to herniation risk 1, 2

Neuroimaging Algorithm

MRI with diffusion-weighted imaging is the gold standard for identifying etiology and should be obtained when clinically feasible. 8, 1, 2

Imaging sequence based on clinical stability:

1. Head ultrasound: Initial bedside imaging if infant unstable or MRI unavailable; identifies intraventricular hemorrhage, hydrocephalus, white matter changes, but has low sensitivity for hypoxic-ischemic injury and small infarctions 1, 2
2. MRI with diffusion-weighted imaging: Most sensitive for hypoxic-ischemic encephalopathy, provides additional diagnostic information beyond ultrasound in 39.8% of patients 2
3. CT head: Limited but specific role for detecting hemorrhagic lesions in encephalopathic infants with birth trauma history, low hematocrit, or coagulopathy 2

Emergent neuroimaging indications:

• Postictal focal deficit that does not quickly resolve 8
• Failure to return to baseline within several hours after seizure 8

Nonurgent MRI strongly recommended for:

• Significant cognitive or motor impairment of unknown etiology 8
• Unexplained abnormalities on neurologic examination 8
• Seizure of partial onset with or without secondary generalization 8
• Age <1 year 8

Electroencephalography

Continuous video-EEG monitoring is essential to recognize seizures and assess prognosis, as not all clinical movements have EEG correlates and not all EEG seizures have clinical manifestations. 2

• Many neonatal seizures are subclinical or exclusively electroencephalographic without clinical signs 2
• EEG is recommended as part of neurodiagnostic evaluation for apparent first unprovoked seizure 8

Genetic and Metabolic Testing

If primary biochemical investigations exclude precipitating conditions, initiate trial with pyridoxine, pyridoxal-5-phosphate, or folinic acid regardless of presumptive seizure cause. 7

For unclear etiologies after initial workup:

• Targeted next-generation sequencing panels show high diagnostic yield in epileptic encephalopathy 7
• Whole-genome analysis can identify pathogenic mutations in 100% of early infantile epileptic encephalopathy cases where prior genetic tests were non-diagnostic 9
• Consider rapid exome or genome sequencing in critically ill neonates to enable timely diagnosis and precision treatment 4

Clinical Recognition Patterns

The constellation of current or recent febrile illness with altered behavior, personality, cognition or consciousness, new-onset seizures, or new focal neurological signs should raise suspicion of encephalitis or CNS infection. 8

Features suggesting non-encephalitic encephalopathy (metabolic, toxic, autoimmune):

• Past history of similar episodes 8
• Symmetrical neurological findings 8
• Myoclonus (brief jerking without rhythmicity) 8
• Clinical signs of liver failure 8
• Lack of fever 8
• Acidosis or alkalosis 8

Prognostic Considerations

An underlying cause can be identified in approximately 95% of neonatal seizures with systematic evaluation. 8, 3, 2

• Absence of major cerebral lesions on MRI is highly predictive of normal neurological outcome 2
• At 24 months, 58% of infants with first-year epilepsy onset achieve seizure freedom, but only 46% have both seizure freedom and age-appropriate cognitive development 6
• Early age at onset is NOT an independent risk factor for poor outcome when etiology is controlled for 6
• Mortality in first 2 years is 4.4%, with SUDEP risk in specific genetic epilepsies (e.g., SCN2A mutations) 6