Topic Brief: Infantile Epilepsy

• PATIENT-CENTERED OUTCOMES RESEARCH INSTITUTE pear�. TOPIC BRIEF DECEMBER 2019

1828 L STREET NW, SUITE 900 I WASHINGTON, DC 20036 I 202.827.7700

Authors: Julia Rollison, Arthur Partikian, Goke Akinniranye, Sachi Yagyu, Aneesa Motala, and Susanne Hempel

RAND Corporation

December 2019

All statements, findings, and conclusions in this publication are solely those of the authors and do not necessarily represent the views of the Patient-Centered Outcomes Research Institute (PCORI) or its Board of Governors. This publication was developed through a contract to support PCORI's work. Questions or comments may be sent to PCORI at [email protected] or by mail to Suite 900, 1828 L Street, NW, Washington, DC 20036.

Contents

Abstract ...... i Acknowledgments...... i Introduction and Background ...... 1 Objective ...... 1 Key questions ...... 2 Methods ...... 2 Stakeholder call ...... 2 Literature searches ...... 2 Sources ...... 2 Inclusion screening ...... 3 Categorization ...... 4 Analysis ...... 4 Results ...... 5

Key Question 1: What is the available evidence regarding the effectiveness and comparative effectiveness of infantile epilepsy management strategies? ...... 5 Published studies ...... 5 Table 1. Published Evidence ...... 6 Table 1. Published Evidence (continued) ...... 7 Ongoing studies ...... 8 Key Question 2: What is the applicability and generalizability of research evidence to children aged 0-3 years? ...... 8 Table 2. Studies in Infants and Other Pediatric/Mixed Samples by Intervention Type ...... 9 Discussion and Conclusion ...... 10 References ...... 12 Appendix A: Search Strategy ...... 43 PubMed ...... 43 EMBASE ...... 44 Clinicaltrials.gov, EU Clinical Trials Register, WHO ISRCTN, ISRCTN Registry ...... 46

Abstract

Epilepsy is more common in children than in adults, with several unique childhood-onset epilepsy syndromes. Despite its significant prevalence, limited research exists on infantile epilepsy. The objective of the topic brief is to identify and categorize the existing literature on management strategies for infantile epilepsy to help the Patient-Centered Outcomes Research Institute (PCORI) and the American Epilepsy Society determine whether there is sufficient literature to warrant a systematic review on the topic. We identified 401 empirical published or ongoing research studies that include children up to 3 years of age in a scoping search in June 2019. Most studies used an uncontrolled postintervention design. Only 21 identified studies were exclusively in the age group of interest (ie, aged 0-3), with 16 focused on pharmaceutical interventions. A systematic review of infantile epilepsy appears to be feasible, especially if the literature search is combined with an effort of contacting authors of existing studies to request data from the subgroup of infants and reviewing the existing evidence base on pediatric samples for generalizability to infants. The results of the topic brief are only an estimate of the available literature; a systematic review will likely identify additional relevant publications.

Acknowledgments

We thank William D. Gaillard, Zachary Grinspan, Shlomo Shinnar, Rebecca Anhang-Price, Joy Keller, Paul Koegel, Jeanne Ringel, Rachel Andricosky, Michelle Althuis, William Lawrence, and Jody Larkin for helpful comments.

Infantile Epilepsy • December 2019 i

Introduction and Background

Epilepsy is a condition characterized by an enduring predisposition to have seizures. A recent operational definition of epilepsy describes it as “a disease of the brain defined by any of the following conditions: 1) at least two unprovoked (or reflex) seizures occurring >24 hours apart; 2) one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next ten years; or 3) diagnosis of an epilepsy syndrome.”1 A seizure is a paroxysmal change in behavior or sensation caused by transient abnormal rhythmic neuronal brain activity. Epilepsy is more common in children than adults, with several epilepsy syndromes exclusive to the pediatric population. According to a study published in 2012, the estimated prevalence of reported lifetime epilepsy or seizure disorder was 1% among children aged 0-17 years, with a weighted prevalence estimate of 6.3 per 1000 US children aged 0-5.2 One example of an epilepsy syndrome is infantile spasms (also known as West syndrome). Estimates from the Child Neurology Foundation suggest that an infant is diagnosed with infantile spasms—which is a common form of epilepsy causing developmental regression—every 12 minutes globally.3 Infantile spasms typically occur in the first year of life, and early recognition and treatment are critical for improved outcomes (eg, morbidity and mortality, complications and adverse events, functional, quality of life), as already recommended by the American Academy of Neurology and Child Neurology Society.4 Although there are strong recommendations for treatment of infantile spasms, most epilepsy in infants is nonsyndromic (ie, the symptoms and clinical course do not follow a well-described epilepsy syndrome). Prior reviews for nonsyndromic infantile epilepsy have highlighted the lack of evidence for treatment in this group.4 Infantile epilepsies can be managed through a range of intervention approaches, including medication (eg, hormonal therapy, antiepileptic drugs), surgery (eg, removal of brain lesions or disconnection procedures), dietary changes or therapy, and implantation of medical devices.5 There has been some exploration of the evidence base for interventions related to pediatric epilepsy, such as a recent systematic review on self-management interventions6 and a meta-analysis on the comparative efficacy of antiepileptic drugs in children and adolescents.7 However, these reviews focused on a population ranging from birth to 18 years old. The American Epilepsy Society, International League Against Epilepsy (ILAE), and other professional organizations developed guidelines and practice parameters related to the care and treatment of epilepsy, including evidence guidelines that affect the infant population (ie, defined as aged 0-3 years). In 2015, the ILAE Commission of Pediatrics published a summary of recommendations for the management of infantile seizures, but it stated that no high-level evidence existed to support any specific agent for use in most infantile epilepsies.8 Now, the American Epilepsy Society (AES) would like to determine whether evidence is sufficient to conduct a thorough systematic review to answer key questions regarding management strategies for infantile epilepsy, specifically.

Objective To identify and categorize the existing literature on management strategies for infantile epilepsy to help the Patient-Centered Outcomes Research Institute (PCORI) and AES determine whether literature is sufficient to warrant a systematic review on the topic.

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Key questions The topic brief aims to answer 2 key questions: 1. What is the available evidence regarding the effectiveness and comparative effectiveness of infantile epilepsy management strategies? 2. What is the applicability and generalizability of research evidence on older children to children aged 0-3 years?

Methods

The topic brief was informed by the literature and content experts.

Stakeholder call A stakeholder call with the topic nominator, AES (the group that suggested the systematic review topic based on an outreach activity by PCORI for nominations), provided input to ensure the review was appropriately targeted to answer the 2 key questions for the topical brief.

Literature searches A reference librarian specializing in literature reviews developed, executed, and documented the search strategy; a senior Evidence-based Practice Center librarian peer reviewed the strategy. This strategy was informed by content experts and existing reviews on the topic and executed in June 2019. This topic brief informs the feasibility of a systematic review and the searches are exploratory. The searches did not include every source that would be searched in a comprehensive systematic review. However, the sources are sufficiently informative to answer the 2 key questions and, while not designed to be comprehensive, allow conclusions that likely reflect the full evidence base. Sources For published literature, we searched the following research databases: • PubMed (biomedical literature) • EMBASE (Excerpta Medica database) (pharmacological research) The databases are most relevant to the infantile epilepsy topic and well suited to determine the literature volume. The search strategy is outlined in Appendix A. In addition, we reference- mined existing systematic reviews on the topic, focusing on children to identify randomized controlled trials (RCTs)—a study design included in most systematic reviews—in the age group of interest. We identified systematic reviews through a PubMed search. For unpublished and ongoing research, we searched the following research registries: • Clinicaltrials.gov • EU Clinical Trials Register • World Health Organization’s International Clinical Trials Registry Platform (WHO ICTRP) • ISRCTN Registry

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Clinicaltrials.gov is well maintained, automatically indexes research from other databases by screening for the unique trial ID, and includes trials and large observational studies. We restricted the search to trials that have stopped recruiting (ie, those that are close to completion and likely relevant for a systematic review in the near future). Following advice from content experts, we also searched European and international registries. In addition, we searched PCORI’s Research Portfolio for ongoing studies that may inform a future systematic review. Since the initial search did not identify any surgical studies in infants, we undertook additional targeted searches. Inclusion screening We developed the inclusion criteria with input from the topic nominator, taking the requirements for a future systematic review and existing clinical guidance into account. An experienced literature reviewer screened the literature search results for relevance. We documented the screening results in a citation management software program. The inclusion screening criteria were as follows: • Population: Infants and children up to 3 years old with focal (partial) or generalized epilepsy. We did not consider infants with seizures not attributable to epilepsy (eg, acute symptomatic seizures such as febrile seizures or most acutely triggered forms of neonatal seizures) and samples focused only on cohorts with infantile spasms (ie, West syndrome) based on input from the American Epilepsy Society.a • Interventions: Medications, surgical interventions, devices, and dietary therapies to treat epilepsy. We did not consider diagnostic research, provider interventions, and organizational interventions not directly aimed at patients (eg, epilepsy awareness campaigns) and interventions for febrile seizures, infantile spasms/West syndrome, status epilepticus (eg, acute prolonged seizures, acute repetitive seizures), or acute seizure clustering alone. • Outcomes: Patient outcomes such as mortality, morbidity, complications of epilepsy, adverse events, development of other seizure types, neurodevelopmental outcomes, cognition, behavior, quality of life, and functional outcomes (eg, school performance). Publications had to report on the effect of an intervention to be eligible. We did not consider other outcomes, such as provider knowledge, service utilization, costs, physiological characteristics, biomarker measures, or imaging indicators. • Study design: RCT; clinical trials without randomization, cohort studies comparing 2 or more treatment cohorts (ie, observational study, treatment group was not assigned by the investigator); case series, time series, and pre–post studies comparing the outcome before the intervention with postintervention; post-only studies (ie, following participants after an intervention); and case-control studies (defined by an eligible outcome; studies have to link outcomes to interventions to be eligible). We considered case studies and publications in abbreviated form (eg, indexed without abstract, conference abstracts) only if the record included numerical data describing the treatment effects. We retained systematic reviews referring to the effects of epilepsy treatment exclusively in children for reference mining.

a We excluded most forms of neonatal seizures because they are most often triggered for a short time and not necessarily thought of as chronic epilepsies. We excluded infantile spasms because AES felt published practice parameters and guidelines regarding this form of infantile epilepsy syndrome already exist.

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We placed no restrictions on the comparator, timing of the intervention or the follow-up, or the setting. Given that multiple publications are very common, the literature reviewers paid particular attention to linked publications so multiple publications from a single trial were not counted multiple times but identified as one research study. Where systematic reviews had been updated, we considered only the latest update. Categorization We categorized the relevant literature using a broad categorization system to support answers to the topic brief questions. We documented study characteristics using the following categories: • Study design o RCT (need to state random allocation to intervention group) o Clinical trial (intervention assignment by investigator but not randomized) o Cohort study (2 or more cohorts of patients with different interventions) o Pre–post study, case series, single-arm trial, and time series (historic comparator, status before the intervention) o Post-only study (postintervention, likely no preintervention data) o Case-control study (defined by the outcome, not the intervention) • Study population o Infants (infants and children up to 3 years of age) o Pediatric mix (mixed sample that includes infants up to 1 year old but covers a broader age range) o Partially included (sample includes the age group 0-3 only partially; eg, may include children ≥2 years of age but not younger children) • Comparator o Other active and specific intervention given to a concurrent control group (comparative effectiveness) o No concurrent comparator, usual care, or different management strategies (effectiveness) We determined the relevance of the studies based on the inclusion of the particular age group. We distinguished studies exclusively in infants and children up to 3 years of age from other studies, studies that included this age group among others, and studies that partially included the age group of interest (eg, studies that were open to children aged 2 years and older). We documented available comparative effectiveness studies (ie, studies that compare 2 specific active interventions in concurrent groups, in relevant studies). We based the categorization on the title and abstract of the publication in most studies to allow us to process a large amount of data in a short time. The study team reviewed full text on a case-by-case basis when information was unavailable in the abstract (they obtained 365 full-text publications). This included open-access publications and those available through the RAND knowledge service department (which subscribes to 30 000 journals). Analysis To answer key question 1, we listed studies that met inclusion criteria and stratified them by study design and population. We placed particular emphasis on studies exclusively in infants. To answer key question 2, we determined whether results in identified studies were exclusively based on infants, in which case the intervention and the study results would be relevant. Furthermore, we determined in broader age samples whether the full age range of infants was

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included. In that case, we considered the intervention applicable but the results of the studies as needing to be regarded with caution because they are not based exclusively on the age group of interest. However, data on infants in these studies already exist and could be obtained from the study authors in the future. We identified the number of infants (where available) to estimate how much additional data could be available.

Results

The searches for the topic brief identified 2670 citations. This included 65 systematic reviews reporting specifically on the effect of epilepsy treatment in children.7, 9-72

Key Question 1: What is the available evidence regarding the effectiveness and comparative effectiveness of infantile epilepsy management strategies? Regarding key question 1, we identified 403 relevant empirical studies reported in 429 publications. 73-302, 303-498 There were 21 studies exclusively in the age group of interest (20 published, 1 ongoing).76, 83, 102, 128, 139, 153, 157, 168, 176, 189, 194, 210, 226, 237, 258, 377, 381, 382, 419, 462, 463

Published studies The published studies are categorized in Table 1. All studies included in this table are at least partially published (eg, first results are available) in publicly available, full-text, scientific journal articles.

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Table 1. Published Evidence

Study Design Population Intervention and Comparator in (Number of Studies) Effectiveness and Comparative Effectiveness Studies in Infants RCTs Infants (N = 5)139, 168, 176, 194, 226 Adjunctive levetiracetam vs (N = 86)77, 79, 80, 84, 88, 92-95, 98, Pediatric mix (N = 10)79, 88, 94, 132, 154, adjunctive placebo176; adjunctive 100, 103, 105, 106, 110, 111, 131, 132, 156, 233, 395, 401, 408 lamotrigine vs non-enzyme- 135, 136, 138, 139, 150, 154, 156, 162, Partially included (N = 39)77, 80, 84, 95, inducing antiepileptic drugs, 168, 176, 181, 184, 188, 194, 208, 212, 98, 100, 103, 105, 110, 111, 135, 136, 138, 162, 181, 184, valproate, or enzyme-inducing 215, 222, 225, 226, 230, 233, 247, 251, 188, 215, 225, 230, 251, 272, 281, 282, 284, 288, 293, 294, antiepileptic drugs alone194; 271, 272, 274, 281, 282, 284, 285, 288, 304, 330, 342, 360, 363, 376, 404, 407, 413, 416, 432 different doses of oxcarbazepine 293, 294, 296, 304, 313, 318, 324, 327, Unclear (N = 32)92, 93, 106, 131, 150, 208, 212, adjunctive therapy226; adjunctive 329-331, 333, 342, 343, 359, 360, 363, 222, 247, 271, 274, 285, 296, 313, 318, 324, 327, 329, 331, topiramate vs adjunctive 368, 369, 376, 395, 401, 404, 407-410, 333, 343, 359, 368, 369, 409, 410, 417, 421, 426, 435, 441, placebo168; and adjunctive 413, 416, 417, 421, 426, 432, 435, 441, 445 topiramate vs adjunctive placebo139 445

Clinical trials Infants (N = 1)157 Preventative antiepileptic treatment (N = 24)85, 122, 123, 126, 149, 157, Pediatric mix (N = 5)178, 207, 283, 339, 357 vs usual care157 163, 178, 179, 198, 207, 252, 256, 278, Partially included (N = 7)85, 122, 149, 163, 283, 326, 328, 338, 339, 357, 362, 365, 198, 252, 328 438, 440 Unclear (N = 11)123, 126, 179, 256, 278, 326, 338, 362, 365, 438, 440 Cohort studies Infants (N = 1)83 Levetiracetam vs phenobarbital83 (N = 23)83, 107, 130, 151, 166, 193, Pediatric mix (N = 6)151, 166, 193, 385, 448, 218, 241, 354, 384, 385, 390, 403, 422, 456 425, 446-448, 452, 454, 456, 466, 467 Partially included (N = 6)107, 130, 218, 384, 403, 467 Unclear (N = 10)241, 354, 390, 422, 425, 446, 447, 452, 454, 466 Pre–post studies Infants (N = 6)102, 153, 210, 237, 258, 382 Topiramate,153, 237 lamotrigine,258 (N = 126)73-75, 78, 81, 86, 89-91, Pediatric mix (N = 35)75, 86, 89, 124, 137, levetiracetam,102 liposteroid,210 and 96, 97, 99, 101, 102, 108,113-115, 117, 169, 174, 200, 205, 213, 223, 232, 240, 253, 254, 265, 273, ketogenic diet382 compared with 118, 124, 125, 129, 137, 141, 143, 144, 287, 299, 301, 308, 320, 336, 350, 371, 400, 436, 451, 453, baseline 153, 158, 159, 161, 164, 165, 169, 171, 455, 457-459, 468, 469 174, 177, 182, 185, 186, 190, 196, 197, Partially included (N = 43)78, 90, 91, 96, 200, 205, 210, 213, 219, 221, 223, 227, 97, 101, 108, 113-115, 117, 118, 125, 129, 143, 158, 159,

232, 237, 238, 240, 242, 248, 253-255, 161, 165, 171, 177, 186, 196, 197, 221, 238, 242, 255, 263,

258, 263-266, 268, 273, 277, 279, 280, 264, 266, 277, 292, 298, 306, 309, 346, 356, 366, 398, 402, 287, 290, 292, 295, 298, 299, 301, 302, 411, 428 306, 308, 309, 317, 320, 322, 323, 336, Unclear (N = 42)73, 74, 81, 99, 141, 144, 164, 346, 350, 356, 364, 366, 371, 382, 391, 182, 185, 190, 219, 227, 248, 268, 279, 280, 290, 295, 302,

397, 398, 400, 402, 405, 411, 412, 418, 317, 322, 323, 364, 391, 397, 405, 412, 418, 420, 423, 424, 420, 423, 424, 428-431, 434, 436, 439, 429-431, 434, 439, 443, 460, 461, 471-473 443, 451, 453, 455, 457-461, 468, 469, 471-473

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Table 1. Published Evidence (continued)

Study Design Population Intervention and Comparator in (Number of Studies) Effectiveness and Comparative Effectiveness Studies in Infants Post-only studies Infants (N = 7)76, 128, 189, 381, 419, 462, 463 Lacosamide,76 levetiracetam,189 (N = 134)76, 82, 87, 104, 109, 112, Pediatric mix (N = 38)82, 119, 121, 133, 152, antiepileptics plus pyridoxine,128 116, 119-121, 127, 128, 133, 134, 142, 167, 172, 192, 211, 216, 224, 228, 229, 234, 236, 239, 243- intravenous pyridoxine plus 145, 146, 148, 152, 155, 160, 167, 170, 245, 250, 260, 262, 267, 291, 297, 303, 305, 310, 314, 321, multiple anticonvulsants,128 vagus 172, 173, 175, 180, 183, 187, 189, 191, 325, 335, 345, 373, 380, 383 nerve stimulation,381 epilepsy 192, 195, 199, 201, 202, 206, 209, 211, Partially included (N = 37)104, 109, 112, surgery,462 cortical resection,463 and 214, 216, 217, 220, 224, 228, 229, 231, 134, 146, 160, 173, 180, 187, 195, 199, 201, 202, 217, 220, no comparator 234-236, 239, 243-246, 249, 250, 257, 231, 235, 246, 249, 275, 286, 311, 332, 334, 337, 344, 347, 259-262, 267, 269, 270, 275, 276, 286, 352, 367, 370, 372, 374, 375, 387, 389, 396 289, 291, 297, 300, 303, 305, 307, Unclear (N = 52)87, 116, 120, 127, 142, 145, 148, 310-312, 314-316, 319, 321, 325, 332, 155, 170, 175, 183, 191, 206, 209, 214, 257, 259, 261, 269,

334, 335, 337, 340, 341, 344, 345, 270, 276, 289, 300, 307, 312, 315, 316, 319, 340, 341, 348,

347-349, 351-353, 358, 361, 367, 370, 349, 351, 353, 358, 361, 386, 388, 392-394, 399, 406, 414, 372-375, 380, 381, 383, 386-389, 427, 433, 442, 444, 449, 464, 465, 470 392-394, 396, 399, 406, 414, 415, 419,

427, 433, 437, 442, 444, 449, 450, 462-465, 470 Case-control studies Infants (N = 0) Not applicable (N = 4)140, 147 ,203, 204 Pediatric mix (N = 1)147 Partially included (N = 0) Unclear (N = 3)140, 203, 204

Note: Infants = infants and children up to 3 years of age specific (no children older than 3 years of age); pediatric mix = mixed sample that includes infants up to 1 year old but covers a broader age range; partially included = sample includes the age group 0-3 only partially (eg, may include children aged ≥2 years but not younger children). Abbreviation: N = number of studies.

We identified 86 RCTs that included the age group of interest at least partially. However, only 6 studies were exclusively in infants. These studies compared adjunctive levetiracetam vs adjunctive placebo,176 adjunctive lamotrigine vs nonenzyme-inducing antiepileptic drugs, valproate vs enzyme-inducing antiepileptic drugs alone,194 different doses of oxcarbazepine adjunctive therapy,226 and adjunctive topiramate vs adjunctive placebo.139, 168 All other studies included either older children or the age group of interest only partially (eg, children aged 2 and older). In some cases, we could not determine the age group. Our search identified 24 clinical trials without randomization. These included one trial exclusively conducted in infants. The trial used antiepileptic medication in infants with tuberous sclerosis complex and multifocal activity on EEG prior to the onset of seizures.157 All other studies included a broader age range. The identified cohort studies compared cohorts of patients on different treatments for epilepsy. The identified cohort study exclusively in infants compared the use of levetiracetam versus phenobarbital.83

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We identified more than 100 case series (ie, uncontrolled studies that compared the effects of the intervention against the participants’ health outcomes before the intervention). Six studies were specific to infants and included this age group exclusively. These studies assessed the effects of topiramate,153, 237 lamotrigine,153, 258 levetiracetam,102 and liposteroid210 or assessed the effects of a ketogenic diet.382 Some of these uncontrolled studies were not exclusively in infants with epilepsy as defined for this topic brief but included some children with other epilepsy encephalopathy syndromes, including Lennox-Gastaut syndrome and spasms without hypsarrthymia.210, 382 The largest identified group of studies was post-only studies (ie, studies that followed children after exposure to an intervention without control group). The study summaries did not indicate that baseline data were available for the included participants. Several such studies were retrospective chart reviews. The 7 identified studies in infants assessed lacosamide,76 levetiracetam,189 antiepileptics plus pyridoxine,128 intravenous pyridoxine plus multiple anticonvulsants,128 vagus nerve stimulation,381 and epilepsy surgery (eg, cortical resection).462, 463 Our searches also identified a few case-control studies that predicted outcomes, including adverse events, from intervention variables. A future systematic review may use these studies but none of the case control studies indicated the study was specific to infants. Ongoing studies We identified 4 relevant ongoing studies. The studies included one ongoing RCT on the ketogenic diet exclusively in infants.377 One ongoing RCT assesses fenfluramine in children and young adults with Dravet syndrome,355 1 ongoing clinical trial evaluates pulsatile dexamethasone therapy compared with placebo,378 and 1 ongoing uncontrolled multicenter study assesses the effects of lacosamide in a pediatric sample.379 We restricted our search to studies that have stopped recruiting (where tracked in the database) and that may be close to publication and therefore available to be included in a systematic review in the near future. Key Question 2: What is the applicability and generalizability of research evidence to children aged 0-3 years? We identified numerous empirical studies for this topic brief, but this included only 18 published and ongoing studies that focused on infants exclusively.76, 83, 102, 128, 133, 139, 153, 157, 168, 176, 189, 194, 210, 226, 237, 258, 377, 381 As Table 2 shows, most evidence in these studies exclusively in the age group of interest focused on medication-related therapies. The evidence base includes other relevant research studies that could be, at least partially, included in an evidence review on infantile epilepsy.

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Table 2. Studies in Infants and Other Pediatric/Mixed Samples by Intervention Type

Intervention Studies Studies With Studies With Infants Studies With Type Exclusively in Mixed Pediatric Partially Included Unclear Age Infants Samples Information Medication and N = 1676, 83, 102, 128, N = 6089, 94, 119, 124, N = 8677, 78, 80, 84, 85, 91, 95, N = 10274, 87, 92, 93, 99, supplements 139, 153, 157, 168, 176, 132, 133, 137, 151, 152, 156, 97, 100, 107, 109, 114, 115, 117, 106, 116, 126, 131, 140-142, 144, 189, 194, 210, 226, 237, 166, 167, 169, 192, 193, 200, 118, 129, 130, 134, 138, 143, 146, 155, 164, 175, 182, 183, 191, 204, 258, 419 205, 213, 223, 229, 233, 234, 149, 162, 165, 171, 173, 186, 198, 212, 222, 247, 256, 259, 261, 270, 243-245, 253, 254, 260, 262, 199, 201, 202, 215, 218, 221, 230, 271, 274, 278, 280, 285, 289, 290, 265, 267, 273, 283, 287, 291, 238, 242, 246, 251, 255, 263, 264, 295, 296, 302, 307, 312, 313,

297, 299, 301, 303, 305, 308, 266, 272, 275, 277, 281, 282, 284, 315-319, 322-324, 326, 327, 329,

314, 320, 321, 325, 335, 336, 286, 288, 293, 294, 298, 304, 306, 331, 333, 338, 340, 341, 343, 348,

339, 345, 350, 357, 371, 378, 309, 311, 328, 330, 334, 337, 342, 349, 351, 353, 354, 358, 359, 361,

379, 395, 400, 401, 408, 436, 344, 347, 352, 355, 356, 363, 366, 362, 365, 368, 369, 394, 397, 399, 437 367, 372, 375, 376, 396, 398, 405, 406, 409, 410, 412, 414, 417, 402-404, 407, 411, 413, 415, 416, 418, 420-427, 429-431, 433-435, 428, 432 438-445 Behavioral and N = 2377, 382 N = 1275, 79, 82, 147, N = 2790, 96, 98, 103, 105, 108, N = 13127, 145, 179, 185, dietary 154, 172, 174, 178, 207, 228, 110, 111, 122, 125, 135, 136, 190, 203, 208, 227, 241, 248, 269, changes 239, 240 158-161, 163, 177, 181, 184, 188, 276, 279 195, 197, 225, 252, 292, 332 Medical N = 1381 N = 486, 121, 373, 380 N = 5220, 346, 360, 370, 374 N = 673, 123, 150, 170, 257, devices 364 Surgery N = 2462, 463 N = 2188, 211, 216, 224, N = 15101, 104, 112, 113, 180, N = 2981, 120, 148, 206, 209, 232, 236, 250, 310, 383, 385, 187, 196, 217, 231, 235, 249, 384, 214, 219, 268, 300, 386, 388, 448, 450, 451, 453, 455-459, 387, 389, 467 390-393, 446, 447, 449, 452, 454, 468, 469 460, 461, 464-466, 470-473 Number of N = 1374 N ≥ 432 N ≥ 208 Not available children younger than 3 years old

Note: Infants = infants and children up to 3 years of age specific (no children older than 3 years of age); pediatric mix = mixed sample that includes infants up to 1 year old but covers a broader age range; partially included = sample includes the age group 0-3 only partially (eg, may include children aged 2 years and older but not younger children). Abbreviation: N = number of studies.

The studies exclusively in infants evaluated different medications, including levetiracetam (N = 3),83, 102, 189 adjunctive levetiracetam (N = 1),176 topiramate (N = 1),237 adjunctive topiramate (N = 3),139, 153, 168 lamotrigine (N = 1),258 adjunctive lamotrigine (N = 1),194 lacosamide (N = 1),76 liposteroid (dexamethasone palmitate) (N = 1),210 multiple anticonvulsants (N = 1),128 oxcarbazepine (N = 1),226 and antiepileptic treatment not further specified (N = 1).157 Two studies evaluated the ketogenic diet (N = 2),377, 382 1 focused on vagus nerve stimulation (N = 1),381 and 2 focused on surgery.462, 463

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In addition to studies exclusively in infants, we identified 97 published studies that, while targeting a broader age range, did include very young children (ie, infants younger than 1 year old). Therefore, the interventions cited in these studies might be applicable to the infant age group of interest. Furthermore, a proportion of the studies (33 studies) was available as full text and reported the number of children younger than the age of 3 included in the study sample. The percentage of children younger than 1 was about 20% in several studies. Across the studies, at least 432 participants were children younger than 3 years of age. Because infants were eligible for the evaluated interventions in these studies, they are relevant and applicable. Nonetheless, results from these studies need to be regarded with caution because they were primarily derived from older children, and in some cases even children and adults. However, the data for infants already exist in these studies, and it may be possible to contact the researchers to share the data for the subgroup of interest. In addition, we identified 133 studies that included part of the age group of interest in the study sample. For example, some of these studies included patients 2 years of age but not younger. Studies evaluated a variety of interventions in these samples and, judging from the available information, these studies include at least 208 participants of interest. Since the data already exist, the authors of these studies could be contacted for information. Finally, we were unable to determine the age groups or the inclusion of infants in 150 studies. The study authors described the samples as pediatric samples or mentioned that children were included in the studies, but the full-text publication was either not available or the number of children younger than 3 years old was not reported. This set of studies is another potential source for an evidence review (but it is not clear how many additional participants would be gained by contacting the study authors).

Discussion and Conclusion

This topic brief identified numerous studies that included children up to 3 years old but few that were exclusively conducted within the age group of interest. The studies support a small systematic review. Given that so few studies involve different treatment options, most evidence statements would be based on a single research study without replication. Most existing studies in infants focused on medication-based interventions (eg, levetiracetam, adjunctive topiramate, adjunctive lamotrigine). Individual studies focused on dietary interventions (ie, ketogenic diet), vagus nerve stimulation, and surgery. Furthermore, the generalizability of the findings from these varied studies might be limited since some studies incorporated specific subpopulations such as infants with tuberous sclerosis or Dravet syndrome. However, these studies may also be viewed as opportunities to inform future targeted therapies in infants with other structural or genetic causes of epilepsy. The identified studies in mixed samples that included infants are potentially relevant for a systematic review given that the interventions were deemed applicable to infants. A future systematic review should build in a step of systematically getting in touch with authors of studies to request information on the subgroups of interest. Similarly, a recent analysis indicated there is much unpublished data on Phase 3 pediatric epilepsy clinical trials.499 Pediatric, and in particular infantile, epilepsy represents a difficult research area given the paucity of trials focused on this participant group and the difficulty of evaluating important

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patient-centered outcomes in young children.500-508 Some authors therefore have proposed novel approaches to conducting research in this population.509-513 A future review team tasked with conducting a systematic review in infant epilepsy, and the guideline team using the systematic review, may need to consider additional ways to extrapolate from research on older children and adults. Multiple authors have suggested exploring the applicability of research findings from older to younger age groups. 68, 512, 514, 515 The approach and the applicability of research in older children or adults should address both the efficacy and the safety of interventions to infants. 77, 139, 480 For example, important age-appropriate considerations of pharmacokinetics and pharmacodynamics should be incorporated when evaluating the applicability of pediatric drug studies to infants. Moreover, particular attention should be paid to age-appropriate outcomes and neurodevelopmental trajectories that might be impacted by various pharmacological, dietary, and surgical interventions in such studies. Research results for infants are also not represented in existing systematic reviews. A search for systematic reviews indicated very few focus specifically on infants. A recent review that focused on infants and toddlers with drug-resistant epilepsy included no RCTs based on the inclusion criteria.16 Two other systematic reviews on epilepsy in infants addressed severe myoclonic epilepsy in infants and Dravet syndrome, and both identified only 2 RCTs focused on the efficacy and tolerability of stiripentol.30, 50 A network meta-analysis examining the comparative efficacy of antiepileptic drugs in children and adolescents identified 46 RCTs. Of these, 14 focused on infantile spasms (also known as West syndrome) and only 3 studies included children younger than 3 years of age.7 This topic brief has important limitations. First, it is based on a limited and exploratory literature search. The search was not comprehensive and primarily designed to estimate the research volume and to answer the question of whether sufficient literature exists for a systematic review. A future systematic review will employ a more comprehensive literature search and likely identify additional relevant publications. Furthermore, the topic brief is primarily based on abstract summaries from the database that indexed the research. A future systematic review will screen the full-text citations of the publications in detail and some studies that appeared to be relevant for the topic brief may not meet all inclusion criteria established by the future systematic review. In conclusion, a systematic review of infantile epilepsy appears to be feasible. However, the literature search should be combined with an effort of contacting authors of existing studies to request data from the subgroup of infants and a critical assessment of the generalizability of existing evidence base from broader pediatric samples to infants. The results of the topic brief are an estimate of the available literature and should be interpreted with caution; a future systematic review will likely identify additional relevant publications.

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Appendix A: Search Strategy

PubMed randomized controlled trial*[tiab] OR randomized control trial*[tiab] OR “clinical trial“[tiab] OR “clinical trials”[tiab] OR “case series” [tiab] OR “pre–post” [tiab] OR “before after” [tiab] OR “time series” [tiab] OR Randomized Controlled Trials as Topic[Majr] OR Controlled Before–After Studies[Majr] OR Clinical Trials as Topic[Majr] OR Clinical Trials as Topic[Majr] OR “Systematic Review” [Publication Type] OR Randomized Controlled Trial [Publication Type] OR Clinical Trial [Publication Type] OR “Systematic review”[ti] AND ((infantile epileps*[tiab] OR “infantile spasms”[tiab] OR Spasms, Infantile[Majr] OR “west syndrome”[tiab] OR familial neonatal epileps*[tiab] OR “early myoclonic encephalopathy”[tiab] OR “early infantile epileptic encephalopathy”[tiab] OR childhood occipital epileps*[tiab] OR “occipital lobe epilepsy”[tiab] OR “childhood epilepsy”[tiab] OR “Ohtahara syndrome”[tiab] OR “myclonic encephalopathy”[tiab] OR “dravet syndrome”[tiab] OR “Lennox-Gastaut syndrome”[tiab] OR “panayiatopoulos syndrome”[tiab] OR “epileptic encephalopathy”[tiab] OR “Landau-Kielfner syndrome”[tiab]) OR ((infant*[tiab] OR child[tiab] OR children[tiab] OR baby[tiab] OR babies[tiab] OR neonatal[tiab] OR pediatric[tiab]) AND (epileptic spasm*[tiab] OR epilepsy[tiab] OR epilepsies[tiab] OR “Epileptic Encephalopathy”[tiab] OR “Encephalopathic Epilepsy”[title] OR seizure[tiab] OR seizures[tiab] OR convulsion[tiab] OR convulsions[tiab] OR “adrenocorticotropic hormone”[tiab] OR “ACTH”[tiab] OR “glucose transporter 1 deficiency”[tiab] OR GLUT1[tiab] OR “pyruvate dehydrogenase deficiency”[tiab]))) AND “patient care management”[Majr] OR “patient care management”[tiab] OR “disease management”[Majr] OR “disease management”[tiab] OR “medication therapy management”[Majr] OR “medication therapy management”[tiab] OR surgery[Majr] OR surgery[tiab] OR “surgical device”[tiab] OR “surgical devices”[tiab] OR resection[tiab] OR resections[tiab] OR neurostimulation[tiab] OR brain stimulation[tiab] OR hemispheretomy[tiab] OR hemispherectomy[tiab] OR “surgical* disconnection”[tiab] OR “antipyretic agents”[tiab] OR “vagus nerve stimulation”[tiab] OR triglyceride[tiab] OR diet[Majr] OR diet[tiab] or diets[tiab] or dieting[tiab] OR ketogenic[tiab] OR Atkins[tiab] OR medium chanin triglyceride[tiab] OR cannabidiol[tiab] OR Medication[tiab] OR Pharmaceutical Preparations[Majr] OR pharmacology[Majr] OR Pharmacology [tiab] OR anticonvulsant[tiab] OR antiepileptic[tiab] OR “Carbamazepine”[Majr] OR Carbamazepine[tiab] OR Carbatrolv[tiab] OR Tegretol[tiab] OR “Phenytoin”[Majr] OR Phenytoin[tiab] OR Dilantin[tiab] OR Valproate[tiab] OR Valproic Acid[Mesh] OR “Valproic Acid”[tiab] OR Depakene[tiab] OR depakote[tiab] OR phenytoin[tiab] OR Dilantin[tiab] OR phenobarbital[tiab] OR lamotrigine[tiab] OR Lamictal[tiab] OR carbamazepine[tiab] OR Tegretol[tiab] OR topiramate[tiab] OR Topamax[tiab] OR oxcarbazepine[tiab] OR Trileptal[tiab] OR zonisamide[tiab] OR Zonegran[tiab] OR gabapentin[tiab] OR Neurontin[tiab] OR levetiracetam[tiab] OR Keppra[tiab] OR pregabalin[tiab] OR Lyrica[tiab] OR clonazepam[tiab] OR Klonopin[tiab] OR

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lacosamide[tiab] OR Vimpat[tiab] OR rufinamide[tiab] OR Banze[tiab] OR vigabatrin[tiab] OR Sabril[tiab] OR Acetazolamide[tiab] OR Brivaracetam[tiab] OR Briviact[tiab] OR Carbamazepine[tiab] OR Carbagen[tiab] OR Tegretol[tiab] OR Clobazam[tiab] OR Frisium[tiab] OR Perizam[tiab] OR Tapclob[tiab] OR Zacco[tiab] OR Clonazepam[tiab] OR “Eslicarbazepine acetate”[tiab] OR Zebinix[tiab] OR Ethosuximide[tiab] OR Everolimus[tiab] OR Votubia[tiab] OR Gabapentin[tiab] OR Neurontin[tiab] OR Lacosamide[tiab] OR Vimpat[tiab] OR Lamotrigine[tiab] OR Lamitcal[tiab] OR Levetiracetam[tiab] OR Desitrend[tiab] OR Keppra[tiab] OR Oxcarbazepine[tiab] OR Trileptal[tiab] OR Perampanel[tiab] OR Fycompa[tiab] OR Phenobarbital[tiab] OR Phenytoin[tiab] OR Epanutin[tiab] OR “Phenytoin Sodium Flynn”[tiab] OR Piracetam[tiab] OR Nootropil[tiab] OR Pregabalin[tiab] OR Alzain[tiab] OR Axalid[tiab] OR Lecaent[tiab] OR Lyrica[tiab] OR Rewisca[tiab] OR Primidone[tiab] OR Rufinamide[tiab] OR Inovelon[tiab] OR “Sodium valproate”[tiab] OR Epilim[tiab] OR Episenta[tiab] OR Epiva[tiab] OR Stiripentol[tiab] OR Diacomit[tiab] OR Tiagabine[tiab] OR Gabitril[tiab] OR Topiramate[tiab] OR Topamax[tiab] OR Convulex[tiab] OR Epilim[tiab] OR Vigabatrin[tiab] OR Sabril[tiab] OR Zonisamide[tiab] OR Zonegran[tiab] ((“Epilepsy”[Mesh] AND “Surgical Procedures, Operative”[Mesh]) OR “Epilepsy/surgery”[Mesh]) AND (((Tokyo[ad] OR Miami[ad] OR UCLA[ad] OR “Los Angeles”[ad] OR (Los[ad] AND Angeles[ad]) OR (Great[ad] AND Ormond[ad] AND Street[ad])))) (((Tokyo[ad] OR Miami[ad] OR UCLA[ad] OR “Los Angeles”[ad] OR (Los[ad] AND Angeles[ad]) OR (Great[ad] AND Ormond[ad] AND Street[ad])))) Filters: Clinical Trial, Clinical Trial, Phase I, Clinical Trial, Phase II, Clinical Trial, Phase III, Clinical Trial, Veterinary, Comparative Study, Evaluation Studies, Randomized Controlled Trial, Clinical Study, Controlled Clinical Trial, Clinical Trial, Phase IV, Multicenter Study, Observational Study, Pragmatic Clinical Trial, Publication date to 2019/06/28, Infant: birth-23 months, Preschool Child: 2-5 years, Infant: 1-23 months

((“Epilepsy/surgery”[Mesh]) OR ((“Surgical Procedures, Operative”[Mesh]) AND (“Epilepsy”[Mesh]))) Filters: Filters activated: Clinical Study, Clinical Trial, Clinical Trial, Phase I, Clinical Trial, Phase II, Clinical Trial, Phase III, Clinical Trial, Phase IV, Comparative Study, Controlled Clinical Trial, Multicenter Study, Observational Study, Randomized Controlled Trial, Infant: birth-23 months. EMBASE Title/abstract/keyword search “Systematic Review” OR “randomized controlled trial” OR “randomized control trials” OR Randomized Controlled Trial OR Randomized Controlled Trials as Topic OR “clinical trial” OR “clinical trials” OR Clinical Trial OR Clinical Trials as Topic OR “clinical trial” OR “clinical trials” OR Clinical Trial OR “case series” OR “pre–post” OR “before after” OR “Controlled Before–After Studies” OR “time series” AND “infantile epilepsy” OR “infantile spasms” OR Spasms, Infantile OR “west syndrome” OR “familial neonatal epilepsy” OR “early myoclonic encephalopathy” OR “early infantile epileptic

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encephalopathy” OR “childhood occipital epilepsy” OR “occipital lobe epilepsy” OR “childhood epilepsy” OR (infant* OR child OR children OR baby OR babies OR neonatal OR pediatric) AND (“myoclonic seizures” OR “epileptic spasms” OR epilepsy OR epilepsies OR “Epileptic Encephalopathy” OR “Encephalopathic Epilepsy” OR seizure OR seizures OR convulsion OR convulsions) OR “Ohtahara syndrome” OR “myclonic encephalopathy” OR “dravet syndrome” OR “febrile seizures” OR “myoclonic-atonic seizures” OR “Lennox-Gastaut syndrome” OR “panayiatopoulos syndrome” OR “epileptic encephalopathy” OR “Landau-Kielfner syndrome” OR “frontal lobe epilepsy” AND “adrenocorticotropic hormone” OR “ACTH” OR “glucose transporter 1 deficiency” OR GLUT1OR “pyruvate dehydrogenase deficiency” OR “antipyretic agents” OR “vagus nerve stimulation” OR “patient care management” OR “disease management” OR “disease management” OR “medication therapy management” OR “medication therapy management” OR surgery OR surgery OR “surgical device” OR “surgical devices” OR resection OR neurostimulation OR brain stimulation OR hemispheretomy OR hemispherectomy OR “surgical* disconnection” OR diet OR diet OR diets OR dieting OR ketogenic OR Atkins OR triglyceride OR cannabidiol OR Medication OR Pharmaceutical Preparations OR pharmacology OR Pharmacology OR anticonvulsant OR antiepileptic OR “Carbamazepine” OR Carbamazepine OR Carbatrolv OR Tegretol OR “Phenytoin” OR Phenytoin OR Dilantin OR Valproate OR “Valproic Acid” OR “Valproic Acid” OR Depakene OR depakote OR phenytoin OR Dilantin OR phenobarbital OR lamotrigine OR Lamictal OR carbamazepine OR Tegretol OR topiramate OR Topamax OR oxcarbazepine OR Trileptal OR zonisamide OR Zonegran OR gabapentin OR Neurontin OR levetiracetam OR Keppra OR pregabalin OR Lyrica OR clonazepam OR Klonopin OR lacosamide OR Vimpat OR rufinamide OR Banze OR vigabatrin OR Sabril OR Acetazolamide OR Brivaracetam OR Briviact OR Carbamazepine OR Carbagen OR Tegretol OR Clobazam OR Frisium OR Perizam OR Tapclob OR Zacco OR Clonazepam OR “Eslicarbazepine acetate” OR Zebinix OR Ethosuximide OR Everolimus OR Votubia OR Gabapentin OR Neurontin OR Lacosamide OR Vimpat OR Lamotrigine OR Lamitcal OR Levetiracetam OR Desitrend OR Keppra OR Oxcarbazepine OR Trileptal OR Perampanel OR Fycompa OR Phenobarbital OR Phenytoin OR Epanutin OR “Phenytoin Sodium Flynn” OR Piracetam OR Nootropil OR Pregabalin OR Alzain OR Axalid OR Lecaent OR Lyrica OR Rewisca OR Primidone OR Rufinamide OR Inovelon OR “Sodium valproate” OR Epilim OR Episenta OR Epiva AND l OR Stiripentol OR Diacomit OR Tiagabine OR Gabitril OR Topiramate OR Topamax OR Convulex OR Epilim OR Vigabatrin OR Sabril OR Zonisamide OR Zonegran

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Clinicaltrials.gov, EU Clinical Trials Register, WHO ISRCTN, ISRCTN Registry Terms childhood epilepsy childhood occipital epilepsy early infantile epileptic encephalopathy early myoclonic encephalopathy familial neonatal epilepsy infantile epilepsy infantile spasms occipital lobe epilepsy West syndrome Study designs All ongoing studies that have stopped recruiting (where restriction was possible)

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