Early Life Epilepsy Research Articles

The impact of early life epilepsy on long term neurological development: a comprehensive study of pediatric patients

Background: Early-onset epilepsy disrupts brain development during critical childhood periods, impacting cognitive, motor, and behavioural functions. Objectives: This study aimed to evaluate the long-term effects of early-life epilepsy on paediatric neurological development and compare outcomes across pharmacological therapy, surgical interventions, and alternative therapies (e.g., ketogenic diets, neurostimulation). Methods: A prospective observational study was conducted at different teaching hospitals of Lahore, Pakistan from October 2023 to October 2024. A total of 150 children (aged 0–5 years) with diagnosed epilepsy were enrolled. Patients were categorized into three groups: pharmacological therapy (n=70), surgical intervention (n=40), and alternative therapies (n=40). Standardized tools assessed cognitive (WPPSI), motor (PDMS-2), and behavioural outcomes (CBCL, SRS), along with seizure control and treatment side effects. Results: Surgical intervention demonstrated the best outcomes, with significant improvements in IQ (92.7 ± 8.9), motor skills (fine: 89.2 ± 9.5, gross: 88.0 ± 9.7), and social interaction (90.4 ± 8.5). Seizure freedom was achieved in 75% of surgical cases compared to 21.4% in pharmacological therapy and 45% in alternative therapies. Behavioural issues and side effects, such as attention deficits (40%) and drowsiness (50%), were most prevalent in the pharmacological group. Conclusion: Surgical interventions significantly improved developmental outcomes and seizure control in drug-resistant epilepsy cases. Early diagnosis and personalized, targeted treatments are essential to mitigate the neurodevelopmental impact and enhance the quality of life for affected children.

WONOEP appraisal: Targeted therapy development for early onset epilepsies.

The early onset epilepsies encompass a heterogeneous group of disorders, some of which result in drug-resistant seizures, developmental delay, psychiatric comorbidities, and sudden death. Advancement in the widespread use of targeted gene panels as well as genome and exome sequencing has facilitated the identification of different causative genes in a subset of these patients. The ability to recognize the genetic basis of early onset epilepsies continues to improve, with de novo coding variants accounting for most of the genetic etiologies identified. Although current disease-specific and disease-modifying therapies remain limited, novel precision medicine approaches, such as small molecules, cell therapy, and other forms of genetic therapies for early onset epilepsies, have created excitement among researchers, clinicians, and caregivers. Here, we summarize the main findings of presentations and discussions on novel therapeutic strategies for targeted treatment of early onset epilepsies that occurred during the Workshop on Neurobiology of Epilepsy (WONOEP XVI, Talloires, France, July 2022). The presentations discussed the use of chloride transporter inhibitors for neonatal seizures, targeting orexinergic signaling for childhood absence epilepsy, targeting energy metabolism in Dravet syndrome, and the role of cannabinoid receptor type 2, reversible acetylcholinesterase inhibitors, cell therapies, and RNA-based therapies in early life epilepsies.

WONOEP appraisal: The role of glial cells in focal malformations associated with early onset epilepsies.

Epilepsy represents a common neurological disorder in patients with developmental brain lesions, particularly in association with malformations of cortical development and low-grade glioneuronal tumors. In these diseases, genetic and molecular alterations in neurons are increasingly discovered that can trigger abnormalities in the neuronal network, leading to higher neuronal excitability levels. However, the mechanisms underlying epilepsy cannot rely solely on assessing the neuronal component. Growing evidence has revealed the high degree of complexity underlying epileptogenic processes, in which glial cells emerge as potential modulators of neuronal activity. Understanding the role of glial cells in developmental brain lesions such as malformations of cortical development and low-grade glioneuronal tumors is crucial due to the high degree of pharmacoresistance characteristic of these lesions. This has prompted research to investigate the role of glial and immune cells in epileptiform activity to find new therapeutic targets that could be used as combinatorial drug therapy. In a special session of the XVI Workshop of the Neurobiology of Epilepsy (WONOEP, Talloires, France, July 2022) organized by the Neurobiology Commission of the International League Against Epilepsy, we discussed the evidence exploring the genetic and molecular mechanisms of glial cells and immune response and their implications in the pathogenesis of neurodevelopmental pathologies associated with early life epilepsies.

Functional analysis of a novel nonsense PPP1R12A variant in a Chinese family with infantile epilepsy

BackgroundDefects in PPP1R12A can lead to genitourinary and/or brain malformation syndrome (GUBS). GUBS is primarily characterized by neurological or genitourinary system abnormalities, but a few reported cases are associated with neonatal seizures. Here, we report a case of a female newborn with neonatal seizures caused by a novel variant in PPP1R12A, aiming to enhance the clinical and variant data of genetic factors related to epilepsy in early life.MethodsWhole-exome and Sanger sequencing were used for familial variant assessment, and bioinformatics was employed to annotate the variant. A structural model of the mutant protein was simulated using molecular dynamics (MD), and the free binding energy between PPP1R12A and PPP1CB was analyzed. A mutant plasmid was constructed, and mutant protein expression was analyzed using western blotting (WB), and the interaction between the mutant and PPP1CB proteins using co-immunoprecipitation (Co-IP) experiments.ResultsThe patient experienced tonic-clonic seizures on the second day after birth. Genetic testing revealed a heterozygous variant in PPP1R12A, NM_002480.3:c.2533 C > T (p.Arg845Ter). Both parents had the wild-type gene. MD suggested that loss of the C-terminal structure in the mutant protein altered its structural stability and increased the binding energy with PPP1CB, indicating unstable protein–protein interactions. On WB, a low-molecular-weight band was observed, indicating that the protein was truncated. Co-IP indicated that the mutant protein no longer interacted with PPP1CB, indicating an effect on the structural stability of the myosin phase complex.ConclusionThe PPP1R12A c.2533 C > T variant may explain the neonatal seizures in the present case. The findings of this study expand the spectrum of PPP1R12A variants and highlight the potential significance of truncated proteins in the pathogenesis of GUBS.

WONOEP appraisal: Modeling early onset epilepsies.

Epilepsy has a peak incidence during the neonatal to early childhood period. These early onset epilepsies may be severe conditions frequently associated with comorbidities such as developmental deficits and intellectual disability and, in a significant percentage of patients, may be medication-resistant. The use of adult rodent models in the exploration of mechanisms and treatments for early life epilepsies is challenging, as it ignores significant age-specific developmental differences. More recently, models developed in immature animals, such as rodent pups, or in three-dimensional organoids may more closely model aspects of the immature brain and could result in more translatable findings. Although models are not perfect, they may offer a more controlled screening platform in studies of mechanisms and treatments, which cannot be done in pediatric patient cohorts. On the other hand, more simplified models with higher throughput capacities are required to deal with the large number of epilepsy candidate genes and the need for new treatment options. Therefore, a combination of different modeling approaches will be beneficial in addressing the unmet needs of pediatric epilepsy patients. In this review, we summarize the discussions on this topic that occurred during the XVI Workshop on Neurobiology of Epilepsy, organized in 2022 by the Neurobiology Commission of the International League Against Epilepsy. We provide an overview of selected models of early onset epilepsies, discussing their advantages and disadvantages. Heterologous expression models provide initial functional insights, and zebrafish, rodent models, and brain organoids present increasingly complex platforms for modeling and validating epilepsy-related phenomena. Together, these models offer valuable insights into early onset epilepsies and accelerate hypothesis generation and therapy discovery.

183 Earlier Surgery is Associated With Improved Post-operative Language Development in Children With Tuberous Sclerosis Complex (TSC)

INTRODUCTION: Early life epilepsy in TSC has been strongly associated with lifelong intellectual disability. While improved seizure control correlates with improvements in quality of life and cognition, the importance of surgery timing in young children has not been well-studied. METHODS: Changes in patients’ preoperative (0-12 months) to postoperative (36 months) scores in neuropsychologic tests—including the Mullen Scales of Early Learning (MSEL), Vineland Adaptive Behavior Scales, Second Edition (VABS-II), and the Preschool Language Scales, 5th addition (PLS-5)—were calculated. Pearson correlation and multivariate linear regression models were used to correlate changes in test scores with age at surgery and separately with duration of epilepsy prior to surgery. Analysis was limited to those patients who demonstrated improved seizure control post-operatively (n = 18). RESULTS: Age at surgery had a statistically significant negative correlation with changes in the combined verbal sub-tests of the MSEL (R = -0.41, p = 0.04) and predicted the change in that measure outcome in a multivariate linear regression model (β: -0.09, p = 0.03). Similar trends were seen for the change in the total language score of the PLS-5 (R = -0.38, p = 0.06; β: -0.21, p = 0.07). Results were similar when the duration of epilepsy prior to surgery was assessed as the independent variable. However there were no clear trends with the VABS-II questionnaires, even in language domains. CONCLUSIONS: Our data shows that successful earlier surgery and shorter epilepsy duration prior to surgery are both associated with improved post-operative language development in a small cohort of patients with TSC. Prospective clinical trials are necessary to further elucidate this relationship.

Discovery and characterization of a specific inhibitor of serine-threonine kinase cyclin-dependent kinase-like 5 (CDKL5) demonstrates role in hippocampal CA1 physiology.

Pathological loss-of-function mutations in cyclin-dependent kinase-like 5 (CDKL5) cause CDKL5 deficiency disorder (CDD), a rare and severe neurodevelopmental disorder associated with severe and medically refractory early-life epilepsy, motor, cognitive, visual, and autonomic disturbances in the absence of any structural brain pathology. Analysis of genetic variants in CDD has indicated that CDKL5 kinase function is central to disease pathology. CDKL5 encodes a serine-threonine kinase with significant homology to GSK3β, which has also been linked to synaptic function. Further, Cdkl5 knock-out rodents have increased GSK3β activity and often increased long-term potentiation (LTP). Thus, development of a specific CDKL5 inhibitor must be careful to exclude cross-talk with GSK3β activity. We synthesized and characterized specific, high-affinity inhibitors of CDKL5 that do not have detectable activity for GSK3β. These compounds are very soluble in water but blood-brain barrier penetration is low. In rat hippocampal brain slices, acute inhibition of CDKL5 selectively reduces postsynaptic function of AMPA-type glutamate receptors in a dose-dependent manner. Acute inhibition of CDKL5 reduces hippocampal LTP. These studies provide new tools and insights into the role of CDKL5 as a newly appreciated key kinase necessary for synaptic plasticity. Comparisons to rodent knock-out studies suggest that compensatory changes have limited the understanding of the roles of CDKL5 in synaptic physiology, plasticity, and human neuropathology.

Anti-seizure efficacy of perampanel in two established rodent models of early-life epilepsy

Early-life seizures can be refractory to conventional antiseizure medications (ASMs) and can also result in chronic epilepsy and long-term behavioral and cognitive deficits. Treatments targeting age-specific mechanisms contributing to epilepsy would be of clinical benefit. One such target is the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subtype of excitatory glutamate receptor, which is upregulated in the developing brain. Perampanel is a non-competitive, selective AMPAR antagonist that is FDA-approved for focal onset seizures (FOS) or primary generalized tonic-clonic seizures (PGTC) in children and adults. However, the efficacy of perampanel treatment in epilepsy patients younger than 4 years has been less documented. We thus tested the efficacy of perampanel in two early-life seizure models: (1) a rat model of hypoxia-induced neonatal seizures and (2) a mouse model of Dravet syndrome with hyperthermia-induced seizures. Pretreatment with perampanel conferred dose-dependent protection against early-life seizures in both experimental models. These findings suggest that AMPAR-mediated hyperexcitability could be involved in the pathophysiology of early-life seizures, which may be amenable to treatment with perampanel.

Medical treatment in infants and young children with epilepsy: Off-label use of antiseizure medications. Survey Report of ILAE Task Force Medical Therapies in Children.

Antiseizure medications (ASMs) remain the mainstay of epilepsy treatment. These ASMs have mainly been tested in trials in adults with epilepsy, which subsequently led to market authorization (MA). For treatment of - especially young - children with epilepsy, several ASMs do not have a MA and guidelines are lacking, subsequently leading to "off-label" use of ASMs. Even though "off-label" ASM prescriptions for children could lead to more adverse events, it can be clinically appropriate and rational if the benefits outweigh the risks. This could be the case if "on-label" ASM, in mono- or polytherapy, fails to achieve adequate seizure control. The Medical Therapies Task Force of the International League Against Epilepsy (ILAE) Commission for Pediatrics performed a survey to study the current treatment practices in six classic, early life epilepsy scenarios. Our aim was not only to study first- and second-line treatment preferences but also to illustrate the use of "off-label" drugs in childhood epilepsies. Our results reveal that several ASMs (e.g. topiramate, oxcarbazepine, benzodiazepines) are prescribed "off-label" in distinct scenarios of young children with epilepsy. In addition, recent scientific guidelines were not always adopted by several survey respondents, suggesting a potential knowledge gap. We report the relatively common use of "off-label" prescriptions that underlines the need for targeted and appropriately designed clinical trials, including younger patients, which will also result in the ability to generate evidence-based guidelines.

EP134: Functional characterization of Variants of Uncertain Significance (VUSs) identified in patients with early-life epilepsy in Hong Kong

Pathogenic variants in genes encoding voltage-gated or ligand-gated ion channels cause monogenic epilepsies, which are collectively referred to as inherited channelopathies associated with epilepsy. Next-generation sequencing based epilepsy panel testing has been routinely used to evaluate early-life epilepsy (ELE) patients at local hospitals in Hong Kong. However, identification of variants of uncertain significance (VUSs) has become a major obstacle. Because loss-of-function (LoF) and gain-of-function (GoF) variants require completely distinct sets of antiepileptic drugs (AEDs) for clinical treatment, it is critical to obtain an accurate molecular diagnosis and understand the pathogenicity mechanism in these patients.

Sporadic hypothalamic hamartoma is a ciliopathy with somatic and bi-allelic contributions.

Hypothalamic hamartoma with gelastic seizures is a well-established cause of drug-resistant epilepsy in early life. The development of novel surgical techniques has permitted the genomic interrogation of hypothalamic hamartoma tissue. This has revealed causative mosaic variants within GLI3, OFD1 and other key regulators of the sonic-hedgehog pathway in a minority of cases. Sonic-hedgehog signalling proteins localize to the cellular organelle primary cilia. We therefore explored the hypothesis that cilia gene variants may underlie hitherto unsolved cases of sporadic hypothalamic hamartoma. We performed high-depth exome sequencing and chromosomal microarray on surgically resected hypothalamic hamartoma tissue and paired leukocyte-derived DNA from 27 patients. We searched for both germline and somatic variants under both dominant and bi-allelic genetic models. In hamartoma-derived DNA of seven patients we identified bi-allelic (one germline, one somatic) variants within one of four cilia genes-DYNC2I1, DYNC2H1, IFT140 or SMO. In eight patients, we identified single somatic variants in the previously established hypothalamic hamartoma disease genes GLI3 or OFD1. Overall, we established a plausible molecular cause for 15/27 (56%) patients. Here, we expand the genetic architecture beyond single variants within dominant disease genes that cause sporadic hypothalamic hamartoma to bi-allelic (one germline/one somatic) variants, implicate three novel cilia genes and reconceptualize the disorder as a ciliopathy.

Febrile seizures, not so benign

Genetic Epilepsy (previously known as idiopathic epilepsy) is a result of a known or presumed genetic defect(s) that is not causative of a brain structural or metabolic disorder. Objectives: Genetic epilepsy with febrile seizures plus is characterized by multiple febrile seizures and by several subsequent types of afebrile generalized seizures with variable degrees of severity. It has a complex and heterogeneous clinical presentation. Dravet Syndrome (DS) is a catastrophic early-life epilepsy disorder of the GEFS plus spectrum in which the seizures are usually refractory to treatment and are associated with intellectual disability. The detection rate of gene variants has gradually increased, and in addition to providing an accurate diagnosis, elucidating the genetic cause of paediatric-onset drug-resistant epilepsy can also help guide clinical management. Method: Here, we selected cases with febrile seizures on presentation who later developed epilepsy, and evaluated those using genetic studies.Results: The genes SCN1A, ADGRV2, GABBR2, and GPR98 as potential causes of GEFS (+) and Dravet syndrome have been highlighted in our report. Conclusion: An improved understanding of the true physiopathology of genetic epilepsy and the identification of factors that are involved in phenotypic variations, will make it easier to understand genotype-phenotype correlations in the future and help implement individualized precision medical treatment regimens.

Parent-Reported Sleep Profile of Children With Early-Life Epilepsies

BackgroundSleep comorbidities are common, and sometimes severe, for children with early-life epilepsies (ELEs). Yet, there is a paucity of data regarding the profile of these sleep disturbances and their complications. MethodsParticipants registered with the Rare Epilepsy Network (REN) were queried about sleep via online questionnaires. Descriptive statistics and logistic regression were performed. ResultsMedian age of the 356 children was 56 months (interquartile range 30 to 99), 56% were female, and 53% (188/356) endorsed a sleep concern. Frequent nighttime awakenings (157 of 350; 45%), difficulty falling asleep (133 of 350; 38%), and very restless sleep (118 of 345; 34%) were most endorsed. Nocturnal seizures were associated with sleep concerns and were reported in 75% (268 of 356) of children. Of the children with nocturnal seizures, 56% (118 of 268) had sleep concerns. Of the children without nocturnal seizures, 43% (38 of 88) had sleep concerns. Sleep concerns were most common in dup15q syndrome (16 of 19; 84%). Children aged 4 to ≤10 years (adjusted odds ratio [aOR] 16.1; 95% confidence interval [CI] 2.0, 131.0) and 10 to <13 years (aOR 22.2; 95% CI 2.6, 188.6) had a greater odds of having a sleep concern compared with children aged ≤6 months. Female sex appeared protective for sleep concerns (aOR 0.6; 95% CI 0.4, 0.9). The association between sleep concerns and nocturnal seizures was weaker when adjusted for sex and age category in a logistic regression model. ConclusionsReported sleep concerns are highly prevalent in children with ELEs and persist with age, in contrast to what is expected in healthy children. There may be unmet sleep-related clinical needs in children with ELEs.

Early-life epilepsy after acute symptomatic neonatal seizures: A prospective multicenter study.

We aimed to evaluate early-life epilepsy incidence, seizure types, severity, risk factors, and treatments among survivors of acute neonatal seizures. Neonates with acute symptomatic seizures born 7/2015-3/2018 were prospectively enrolled at nine Neonatal Seizure Registry sites. One-hour EEG was recorded at age three months. Post-neonatal epilepsy and functional development (Warner Initial Developmental Evaluation of Adaptive and Functional Skills - WIDEA-FS) were assessed. Cox regression was used to assess epilepsy-free survival. Among 282 infants, 37 (13%) had post-neonatal epilepsy by 24-months [median age of onset 7-months (IQR 3-14)]. Among those with post-neonatal epilepsy, 13/37 (35%) had infantile spasms and 12/37 (32%) had drug-resistant epilepsy. Most children with post-neonatal epilepsy had abnormal neurodevelopment at 24-months (WIDEA-FS >2SD below normal population mean for 81% of children with epilepsy vs 27% without epilepsy, RR 7.9, 95% CI 3.6-17.3). Infants with severely abnormal neonatal EEG background patterns were more likely to develop epilepsy than those with mild/moderate abnormalities (HR 3.7, 95% CI 1.9-5.9). Neonatal EEG with ≥3days of seizures also predicted hazard of epilepsy (HR 2.9, 95% CI 1.4-5.9). In an adjusted model, days of neonatal EEG-confirmed seizures (HR 1.4 per day, 95% CI 1.2-1.6) and abnormal discharge examination (HR 3.9, 95% CI 1.9-7.8) were independently associated with time to epilepsy onset. Abnormal (vs. normal) three-month EEG was not associated with epilepsy. In this multicenter study, only 13% of infants with acute symptomatic neonatal seizures developed post-neonatal epilepsy by age 24-months. However, there was a high risk of severe neurodevelopmental impairment and drug-resistant seizures among children with post-neonatal epilepsy. Days of EEG-confirmed neonatal seizures was a potentially modifiable epilepsy risk factor. An EEG at three months was not clinically useful for predicting epilepsy. These practice changing findings have implications for family counseling, clinical follow-up planning, and future research to prevent post-neonatal epilepsy.

Risk for infantile spasms after acute symptomatic neonatal seizures.

Infantile spasms (IS) is a severe epilepsy in early childhood. Early treatment of IS provides the best chance of seizure remission and favorable developmental outcome. We aimed to develop a prediction rule to accurately predict which neonates with acute symptomatic seizures will develop IS. We used data from the Neonatal Seizure Registry, a prospective, multicenter cohort of infants with acute symptomatic neonatal seizures born from July 2015 to March 2018. Neonates with acute symptomatic seizures who received clinical electroencephalography (EEG) and magnetic resonance imaging (MRI) and were younger than 2years of age at the time of enrollment were included. We evaluated the association of neonatal EEG, MRI, and clinical factors with subsequent IS using bivariate analysis and best subsets logistic regression. We selected a final model through a consensus process that balanced statistical significance with clinical relevance. IS developed in 12 of 204 infants (6%). Multiple potential predictors were associated with IS, including Apgar scores, EEG features, seizure characteristics, MRI abnormalities, and clinical status at hospital discharge. The final model included three risk factors: (a) severely abnormal EEG or ≥3days with seizures recorded on EEG, (b) deep gray or brainstem injury on MRI, and (c) abnormal tone on discharge exam. The stratified risk of IS was the following: no factors 0% (0/82, 95% confidence interval [CI] 0%-4%), one or two factors 4% (4/108, 95% CI 1%-9%), and all three factors 57% (8/14, 95% CI 29%-83%). IS risk after acute symptomatic neonatal seizures can be stratified using commonly available clinical data. No child without risk factors, vs >50% of those with all three factors, developed IS. This risk prediction rule may be valuable for clinical counseling as well as for selecting participants for clinical trials to prevent post-neonatal epilepsy. This tailored approach may lead to earlier diagnosis and treatment and improve outcomes for a devastating early life epilepsy.

Seizures in Children.

Epilepsy is one of the most common neurologic disorders seen in children, with the highest incidence in the first year of life. Diagnostic accuracy can be challenging because many seizure mimics must be considered. Electroencephalography and neuroimaging can be critical in determining etiology and syndrome. Genetic testing is a high-yield endeavor, particularly in early-life epilepsies. Up to one-fourth of children with epilepsy will develop drug-resistant seizures. Comorbidities are very common in children with epilepsy, including intellectual disability in 25% and learning disability and attention-deficit/hyperactivity disorder in a significant minority. These comorbidities must be recognized and addressed as part of the child's overall care.

Immediate outcomes in early life epilepsy: A contemporary account

RationaleEarly-life epilepsies (ELEs) include some of the most challenging forms of epilepsy to manage. Given recent diagnostic and therapeutic advances, a contemporary assessment of the immediate short-term outcomes can provide a valuable framework for identifying priorities and benchmarks for evaluating quality improvement efforts. MethodsChildren with newly diagnosed epilepsy and onset <3 years were prospectively recruited through 17 US hospitals, from 2012 to 2015 and followed for 1 year after diagnosis. Short-term outcome included mortality, drug resistance, evolution of nonsyndromic epilepsy to infantile spasms (IS) and from IS to other epilepsies, and developmental decline. Multivariable analyses assessed the risk of each outcome. ResultsSeven hundred seventy-five children were recruited, including 408 (53%) boys. Median age at onset was 7.5 months (interquartile range (IQR): 4.2–16.5), and 509 (66%) had onset in the first year of life. Of 22 deaths that occurred within one year of epilepsy diagnosis, 21 were children with epilepsy onset in infancy (<12 months). Of 680 children followed ≥6 months, 239 (35%) developed drug-resistant seizures; 34/227 (15%) infants with nonsyndromic epilepsy developed IS, and 48/210 (23%) initially presenting with IS developed additional seizure types. One hundred of 435 (23%) with initially typical development or only mild/equivocal delays at seizure onset, had clear developmental impairment within one year after initial diagnosis. Each outcome had a different set of predictors; however, younger age and impaired development at seizure onset were broadly indicative of poorer outcomes. Type of epilepsy and early identification of underlying cause were not reliable predictors of these outcomes. ConclusionEarly-life epilepsies carry a high risk of poor outcome which is evident shortly after epilepsy diagnosis. Onset in infancy and developmental delay is associated with an especially high risk, regardless of epilepsy type. The likelihood of poor outcomes is worrisome regardless of specific clinical profiles.

Seizure burden in severe early-life epilepsy: Perspectives from parents.

ObjectivesSeizure burden is typically measured by seizure frequency yet it entails more than seizure counts, especially for people with severe epilepsies and their caregivers. We aimed to characterize the multi‐faceted nature of seizure burden in young people and their parents who are living with severe early‐life epilepsies.MethodsA one‐day workshop and a series of teleconferences were held with parents of children with severe, refractory epilepsy of early‐life origin and providers for children with epilepsy. The workshop sessions were structured as focus groups and aimed to identify components of seizure burden and their impact from the perspective of parents and providers. Data were gathered, organized, and refined during the workshop using an iterative 4‐step process that drew upon grounded theory.ResultsThree primary components of seizure burden were identified: frequency, severity, and unpredictability, which was as important if not more important at times than frequency and severity. Caregivers noted that the impacts of seizures were experienced as acute‐immediate consequences, longer‐term consequences, and as chronic effects that develop and evolve over time. The severity of the child's neurological and medical status as well as where in the disease journey a family was represented additional contextual factors that influenced the experience of seizure burden.SignificancePatient‐reported and patient‐centered outcomes are increasingly incorporated into the evaluation of treatment effectiveness. Without understanding how the disease creates burden for the patient (or family), it is difficult to know how to assess the impact of treatment. Our preliminary findings indicate seizure burden is a complex construct and unpredictability can be as important as frequency and severity.

Severity Assessment in CDKL5 Deficiency Disorder

BackgroundPathologic mutations in cyclin-dependent kinase-like 5 cause CDKL5 deficiency disorder, a genetic syndrome associated with severe epilepsy and cognitive, motor, visual, and autonomic disturbances. This disorder is a relatively common genetic cause of early-life epilepsy. A specific severity assessment is lacking, required to monitor the clinical course and needed to define the natural history and for clinical trial readiness. MethodsA severity assessment was developed based on clinical and research experience from the International Foundation for CDKL5 Research Centers of Excellence consortium and the National Institutes of Health Rett and Rett-Related Disorders Natural History Study consortium. An initial draft severity assessment was presented and reviewed at the annual CDKL5 Forum meeting (Boston, 2017). Subsequently it was iterated through four cycles of a modified Delphi process by a group of clinicians, researchers, industry, patient advisory groups, and parents familiar with this disorder until consensus was achieved. The revised version of the severity assessment was presented for review, comment, and piloting to families at the International Foundation for CDKL5 Research-sponsored family meeting (Colorado, 2018). Final revisions were based on this additional input. ResultsThe final severity assessment comprised 51 items that comprehensively describe domains of epilepsy; motor; cognition, behavior, vision, and speech; and autonomic functions. Parental ratings of therapy effectiveness and child and family functioning are also included. ConclusionsA severity assessment was rapidly developed with input from multiple stakeholders. Refinement through ongoing validation is required for future clinical trials. The consensus methods employed for the development of severity assessment may be applicable to similar rare disorders.

Medications for Early Life Epilepsy: Evidence Versus Experience?

Comparative Effectiveness of Levetiracetam vs Phenobarbital for Infantile Epilepsy Grinspan ZM, Shellhaas RA, Coryell J, Sullivan JE, Wirrell EC, Mytinger JR, Gaillard WD, Kossoff EH, Valencia I, Knupp KG, Wusthoff C, Keator C, Ryan N, Loddenkemper T, Chu CJ, Novotny EJ Jr, Millichap J, Berg AT. JAMA Pediatr. 2018 Apr 1;172(4):352-360. doi: 10.1001/jamapediatrics.2017.5211.Importance: More than half of infants with new-onset epilepsy have electroencephalographic and clinical features that do not conform to known electroclinical syndromes (ie, nonsyndromic epilepsy). Levetiracetam and phenobarbital are the most commonly prescribed medications for epilepsy in infants, but their comparative effectiveness is unknown. Objective: To compare the effectiveness of levetiracetam versus phenobarbital for nonsyndromic infantile epilepsy. Design, Setting, and Participants: The Early Life Epilepsy Study—a prospective, multicenter, observational cohort study conducted from March 1, 2012, to April 30, 2015, in 17 US medical centers—enrolled infants with nonsyndromic epilepsy and a first afebrile seizure between 1 month and 1 year of age. Exposures: Use of levetiracetam or phenobarbital as initial monotherapy within 1 year of the first seizure. Main Outcomes and Measures: The binary outcome was freedom from monotherapy failure at 6 months, defined as no second prescribed antiepileptic medication and freedom from seizures beginning within 3 months of initiation of treatment. Outcomes were adjusted for demographics, epilepsy characteristics, and neurologic history, as well as for observable selection bias using propensity score weighting and for within-center correlation using generalized estimating equations. Results: Of the 155 infants in the study (81 girls and 74 boys; median age, 4.7 months [interquartile range, 3.0-7.1 months]), those treated with levetiracetam (n = 117) were older at the time of the first seizure than those treated with phenobarbital (n = 38; median age, 5.2 months [interquartile range, 3.5-8.2 months] vs 3.0 months [interquartile range, 2.0-4.4 months]; P < .001). There were no other significant bivariate differences. Infants treated with levetiracetam were free from monotherapy failure more often than those treated with phenobarbital (47 [40.2%] vs 6 [15.8%]; P = .01). The superiority of levetiracetam over phenobarbital persisted after adjusting for covariates, observable selection bias, and within-center correlation (odds ratio, 4.2; 95% confidence interval [CI], 1.1-16; number needed to treat, 3.5 [95% CI, 1.7-60]). Conclusions and Relevance: Levetiracetam may have superior effectiveness compared to phenobarbital for initial monotherapy of nonsyndromic epilepsy in infants. If 100 infants who received phenobarbital were instead treated with levetiracetam, 44 would be free from monotherapy failure instead of 16 by the estimates in this study. Randomized clinical trials are necessary to confirm these findings.