Early infantile Epileptic Encephalopathy

Early infantile Epileptic Encephalopathy – Introduction

• Severe neonatal epileptic encephalopathy characterized by frequent and intractable tonic spasms with progressive disruption of cerebral functions^(1,2)

Synonyms

•  Early infantile epileptic encephalopathy with suppression burst
•  Ohtahara syndrome

Definitions

• Epileptic encephalopathy – epileptic activity contributes to neurological and cognitive impairment in addition to underlying pathology⁽³⁾

Epidemiology

Who Is Most Affected

•  Neonates and very young infants^(1,2,3)

Incidence/Prevalence

•  uncommon, reported to account for 0.2%-0.4% of pediatric epilepsies (Brain Dev 2012 Jun;34(6):459)
• incidence of early infantile epileptic encephalopathy 3.6 per 100,000 live births/year in Australia
  •  based on population-based cohort study
  • 114 infants (54% male) with severe epilepsy of infancy with onset before age 18 months were identified in Victoria, Australia from 2011 to 2013
  • severe epilepsy of infancy defined as all of the following
    • onset of frequent seizures (≥ daily for 1 week or ≥ weekly for 1 month) before age 18 months
    • epileptiform abnormality on electroencephalogram
    • ongoing seizures despite trials of 2 appropriate antiseizure medications
  • diagnoses at presentation
    • 7% had EIEE
    • 9% had epilepsy of infancy with migrating focal seizures
    • 47% had West syndrome or West syndrome-like epilepsy (infantile spasms without hypsarrhythmia or modified hypsarrhythmia)
    • 37% had unifocal seizures, unclassified epilepsies, or other variant syndromes
  • incidence per 100,000 live births/year
    • 3.6 for EIEE
    • 4.5 for epilepsy of infancy with migrating focal seizures
    • 32.7 for West syndrome or West syndrome-like epilepsy
  • Reference – Epilepsia 2021 Feb;62(2):358

Etiology and Pathogenesis

Causes

• causes of early-infantile epileptic encephalopathy are heterogeneous and include structural brain abnormalities, inborn errors of metabolism, and genetic abnormalities^(1,2,3)
  • structural brain abnormalities include^(1,3)
    •  hemimegalencephaly
    •  corpus callosum agenesis
    •  porencephaly
    •  mammillary body agenesis
    •  dentato-olivary dysplasia
    •  hypoxic injury
    •  cortical dysplasias
    •  disorders of cerebral migration
  • genetic abnormalities include^(1,2,3)
    •  syntaxin-binding protein 1 (STXBP1)
    •  aristaless-related homeobox (ARX)
    •  solute carrier family 25 member 22 (SLC25A22)
    •  polynucleotide kinase 3′-phosphatase (PNKP)
    •  potassium voltage-gated channel subfamily Q member 2 (KCNQ2)
    •  sodium voltage-gated channel alpha subunit 2 (SCN2A) (Neurotherapeutics 2014 Oct;11(4):796full-text)
    • mutations in potassium sodium-activated channel subfamily T member 1 (KCNT1) and phosphatidylinositol glycan anchor biosynthesis class Q (PIGQ) reported to cause early-infantile epileptic encephalopathy
      •  based on prospective cohort study of 6 children and adolescents (aged < 1 week to 3 months at seizure onset) with severe early-onset epilepsy and their healthy parents had whole-genome sequencing to identify causal genetic mutations
      •  early-infantile epileptic encephalopathy in 4 infants
      •  in patients with early-infantile epileptic encephalopathy, mutations found in KCNT1, PIGQ, KCNQ2, and SCN2A
      •  Reference – Hum Mol Genet 2014 Jun 15;23(12):3200full-text
    • gamma-aminobutyric acid type A receptor alpha1 subunit (GABRA1) mutation reported in 1 infant with early-infantile epileptic encephalopathy
      •  based on prospective cohort study of 671 infants with infantile epilepsies (including early-infantile epileptic encephalopathy, infantile spasms, Lennox-Gastaut syndrome, and early myoclonic epilepsy) had whole exome sequencing or targeted GABRA1-locus sequencing to evaluate GABRA1 mutations
      •  de novo GABRA1 mutations in 6 infants (0.9%)
      •  in infants with GABRA1 mutations, early-infantile epileptic encephalopathy in 1
      •  Reference – Epilepsia 2016 Apr;57(4):566full-text
  • inborn errors of metabolism (less common) include^(1,3)
    •  nonketotic hyperglycinemia
    •  pyridoxine dependency
    •  carnitine palmitoyltransferase deficiency
    •  Leigh encephalopathy
    • biotinidase deficiency
    • deficiencies in mitochondrial respiration
      •  mitochondrial respiratory chain complex 1 deficiency
      •  cytochrome C oxidase deficiency
• other causes of early-infantile epileptic encephalopathy include
  •  severe perinatal infectious disease
  •  Proteus syndrome
  • hypoxic-ischemic encephalopathy (HIE)
  •  Reference – Brain Dev 2012 Jun;34(6):459

Pathogenesis

• multiple etiologies suggest that brain abnormalities (whether due to structural abnormalities, metabolic, or genetic causes) contribute to overall brain dysfunction due to^(1,2)
  •  absent or abnormal neuronal development (such as improper neuronal progenitor migration and proliferation), or
  •  energy depletion during development

History and Physical

Clinical Presentation

•  typically presents in early infancy (ages 2 weeks to 3 months) with tonic spasms lasting ≤ 10 seconds from 10 to 300 times daily^(1,2,3)
• spasms may^(1,2)
  •  be lateralized or generalized
  •  occur singly or in clusters (10-20/day)
  •  occur during wakefulness or sleep
• infants may also develop other seizure types, including
  •  focal motor seizures^(1,3)
  •  generalized tonic-clonic seizures^(1,3)
  •  hemiconvulsions⁽¹⁾
• clinical presentation may vary in infants with genetic causes; clinical findings in early-infantile epileptic encephalopathy caused by⁽²⁾
  • syntaxin-binding protein 1 (STXBP1), reported to account for 10%-33% of cases, includes
    •  frequent tonic spasms
    •  severe intellectual disability
  • aristaless-related homeobox (ARX), reported to account for approximately 5% of early-onset epilepsies, includes
    •  intractable seizures
    •  developmental delay
    •  males affected
    •  ambiguous genitalia
    •  severe movement disorder
  • solute carrier family 25 (SLC25A22), includes
    •  epileptic encephalopathy in first days of neonatal period
    •  hypotonia
    •  microcephaly
  • potassium voltage-gated channel subfamily Q member 2 (KCNQ2), reported to account for 5%-10% of early-onset epilepsies, includes
    •  intellectual disability
    •  tonic seizure
    •  sodium-channel blocker responsive

History

History of Present Illness (HPI)

• ask about observed spasms^(1,2,3)
  •  brief (≤ 10 second) contractions
  •  frequent, occurring 10-300 times daily
  •  may occur once or in clusters (≤ 20/day)
•  ask about changes in behavior after seizure onset, including hypotonia or developmental delay⁽³⁾

Past Medical History (PMH)

• ask about birth history, including delivery and postnatal factors such as
  •  excessive fetal movements which may suggest fetal seizures⁽²⁾
  • neonatal hypoxic-ischemic encephalopathy (HIE) (Brain Dev 2012 Jun;34(6):459)

Family History (FH)

•  ask about consanguineous parental history

Physical

HEENT

• Assess head circumference for acquired microcephaly, which is associated with aristaless-related homeobox (ARX) mutations⁽²⁾

Neuro

•  Evaluate for signs of hypotonia⁽³⁾

Pelvic

• Males with early-infantile epileptic encephalopathy caused by aristaless-related homeobox (ARX) mutations may have ambiguous genitalia⁽²⁾

Diagnosis

Making the Diagnosis

• suspect diagnosis in neonates or young infants with tonic spasms at symptom onset, spasms may be^(1,2,3)
  •  brief (≤ 10 second contractions)
  •  frequent (occurring 10-300 times daily)
  •  single or in clustered (≤ 20/day)
•  diagnosis confirmed by stereotypical clinical findings and electroencephalogram showing burst suppression pattern (high-amplitude spikes and polyspikes followed by suppression phases)^(1,2)
•  diagnosis supported by additional testing to evaluate underlying etiology of disease

Differential Diagnosis

• Early myoclonic encephalopathy⁽¹⁾
• other epileptic encephalopathies with similar presentation include
  • infantile spasms
  •  Dravet syndrome
  • Lennox-Gastaut syndrome
  •  Reference – Brain Dev 2012 Jun;34(6):459
•  hypocalcemia (Pediatr Rev 2012 Sep;33(9):387)
•  stiff startle (Turk Pediatri Ars 2017 Jun;52(2):59full-text)
• supplement-responsive early-onset epilepsies, including
  • biotinidase deficiency
  •  pyridoxine-dependent epilepsy
  •  pyridoxal phosphate-responsive epilepsy
  •  folinic acid-responsive seizures
  •  serine or creatine deficiency syndromes
  •  Reference – Arch Dis Child 2007 Aug;92(8):659full-text

Testing Overview

•  perform electroencephalography (EEG); EEG typically shows high-amplitude slow-wave spike and polyspike bursts interspersed with electric suppression phases (burst suppression) coinciding with tonic spasms during sleep or wakefulness ^(1,2,3)
• to evaluate underlying causes of early-infantile epileptic encephalopathy, consider ^(1,2)
  •  head magnetic resonance imaging (MRI) to assess infant for structural brain abnormalities and magnetic resonance spectroscopy (MRS) to assess for metabolic conditions (Brain 2013 May;136(Pt 5):1578full-text)
  •  metabolic testing to assess infant for metabolic causes, including complete blood count, serum and urine chemistry, and cerebrospinal fluid analysis
  •  molecular genetic testing to evaluate infant for genetic causes (ILAE Grade 2C)
•  consider electroretinogram in infants with early-infantile epileptic encephalopathy caused by solute carrier family 25 (SLC25A22) mutations, which may show abnormal visual evoked potential⁽²⁾
• in infants with suspected metabolic cause of seizures, consider the following to distinguish early-infantile epileptic encephalopathy from treatable causes of early-onset epilepsy
  •  give appropriate vitamin supplements and observe for improved symptoms, or
  •  investigate which biochemical markers are deficient
  •  Reference – Arch Dis Child 2007 Aug;92(8):659full-text

Management

Management Overview

• early-infantile epileptic encephalopathy is highly intractable⁽³⁾
  •  treatment goals include improving quality of life, avoiding hospitalization, and preventing poor cognitive outcomes
  •  no randomized trials exist to guide therapy so recommendations based on evidence from observational studies and expert opinion
  • counsel caregivers before treatment
• treatment options include
  • antiseizure medications for seizure control
    •  first-line treatments include adrenocorticotropic hormones, such as corticotropin and prednisone, and levetiracetam
    •  other antiseizure medications include pyridoxine, zonisamide, vigabatrin, phenobarbital, sodium valproate, benzodiazepines, and topiramate
    •  adrenocorticotrophin hormone (ACTH) reported to suppress seizures in 13% of neonates and infants with early-infantile epileptic encephalopathy (level 3 [lacking direct] evidence)
    •  zonisamide reported to suppress seizures in neonates and infants with early-infantile epileptic encephalopathy (level 3 [lacking direct] evidence)
  • surgery in patients with early-infantile epileptic encephalopathy caused by structural abnormalities, or vagus nerve stimulation in infants not suited for surgical intervention (ILAE Expert opinion, Level U)
  • correcting underlying metabolic deficiencies in infants with early-infantile epileptic encephalopathy caused by metabolic disorders
    •  seizure freedom with biotin 10 mg/day orally in 4-month-old boy with antiseizure medication-refractory early-infantile epileptic encephalopathy caused by biotinidase deficiency in case report (J Child Neurol 2011 Apr;26(4):507)
    •  seizure freedom with pyridoxine 150 mg IV, followed by pyridoxine 100 mg/day orally in 9-month-old girl with early-infantile epileptic encephalopathy caused by pyridoxine deficiency in case report (Brain Dev 2001 Nov;23(7):708)
  • ketogenic diet (ILAE Expert opinion, Level U); reduced seizure frequency (≤ 3 compared to 20-30 per day) for ≤ 10 months in 5-year-old boy with medication-refractory early-infantile epileptic encephalopathy with ketogenic diet (4:1 ratio of fat to protein plus carbohydrates) in case report (Epilepsy Behav Case Rep 2015;3:43full-text)
  • medical marijuana
    •  cannabidiol reported to reduce seizure frequency in children with refractory epilepsy (level 3 [lacking direct] evidence)
    •  cannabidiol reported to reduce monthly motor seizures in patients with treatment-resistant, pediatric-onset, intractable epilepsy (level 3 [lacking direct] evidence)
• treatment efficacy; consider ongoing electroencephalogram monitoring
  •  abnormal electroencephalography (EEG) before antiseizure medication (ASM) withdrawal may increase risk of seizure relapse in children and adolescents with epilepsy (level 2 [mid-level] evidence)
  •  quantitative EEG analysis appears to help predict response to antiseizure treatment in children and adolescents with epilepsy (level 2 [mid-level] evidence)

Diet

•  consider ketogenic diet (which typical consists of high fat, low protein, and very-low carbohydrates) in periods of severe exacerbation (ILAE Expert opinion, Level U) (Epilepsia 2015 Aug;56(8):1185full-text)^(1,3)
•  reduced seizure frequency (≤ 3 seizures compared to 20-30/day) for 10 months in 5-year-old boy with medication-refractory early-infantile epileptic encephalopathy with ketogenic diet (4:1 ratio of fat to protein plus carbohydrates) in case report (Epilepsy Behav Case Rep 2015;3:43full-text)

Counseling

• before treatment begins⁽³⁾
  •  ask caregivers about treatment goals such as seizure reduction, seizure freedom, and/or improved cognitive function
  •  discuss potential adverse effects of treatment

Medications

•  antiseizure medications (ASMs) generally have limited or poor effectiveness to control seizures^(1,3)
• general considerations⁽³⁾
  •  specialist should initiate ASM therapy
  • avoid polytherapy when possible, if necessary
    •  limit prescriptions to synergistic medications
    •  ensure sufficient time taken to assess treatment efficacy
    •  consider adverse effects and ease of dose administration
• for treatment of newly-diagnosed infants, consider
  • corticosteroids^(1,3)
    •  drugs include adrenocorticotropic hormones (corticotropin) and prednisone (Winpred, Lodotra) (ILAE Grade 2C) (Epilepsia 2015 Aug;56(8):1185full-text)
    •  corticotropin dosing in pediatric patients aged < 2 years old may start at 75 units/m² twice daily for 2 weeks followed by 2-week tapering period
    • adrenocorticotrophin hormone (ACTH) reported to suppress seizures in 13% of neonates and infants with early-infantile epileptic encephalopathy (level 3 [lacking direct] evidence)
      •  based on case series
      •  16 children (aged from 11 days to 4 months at diagnosis) with early-infantile epileptic encephalopathy were evaluated for clinical presentation, etiology, pathophysiology, treatment, and prognosis
      • in 15 neonates and infants having ACTH
        •  seizure freedom in 2 (13%)
        •  initial seizure freedom with relapse after < 3 months to > 1 year in 7 (47%)
        •  decreased seizures or no change in seizures in 6 (40%)
      •  Reference – Brain Dev 2002 Jan;24(1):13
  • levetiracetam (Keppra)⁽³⁾
• other medications used for treatment of early-infantile epileptic encephalopathy include
  • pyridoxine (ILAE Grade 2C) (Epilepsia 2015 Aug;56(8):1185full-text)
  • zonisamide (Zonegran)⁽¹⁾
  • vigabatrin (Sabril)⁽³⁾
    •  may be used to treat resistant focal seizures
    • dosing for children aged 1 month to 2 years
      •  initial dose 50 mg/kg/day orally in 2 divided doses
      •  may increase 25-50 mg/kg/day every 3 days to maximum 150 mg/kg/day
      •  discontinue drug if no clinical response after 2 weeks following escalation of therapy
      •  in patients who respond, vigabatrin may be continued for 6-9 months with continued ophthalmic evaluation and periodic treatment reevaluation
    •  continued use increases risk of vigabatrin-associated visual loss
  •  phenobarbital^(1,3)
  • sodium valproate (Depacon, Depakote)⁽¹⁾
    • reported dosages in systematic review of 19 studies with in 11 neonates with early-infantile epileptic encephalopathy having sodium valproate therapy
      • sodium valproate loading doses included
        •  20-25 mg/kg orally
        •  20-30 mg/kg rectally
        •  10-25 mg/kg IV
      • sodium valproate maintenance doses included
        •  5-10 mg/kg orally every 12 hours
        •  15 mg/kg rectally every 12 hours
      •  Reference – J Pediatr Pharmacol Ther 2012 Jan;17(1):31full-text
  •  benzodiazepines such as clobazam [Onfi, Frisium] and clonazepam [Clonapam, Rivotril]⁽¹⁾
  • topiramate (Topamax, Qudexy, Trokendi)
  • zonisamide reported to suppress seizures in neonates and infants with early-infantile epileptic encephalopathy (level 3 [lacking direct] evidence)
    •  based on case series
    •  16 children (aged from 11 days to 4 months at diagnosis) with early-infantile epileptic encephalopathy were evaluated for clinical presentation, etiology, pathophysiology, treatment, and prognosis
    •  seizure freedom in 3 neonates and infants having zonisamide (reported dosage in 1 infant 20 mg/day orally)
    •  Reference – Brain Dev 2002 Jan;24(1):13

Surgery and Procedures

• consider surgical intervention with hemispherectomy or focal resection in infants with early-infantile epileptic encephalopathy caused by structural abnormalities, such as cortical dysplasia or hemimegalencephaly⁽¹⁾
  •  seizure reduction to 1-5 seizures/day 16 months post functional hemispherectomy in 5-month-old male with early-infantile epileptic encephalopathy caused by hemimegalencephaly in case report (J Child Neurol 2015 Mar;30(4):522)
  •  reduced seizures to 0-2 seizures/day after lesionectomy and continued antiseizure treatment in 4-month-old boy with early-infantile epileptic encephalopathy caused by focal lesion in case report (Epilepsia 1999 Mar;40(3):365PDF)
•  although there is insufficient evidence to evaluate vagus nerve stimulation efficacy in infants with seizures, vagus nerve stimulation may be considered in infants with refractory seizures contraindicated for surgical treatment (ILAE Expert opinion, Level U) (Epilepsia 2015 Aug;56(8):1185full-text)

Other Management

• correcting underlying metabolic disorders may be effective treatment in infants with early-infantile epileptic encephalopathy caused by underlying metabolic disorders⁽¹⁾
  •  seizure freedom with biotin 10 mg/day orally in 4-month-old boy with antiseizure medication-refractory early-infantile epileptic encephalopathy caused by biotinidase deficiency in case report (J Child Neurol 2011 Apr;26(4):507)
  •  seizure freedom with pyridoxine 150 mg IV, followed by pyridoxine 100 mg/day orally in 9-month-old girl with early-infantile epileptic encephalopathy caused by pyridoxine deficiency in case report (Brain Dev 2001 Nov;23(7):708)
• medical marijuana
  • cannabidiol reported to reduce seizure frequency in children with refractory epilepsy
    •  based on survey of parents who used cannabidiol to treat their children with epilepsy
    •  53 parents of children (mean age 8 years) with refractory epilepsy having cannabidiol were surveyed to evaluate seizure response
    •  epilepsy diagnoses included myoclonic-astatic epilepsy, early-infantile epileptic encephalopathy, Dravet syndrome, and Lennox-Gastaut syndrome
    •  survey analyzed 43 responses from parents of children in Mexico (81%)
    •  early-infantile epileptic encephalopathy in 1 child (2.3%)
    • most common cannabidiol
      •  dose 1-3.9 mg/kg/day orally in 27 children (63%)
      •  treatment duration, 3-4 months in 12 children (28%)
    • parents reported
      •  seizure freedom in 7 children (16%)
      •  ≥ 50% seizure reduction in 22 children (51%)
    •  mild adverse effects reported in 15 children (35%), including increased or decreased appetite and poor sleep
    •  Reference – Neurol Res Int 2017;2017:2985729full-text
  • cannabidiol reported to reduce monthly motor seizures in patients with treatment-resistant, pediatric-onset, intractable epilepsy (level 3 [lacking direct] evidence)
    •  based on uncontrolled trial
    • 214 infants, children, adolescents, and adults aged 1-30 years (mean age 11 years) with treatment-resistant, intractable, childhood-onset epilepsy received oil-based cannabidiol 2-5 mg/kg/day orally divided in 2 doses
      •  early-infantile epileptic encephalopathy in 4 patients (< 2%)
      •  all patients had ≥ 4 countable seizures with motor component in 4-week period and were receiving stable treatment (doses of antiepileptics drug dosage, diet ratios, vagus nerve stimulator settings) for ≥ 4 weeks
      •  baseline seizure frequency assessed prospectively during 4-week pretreatment period
      •  cannabidiol dose was titrated up 2-5 mg/kg once weekly until intolerance or maximum dose of 50 mg/kg/day (25 mg/kg/day at some study sites)
    •  24% of patients without 12-week follow-up were excluded from analyses
    • 64% of patients with ≥ 12-week follow-up and motor seizures during baseline period were included in efficacy analysis
      •  median monthly motor seizures decreased from 30 to 15.8
      •  median 36.5% decrease in monthly motor seizures
      •  median 34.6% decrease in total seizures
      •  during weeks 8-12, 11% were free from motor seizures and 7% were free from all seizures
      •  greatest reduction in seizures occurred in patients with focal or atonic seizures
    • 76% of patients with ≥ 12-week follow-up included in safety analysis
      •  20% had Dravet syndrome and 19% had Lennox-Gastaut syndrome
      •  mean cannabidiol dose 22.9 mg/kg at 12 weeks
      •  79% reported adverse events, with most mild-to-moderate and transient
      •  adverse events reported in > 10% of patients included somnolence, decreased appetite, diarrhea, fatigue, and convulsion
      •  12% reported serious adverse events possibly related to treatment, most commonly status epilepticus
    •  Reference – Lancet Neurol 2016 Mar;15(3):270, correction can be found in Lancet Neurol 2016 Apr;15(4):352, editorial can be found in Lancet Neurol 2016 Mar;15(3):235

Follow-up

• consider electroencephalogram (EEG)-mediated monitoring with antiseizure (ASM) treatment as it may help determine treatment effectiveness and predict ASM failure
  •  abnormal EEG before antiseizure (ASM) withdrawal may increase risk of seizure relapse in children and adolescents with epilepsy (level 2 [mid-level] evidence)
    •  based on Cochrane review of trials with methodologic limitations
    •  systematic review of 5 randomized trials comparing early withdrawal (< 2 years seizure-free) vs. late withdrawal (≥ 2 years seizure-free) of ASMs in 924 children and adolescents aged < 17 years old with epilepsy
    •  methodologic limitations included inadequate randomization or unclear allocation concealment
    •  increased risk of seizure recurrence associated with abnormal EEG before ASM withdrawal, risk ratio (RR) 1.44 (95% CI 1.13-1.83) in analysis of 2 trials with 594 children and adolescents
    •  Reference – Cochrane Database Syst Rev 2015 Feb 11;(2):CD001902
  • quantitative EEG analysis appears to help predict response to antiseizure treatment in children and adolescents with epilepsy
    •  based on prospective cohort study
    • 20 children and adolescents aged 5-18 years with epilepsy were monitored for ASM effectiveness and analyzed for response to treatment with quantitative EEG analysis at 0, 1-3, and 6 months
      •  quantitative EEG uses algorithms to process EEG segments over time to evaluate and track changes in brain function
      •  seizure types included generalized and focal seizures
      •  ASMs included sodium valproate, oxcarbazepine, clonazepam, levetiracetam, lamotrigine, topiramate, clobazam, and zonisamide
    • at 6-month follow-up
      •  > 50% seizure reduction in 11 patients (mean 98.2% decrease)
      •  ≤ 50% seizure reduction in 9 patients (mean 2.5% increase)
    •  6 EEG features were found to correctly classify ASMs as effective or ineffective after 1-3 months of ASM treatment
    •  Reference – Brain Dev 2018 Jan;40(1):26
  •  seizure interruption and remission observed with video EEG monitoring after treatment with phenytoin 20 mg/kg IV in 2-day-old male neonate with epileptic encephalopathy in case report (Brain Dev 2017 Apr;39(4):345)

Complications

• Seizure onset associated with
  • Hypotonia⁽³⁾
  • Developmental delay⁽³⁾
  • Intellectual disability⁽²⁾
• Psychomotor impairments may occur with or without seizure control^(1,2)

Prognosis

• Generally poor prognosis, with death frequently during infancy^(1,2,3)
• early-infantile epileptic encephalopathy may evolve into other epileptic encephalopathy syndromes in some infants with concomitant changes in ictal electroencephalography^(1,2,3)
  •  75% of infants reported to develop infantile spasms (West syndrome) from ages 2 to 6 months
  •  in infants developing infantile spasms, 12% reported to develop Lennox-Gastaut syndrome
  •  less frequent in infants with early-infantile epileptic encephalopathy caused by potassium voltage-gated channel subfamily Q member 2 (KCNQ2) mutations
• EIEE associated with high mortality and severe developmental delay at 2 years
  •  based on population-based cohort study
  • 114 infants (54% male) with severe epilepsy of infancy with onset before age 18 months were identified in Victoria, Australia from 2011 to 2013
  • severe epilepsy of infancy defined as all of the following
    • onset of frequent seizures (≥ daily for 1 week or ≥ weekly for 1 month) before age 18 months
    • epileptiform abnormality on electroencephalogram
    • ongoing seizures despite trials of 2 appropriate antiseizure medications
  • diagnoses at presentation
    • 7% of infants (8) had EIEE
    • 9% of infants (10) had epilepsy of infancy with migrating focal seizures
    • 47% had West syndrome or West syndrome-like epilepsy (infantile spasms without hypsarrhythmia or modified hypsarrhythmia)
    • 37% had unifocal seizures, unclassified epilepsies, or other variant syndromes
  • 2-year mortality
    • 50% in infants with EIEE
    • 60% in infants with epilepsy of infancy with migrating focal seizures
    • 16% overall
  • rates of severe-profound developmental delay in survivors at 2 years
    • 100% in infants with EIEE
    • 100% in infants with epilepsy of infancy with migrating focal seizures
    • 42% overall
  • Reference – Epilepsia 2021 Feb;62(2):358
• severe handicap or early mortality associated with early-infantile epileptic encephalopathy
  •  based on small cohort study
  •  16 children (aged from 11 days to 4 months at diagnosis) with early-infantile epileptic encephalopathy were evaluated for clinical presentation, etiology, pathophysiology, treatment, and prognosis
  • among in infants aged
    •  5-28 years at follow-up, 8 were severely handicapped with hemiplegia or quadriplegia
    •  7 months to 12 years at follow-up, 8 were deceased
  •  Reference – Brain Dev 2002 Jan;24(1):13
•  early-infantile epileptic encephalopathy can evolve into severe focal epilepsy⁽¹⁾

Prevention and Screening

•  not applicable

Guidelines and Resources

Guidelines

•  International League Against Epilepsy (ILAE) Commission of Pediatrics summary of recommendations on management of infantile seizures can be found in Epilepsia 2015 Aug;56(8):1185full-text

Review Articles

•  review can be found in Brain Dev 2012 Jun;34(6):459
•  review of epileptic encephalopathies can be found in Neurobiol Dis 2016 Aug;92(Pt A):72
•  review of epileptic encephalopathies in infants and children can be found in J Clin Neurophysiol 2012 Oct;29(5):420
•  review of syntaxin-binding protein 1 (STXBP1)-associated epileptic encephalopathies can be found in GeneReviews 2016 Dec 1full-text
•  review of distinguishing early-infantile epileptic encephalopathy and early myoclonic encephalopathy can be found in Epilepsy Res 2006 Aug;70 Suppl 1:S58

MEDLINE Search

•  to search MEDLINE for (Early-infantile epileptic encephalopathy or Ohtahara syndrome) with targeted search (Clinical Queries), click therapy, diagnosis, or prognosis

Patient Information

•  handout from Young Epilepsy PDF
•  handout from Epilepsy Action
•  handout from Epilepsy Foundation

References

General References Used

1. Beal JC, Cherian K, Moshe SL. Early-onset epileptic encephalopathies: Ohtahara syndrome and early myoclonic encephalopathy. Pediatr Neurol. 2012 Nov;47(5):317-23full-text.
2. Gürsoy S, Erçal D. Diagnostic Approach to Genetic Causes of Early-Onset Epileptic Encephalopathy. J Child Neurol. 2016 Mar;31(4):523-32.
3. McTague A, Cross JH. Treatment of epileptic encephalopathies. CNS Drugs. 2013 Mar;27(3):175-84.