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Management Strategies for Infantile Epilepsy

Key Questions

Open for comment through Aug 13, 2020

Background

The Patient-Centered Outcomes Research Institute (PCORI) is partnering with AHRQ to develop a systematic evidence review on interventions for infantile epilepsy. The American Epilepsy Society (AES) aims to develop an evidence-based clinical guideline focused on management of infants and children (ages 0–3) with epilepsy.

A seizure is the clinical manifestation of an episode of abnormal electrical activity in the brain.1 Infants and young children that fall in one of the following categories are diagnosed with infantile epilepsy: two unprovoked seizures over more than one day, one unprovoked seizure and the likelihood of additional seizures due to underlying physiology, or diagnosis of an epilepsy syndrome.1 Management options for infant epilepsy include various medications; resective or palliative surgeries; brain stimulation strategies (including but not limited to vagus nerve stimulation); and dietary therapies.

Emerging Issues in the Field

Managing epilepsy in infants and young children is a distinct and important challenge. Epilepsy disproportionately affects children 0–3 years compared to other age groups; it is clinically different from epilepsies in older children and adults; it can lead to significant, long-term, negative outcomes for the child; and the population is uniquely challenging to treat.

In developed countries, the incidence of epilepsy in infants is higher than in any other age group.1,2 New onset of epilepsy among infants is estimated at 70–100/100,000 in the first year of life and 65/100,000 per year for children aged 1-4 years.2,3 The etiology, clinical manifestations, electroencephalogram patterns and medication response in infantile epilepsy is very different from that of epilepsy in older children and adults.1,3,4 In addition, caring for an infant or young child diagnosed with epilepsy can be difficult; parents and healthcare providers need to balance seizure control with the potential harms of the treatments.5 Seizure control is important because of the "profound developmental, behavioral and psychological effects that may be associated with continuing seizures."6

Although strong recommendations exist for the treatment of infantile spasms,7 also called West syndrome, systematic reviews have revealed that evidence supporting treatment strategies for epilepsy in infants and young children is lacking and few recommendations or guidelines are available.7,8 A consensus document of recommendations for the management of infantile seizures released by the International League Against Epilepsy (ILAE) Commission of Pediatrics released in 2015 concluded that none of the current antiseizure medications (ASMs) used to treat infant epilepsy are supported by high-quality evidence.2 Infants with select subtypes of epileptic seizures may be considered for ketogenic diet therapy or epilepsy surgery.2 Also, the recommendations indicated that patients with refractory seizures who are not eligible for surgery may be treated with vagus nerve stimulation despite little evidence for benefits associated with the procedure.2

The National Institute for Health and Care Excellence (NICE) also released an epilepsy guideline in 2012 (updated in 2020) but the recommendations are focused on the broader population of children, adolescents and adults.6 Similarly, the handful of systematic reviews that have been published on this general topic included children 0-18 years and did not focus specifically on patients 0–3 years.9,10

The American Epilepsy Society (AES) is interested in a systematic review of strategies for managing focal or generalized epilepsy in infants and young children. An initial literature search identified 21 studies exclusively on infants and young children (0–3) including 16 on pharmaceutical treatments. Additional research may emerge during the literature search that is focused on a broader population but stratifies the results by the 0–3 age group.8 Further, a more robust literature search, informed by topic experts, with broader inclusion of surgical interventions and brain stimulation strategies may also increase the number of available studies. This literature base would allow for a small systematic review on the topic.

Draft Key Questions

KQ1. What is the effectiveness and comparative effectiveness of pharmacologic treatments for infantile epilepsy?

KQ2. What is the effectiveness and comparative effectiveness of non-pharmacologic treatments for infantile epilepsy (i.e. resective or palliative surgeries; brain stimulation therapies; and dietary therapies), including comparisons to other non-pharmacologic and/or pharmacologic therapies?

KQ3. What are the harms or comparative harms of treatments for infantile epilepsy?

Contextual questions (CQ):

CQ1. What are the parental preferences for treatment options for infantile epilepsy?

CQ2. What are the harms or comparative harms of not treating infantile epilepsy?

Draft Analytic Framework

This figure depicts the Analytic Framework for Key Questions 1 to 3 within the context of the eligibility criteria described below. In general, the figure illustrates the potential effects and harms of pharmacologic (including diet and surgery) and non-pharmacologic interventions in children (birth to 3 years) with diagnosis of focal or generalized epilepsy. The figure shows the comparison of pharmacologic (key question 1) and non-pharmacologic (key question 2) interventions in children (birth to 3 years) with diagnosis of focal or generalized epilepsy to other pharmacologic or non-pharmacologic interventions or usual care. Interventions may result in a range of health outcomes including intermediate outcomes of seizure frequency and severity and increase or decrease in medication and final health outcomes of seizure frequency and severity, Sudden Unexpected Death in Epilepsy (SUDEP), all-cause mortality, quality of life, neurodevelopment, behavior and cognitive function. All interventions may have harms (key question 3), which include somnolence, infection, dizziness, irritability, new neurological deficits, surgical complications, and drug toxicity.

PICOTS

Table 1: PICOTS for a systematic review of treatments for infantile epilepsy

  Inclusion Exclusion
Population
  • Children, birth to 3 years
  • Focal or generalized epilepsy
  • Subpopulations: baseline seizure severity/frequency, history of previous treatment
  • Febrile seizures
  • West syndrome/infantile spasms
  • Seizures not attributed to epilepsy
Intervention
  • KQ 1, 3: Pharmacologica interventions
  • KQ 2, 3: Non-pharmacologicb intervention such as resective or palliative surgeries; brain stimulation strategies; and dietary therapies
  • Diagnostic research
  • Provider/organization interventions such as awareness campaigns
Comparator

KQ1: other pharmacologic interventions or usual care

KQ2: other pharmacologic or non-pharmacologic interventions or usual care

KQ3: inclusive of comparators for KQ1&2

 
Outcomes
  • Change in seizure frequency and severity
  • Seizure freedom
  • Sudden Unexpected Death in Epilepsy (SUDEP)
  • All-cause mortality
  • Remission
  • Time to seizure remission or reduction
  • Increase or decrease in medication
  • Quality of life
  • General health status
  • Social function
  • Behavioral function
  • Cognitive function
  • Neurodevelopmental milestones met
  • Functional performance (e.g. school)
  • Adverse events (infection, new neurological deficits, surgical complications, irritability, somnolence, dizziness, drug toxicity, etc.)
 
Timing Follow-up not limited  
Setting Setting not limited  
Study Design
  • RCTs & CTs
  • Cohorts
  • Case-control studies
  • Other observational designs including post-only and pre-post studies
  • Case-series: harms (KQ3); other KQs as determined during Topic Refinement
 

Note: PICOTS apply to all KQ unless otherwise specified. Abbreviations: RCT=Randomized Controlled Trials  CT=Controlled Trials

  1. Pharmacologic interventions include, but not limited to: medications such as levetiracetam, lamotrigine, lacosamide, dexamethasone palmitate, valproate, oxcarbazepine, topiramate, enzyme-inducing and non-enzyme inducing antiepileptic drugs
  2. Non-pharmacologic interventions include, but not limited to: resective or palliative surgeries; brain stimulation strategies (including but not limited to vagus nerve stimulation); and dietary therapies such as the ketogenic diet.

Definition of Terms

Term Definition
AES American Epilepsy Society
ASM Antiseizure medications
ILAE International League Against Epilepsy
NICE National Institute for Health Care Excellence
PCORI Patient-Centered Outcomes Research Institute
SUDEP Sudden Unexpected Death in Epilepsy

References

  1. Wilfong A. Seizures and epilepsy in children: Classification, etiology, and clinical features. In: Dashe JF, editor. UpToDate. Waltham, MA2020.
  2. Wilmshurst JM, Gaillard WD, Vinayan KP, Tsuchida TN, Plouin P, Van Bogaert P, et al. Summary of recommendations for the management of infantile seizures: Task Force Report for the ILAE Commission of Pediatrics. Epilepsia. 2015; 56:1185-97.
  3. Wirrell EC, Grossardt BR, Wong-Kisiel LC, Nickels KC. Incidence and classification of new-onset epilepsy and epilepsy syndromes in children in Olmsted County, Minnesota from 1980 to 2004: a population-based study. Epilepsy Res. 2011; 95:110-8.
  4. Wilfong A. Seizures and epilepsy in children: Initial treatment and monitoring. In: Dashe JF, editor. UpToDate. Waltham, MA2020.
  5. Alam S, Lux AL. Epilepsies in infancy. Arch Dis Child. 2012; 97:985-92.
  6. National Institute for Clinical Excellence (NICE). The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care. National Institute for Clinical Excellence; 2012.
  7. Go CY, Mackay MT, Weiss SK, Stephens D, Adams-Webber T, Ashwal S, et al. Evidence-based guideline update: medical treatment of infantile spasms. Report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology. 2012; 78:1974-80.
  8. Rollison J, Partikian A, Akinniranye G, Yagyu S, Motala A, Hempel S. Infantile Epilepsy 2019 [April 6, 2020].
  9. Rosati A, Ilvento L, Lucenteforte E, Pugi A, Crescioli G, McGreevy KS, et al. Comparative efficacy of antiepileptic drugs in children and adolescents: A network meta-analysis. Epilepsia. 2018; 59:297-314.
  10. Wagner JL, Modi AC, Johnson EK, Shegog R, Escoffery C, Bamps Y, et al. Self-management interventions in pediatric epilepsy: What is the level of evidence? Epilepsia. 2017; 58:743-54.