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Stiripentol (Diacomit®) (STP) is an orally active antiseizure medication (ASM) indicated as adjunctive therapy, for the treatment of seizures associated with Dravet syndrome (DS), a severe form of childhood epilepsy, in conjunction with clobazam and, in some regions valproic acid. Since the discovery of STP, several mechanisms of action (MoA) have been described that may explain its specific effect on seizures associated with DS. STP is mainly considered as a potentiator of gamma-aminobutyric acid (GABA) neurotransmission: (i) via uptake blockade, (ii) inhibition of degradation, but also (iii) as a positive allosteric modulator of GABAA receptors, especially those containing α3 and δ subunits. Blockade of voltage-gated sodium and T-type calcium channels, which is classically associated with anticonvulsant and neuroprotective properties, has also been demonstrated for STP. Finally, several studies indicate that STP could regulate glucose energy metabolism and inhibit lactate dehydrogenase. STP is also an inhibitor of several cytochrome P450 enzymes involved in the metabolism of other ASMs, contributing to boost their anticonvulsant efficacy as add-on therapy. These different MoAs involved in treatment of DS and recent data suggest a potential for STP to treat other neurological or non-neurological diseases. [ABSTRACT FROM AUTHOR]

Epilepsies are a diverse group of disorders which differ regarding prognosis for seizure control and associated comorbidities. Accurate classification is critical to choose the highest yield investigations and best therapeutic options and to provide the most accurate prognoses regarding the expected degree of seizure control, possible remission, and risk of associated comorbidities to patients and their families. This article reviews the recent updates in epilepsy classification to illustrate how accurate classification impacts care for persons with epilepsy. The authors discuss the ILAE 2017 Classification of the Epilepsies along with the modification of the classification for neonatal seizures and epilepsies. They also discuss the ILAE position papers on Epilepsy syndromes in neonates and infants and children of variable age and the Idiopathic Generalized Epilepsies. Accurate epilepsy classification allows selection of the highest yield investigations, choice of optimal therapies, and accurate prognostication of seizures (likelihood of response to antiseizure treatments and likelihood of remission with age), as well as comorbidities (likelihood, type, and severity). As we move into the era of disease modifying therapy, early accurate identification of underlying causes with timely introduction of specific treatments will be crucial to lessen the severity of epilepsy, with improved seizure control and attenuation of associated comorbidities. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to determine areas of consensus among an international panel of experts for the clinical presentation and diagnosis of epilepsy with eyelid myoclonia (EEM; formerly known as Jeavons syndrome) to improve a timely diagnosis. Methods: An international steering committee was convened of physicians and patients/caregivers with expertise in EEM. This committee summarized the current literature and identified an international panel of experts (comprising 25 physicians and five patients/caregivers). This international expert panel participated in a modified Delphi process, including three rounds of surveys to determine areas of consensus for the diagnosis of EEM. Results: There was a strong consensus that EEM is a female predominant generalized epilepsy syndrome with onset between 3 and 12 years of age and that eyelid myoclonia must be present to make the diagnosis. There was a strong consensus that eyelid myoclonia may go unrecognized for years prior to an epilepsy diagnosis. There was consensus that generalized tonic–clonic and absence seizures are typically or occasionally seen in patients. There was a consensus that atonic or focal seizures should lead to the consideration of reclassification or alternate diagnoses. There was a strong consensus that electroencephalography is required, whereas magnetic resonance imaging is not required for diagnosis. There was a strong consensus to perform genetic testing (either epilepsy gene panel or whole exome sequencing) when one or a combination of factors was present: family history of epilepsy, intellectual disability, or drug‐resistant epilepsy. Significance: This international expert panel identified multiple areas of consensus regarding the presentation and evaluation of EEM. These areas of consensus may be used to inform clinical practice to shorten the time to the appropriate diagnosis. [ABSTRACT FROM AUTHOR]

Objective: There are limited data about the treatment and management of epilepsy with eyelid myoclonia (EEM). The objective of this study was to determine areas of consensus among an international panel of experts for the management of EEM (formerly known as Jeavons syndrome). Methods: An international steering committee was convened of physicians and patients/caregivers with expertise in EEM. This committee summarized the current literature and identified an international panel of experts (comprising 25 physicians and five patients/caregivers). This panel participated in a modified Delphi process, including three rounds of surveys to determine areas of consensus for the treatment, other areas of management, and prognosis for EEM. Results: There was a strong consensus for valproic acid as the first‐line treatment, with levetiracetam or lamotrigine as preferable alternatives for women of childbearing age. There was a moderate consensus that ethosuximide and clobazam are also efficacious. There was a strong consensus to avoid sodium channel‐blocking medications, except for lamotrigine, as they may worsen seizure control. There was consensus that seizures typically persist into adulthood, with remission occurring in <50% of patients. There was less agreement about other areas of management, including dietary therapy, lens therapy, candidacy for driving, and outcome. Significance: This international expert panel identified multiple areas of consensus regarding the optimal management of EEM. These areas of consensus may inform clinical practice to improve the management of EEM. In addition, multiple areas with less agreement were identified, which highlight topics for further research. [ABSTRACT FROM AUTHOR]

Stiripentol (STP) is a structurally unique molecule with anticonvulsant and neuroprotective properties in animal and human studies. STP enhances gamma-aminobutyric acid (GABA)ergic neurotransmission and inhibits multiple hepatic isoenzymes (i.e. cytochrome P450 system) involved in the metabolism of other antiseizure medications (ASMs) potentiating their anticonvulsant effects and has proven to be a promising therapy in Dravet Syndrome (DS). The authors review randomized clinical trials and observational studies showing STP efficacy, safety, and tolerability when used as adjunctive therapy with VPA and clobazam in patients with DS. Moreover, they include recent evidence of its use in patients<2 years of age. Evidence on STP demonstrates clinically meaningful efficacy in both short and long term in patients with DS. In addition to reducing convulsive seizure frequency, STP also markedly reduces the number of status epilepticus episodes and associated medical complications which are more common in younger children. STP adverse effects are generally not severe and often resolve following STP dose reduction or adjustments of concomitant ASMs. STP is approved by the FDA for children aged 6 months and older with DS who are also taking clobazam, making it the only DS-specific ASM for children under age 1 year. [ABSTRACT FROM AUTHOR]

Dravet syndrome (DS) is a drug-resistant, early-onset, developmental and epileptic encephalopathy where there have been many recently approved therapies with many more in development. With the availability of more syndrome specific treatment options coupled with an earlier diagnosis, DS is well-positioned to be an example of how a precise syndromic diagnosis can guide treatment choices and improve overall outcomes and also allow for the development of potential disease modifying therapies to address more than just seizures. In this review we summarize the current state of DS approved therapies and those that are in various stages of development. [ABSTRACT FROM AUTHOR]

Neuronal ceroid lipofuscinosis type 2 (CLN2) disease is a very rare neurodegenerative lysosomal storage disorder. Progression is rapid and irreversible, making early diagnosis crucial for timely treatment. A group of pediatric neurologists and neuroradiologists with expertise in CLN2 convened to discuss early electroencephalogram (EEG) and magnetic resonance imaging (MRI) findings in CLN2 diagnosis. Of 18 CLN2 cases, 16 (88.9%) had background slowing and 16 (88.9%) had epileptiform discharges on initial EEG. Seven of 17 (41.2%) patients who received intermittent low-frequency photic stimulation had a photoparoxysmal response. Initial MRIs showed subtle cerebellar (n = 14, 77.8%) or cerebral (n = 9, 50.0%) atrophy, white matter abnormalities (n = 11, 61.1%), and basal ganglia T2 hypointensity (n = 6, 33.3%), which became more apparent on follow-up MRI. The recognition of even subtle cerebellar atrophy and white matter signal changes in children aged 2-5 years who present with language delay, new-onset seizures, and an EEG with epileptiform discharges and background slowing should prompt investigation for CLN2. Because these early signs are not unique to CLN2, genetic testing is essential early in the diagnostic journey. [ABSTRACT FROM AUTHOR]

Objectives: Drug treatment for children with epilepsy should, ideally, be governed by evidence from adequate and well‐controlled clinical studies. However, these studies are difficult to conduct, and so direct evidence supporting the informed use of specific drugs is often lacking. The Research Roundtable for Epilepsy (RRE) met in 2020 to align on an approach to therapy development for focal seizures in children age 1 month <2 years of age. Methods: The RRE reviewed the regulatory landscape, epidemiology, seizure semiology, antiseizure medicine pharmacology, and safety issues applicable to this population. Results: After reviewing evidence, the conclusion was that pediatric efficacy trials would be impracticable to conduct but a waiver of the regulatory requirement to conduct any study would lead to an absence of information to guide dosing in a critical population. Review of available data and discussion of RRE attendees led to the conclusion that the requirements for extrapolation of efficacy from older children down to infants from age 1 month to <2 years old appeared to be met. After the RRE, the US Food and Drug Administration (FDA) approved brivaracetam for use in children with focal epilepsy above the age of 1 month in August 2021 and lacosamide in October 2021, both based on the principle of extrapolation from data in older children. Significance: These recommendations should result in more rapid accessibility of antiseizure medications for infants. [ABSTRACT FROM AUTHOR]

There are numerous potential factors that may affect growth in children with epilepsy, and these must be evaluated in any child with appetite and weight concerns. Antiseizure medications (ASMs) have potential adverse effects, and many may affect appetite, thus impacting normal growth and weight gain. The aim of this review is to focus on the impact of both epilepsy and ASMs on appetite and weight in children. We systematically reviewed studies using Medline assessing the impact of ASMs on appetite and weight in children. Eligible studies included randomized controlled trials and open-label studies (open-label extension and interventional) that targeted or included the pediatric population (0–18 years of age). Each study was classified using the American Academy of Neurology (AAN) Classification of Evidence for Therapeutic Studies, and the level of evidence for impact on appetite and weight in children was graded. ASMs associated with decreased appetite and/or weight loss include fenfluramine, topiramate, zonisamide, felbamate, rufinamide, stiripentol, cannabidiol, brivaracetam and ethosuximide; ASMs with minimal impact on weight and appetite in children include oxcarbazepine, eslicarbazepine, lamotrigine, levetiracetam, lacosamide, carbamazepine, vigabatrin and clobazam. The ASM most robustly associated with increased appetite and/or weight gain is valproic acid; however, both pregabalin and perampanel may also lead to modest weight gain or increased appetite in children. Certain ASMs may impact both appetite and weight, which may lead to increased morbidity of the underlying disease and impaired adherence to the treatment regimen. [ABSTRACT FROM AUTHOR]

Objective: This study was undertaken to gain consensus from experienced physicians and caregivers regarding optimal diagnosis and management of Dravet syndrome (DS), in the context of recently approved, DS‐specific therapies and emerging disease‐modifying treatments. Methods: A core working group was convened consisting of six physicians with recognized expertise in DS and two representatives of the Dravet Syndrome Foundation. This core group summarized the current literature (focused on clinical presentation, comorbidities, maintenance and rescue therapies, and evolving disease‐modifying therapies) and nominated the 31‐member expert panel (ensuring international representation), which participated in two rounds of a Delphi process to gain consensus on diagnosis and management of DS. Results: There was strong consensus that infants 2–15 months old, presenting with either a first prolonged hemiclonic seizure or first convulsive status epilepticus with fever or following vaccination, in the absence of another cause, should undergo genetic testing for DS. Panelists agreed on evolution of specific comorbidities with time, but less agreement was achieved on optimal management. There was also agreement on appropriate first‐ to third‐line maintenance therapies, which included the newly approved agents. Whereas there was agreement for recommendation of disease‐modifying therapies, if they are proven safe and efficacious for seizures and/or reduction of comorbidities, there was less consensus for when these should be started, with caregivers being more conservative than physicians. Significance: This International DS Consensus, informed by both experienced global caregiver and physician voices, provides a strong overview of the impact of DS, therapeutic goals and optimal management strategies incorporating the recent therapeutic advances in DS, and evolving disease‐modifying therapies. [ABSTRACT FROM AUTHOR]

This study assessed the effectiveness of genetic testing in shortening the time to diagnosis of late infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease. Individuals who received epilepsy gene panel testing through Behind the Seizure®, a sponsored genetic testing program (Cohort A), were compared to children outside of the sponsored testing program during the same period (Cohort B). Two cohorts were analyzed: children aged ≥24 to ≤60 months with unprovoked seizure onset at ≥24 months between December 2016 and January 2020 (Cohort 1) and children aged 0 to ≤60 months at time of testing with unprovoked seizure onset at any age between February 2019 and January 2020 (Cohort 2). The diagnostic yield in Cohort 1A (n = 1814) was 8.4% (n = 153). The TPP1 diagnostic yield within Cohort 1A was 2.9‐fold higher compared to Cohort 1B (1.0%, n = 18/1814 vs..35%, n = 8/2303; p =.0157). The average time from first symptom to CLN2 disease diagnosis was significantly shorter than previously reported (9.8 vs. 22.7 months, p <.001). These findings indicate that facilitated access to early epilepsy gene panel testing helps to increase diagnostic yield for CLN2 disease and shortens the time to diagnosis, enabling earlier intervention. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to determine whether selection of treatment for children with infantile spasms (IS) varies by race/ethnicity. Methods: The prospective US National Infantile Spasms Consortium database includes children with IS treated from 2012 to 2018. We examined the relationship between race/ethnicity and receipt of standard IS therapy (prednisolone, adrenocorticotropic hormone, vigabatrin), adjusting for demographic and clinical variables using logistic regression. Our primary outcome was treatment course, which considered therapy prescribed for the first and, when needed, the second IS treatment together. Results: Of 555 children, 324 (58%) were non‐Hispanic white, 55 (10%) non‐Hispanic Black, 24 (4%) non‐Hispanic Asian, 80 (14%) Hispanic, and 72 (13%) other/unknown. Most (398, 72%) received a standard treatment course. Insurance type, geographic location, history of prematurity, prior seizures, developmental delay or regression, abnormal head circumference, hypsarrhythmia, and IS etiologies were associated with standard therapy. In adjusted models, non‐Hispanic Black children had lower odds of receiving a standard treatment course compared with non‐Hispanic white children (odds ratio [OR], 0.42; 95% confidence interval [CI], 0.20–0.89; p = 0.02). Adjusted models also showed that children with public (vs. private) insurance had lower odds of receiving standard therapy for treatment 1 (OR, 0.42; CI, 0.21–0.84; p = 0.01). Interpretation: Non‐Hispanic Black children were more often treated with non‐standard IS therapies than non‐Hispanic white children. Likewise, children with public (vs. private) insurance were less likely to receive standard therapies. Investigating drivers of inequities, and understanding the impact of racism on treatment decisions, are critical next steps to improve care for patients with IS. ANN NEUROL 2022;92:32–44 [ABSTRACT FROM AUTHOR]

The 2017 International League Against Epilepsy classification has defined a three‐tier system with epilepsy syndrome identification at the third level. Although a syndrome cannot be determined in all children with epilepsy, identification of a specific syndrome provides guidance on management and prognosis. In this paper, we describe the childhood onset epilepsy syndromes, most of which have both mandatory seizure type(s) and interictal electroencephalographic (EEG) features. Based on the 2017 Classification of Seizures and Epilepsies, some syndrome names have been updated using terms directly describing the seizure semiology. Epilepsy syndromes beginning in childhood have been divided into three categories: (1) self‐limited focal epilepsies, comprising four syndromes: self‐limited epilepsy with centrotemporal spikes, self‐limited epilepsy with autonomic seizures, childhood occipital visual epilepsy, and photosensitive occipital lobe epilepsy; (2) generalized epilepsies, comprising three syndromes: childhood absence epilepsy, epilepsy with myoclonic absence, and epilepsy with eyelid myoclonia; and (3) developmental and/or epileptic encephalopathies, comprising five syndromes: epilepsy with myoclonic–atonic seizures, Lennox–Gastaut syndrome, developmental and/or epileptic encephalopathy with spike‐and‐wave activation in sleep, hemiconvulsion–hemiplegia–epilepsy syndrome, and febrile infection‐related epilepsy syndrome. We define each, highlighting the mandatory seizure(s), EEG features, phenotypic variations, and findings from key investigations. [ABSTRACT FROM AUTHOR]

Epilepsy syndromes have been recognized for >50 years, as distinct electroclinical phenotypes with therapeutic and prognostic implications. Nonetheless, no formally accepted International League Against Epilepsy (ILAE) classification of epilepsy syndromes has existed. The ILAE Task Force on Nosology and Definitions was established to reach consensus regarding which entities fulfilled criteria for an epilepsy syndrome and to provide definitions for each syndrome. We defined an epilepsy syndrome as "a characteristic cluster of clinical and electroencephalographic features, often supported by specific etiological findings (structural, genetic, metabolic, immune, and infectious)." The diagnosis of a syndrome in an individual with epilepsy frequently carries prognostic and treatment implications. Syndromes often have age‐dependent presentations and a range of specific comorbidities. This paper describes the guiding principles and process for syndrome identification in both children and adults, and the template of clinical data included for each syndrome. We divided syndromes into typical age at onset, and further characterized them based on seizure and epilepsy types and association with developmental and/or epileptic encephalopathy or progressive neurological deterioration. Definitions for each specific syndrome are contained within the corresponding position papers. [ABSTRACT FROM AUTHOR]

The goal of this paper is to provide updated diagnostic criteria for the epilepsy syndromes that have a variable age of onset, based on expert consensus of the International League Against Epilepsy Nosology and Definitions Taskforce (2017–2021). We use language consistent with current accepted epilepsy and seizure classifications and incorporate knowledge from advances in genetics, electroencephalography, and imaging. Our aim in delineating the epilepsy syndromes that present at a variable age is to aid diagnosis and to guide investigations for etiology and treatments for these patients. [ABSTRACT FROM AUTHOR]

Objective: Infants with focal‐onset epilepsy are an understudied population, requiring additional evaluation for clinical assessment and prognostication. Our goal was to characterize the etiology and natural history of infantile‐onset focal epilepsy. Methods: We retrospectively identified all infants (0–24 months) with onset of focal epilepsy while resident in Olmsted County, Minnesota, between 1980 and 2018, using the Rochester Epidemiology Project Database. We assessed the impact of etiology on both seizure and neurodevelopmental outcome, and mortality. Results: Of 686 children with epilepsy onset <18 years, 125 (18.2%) presented with focal‐onset seizures in infancy. Median follow‐up for this group was 10.9 years (interquartile range [IQR] 6.2, 19.3). Etiology was identified in 65.6% (structural N = 62, genetic N = 13, both structural and genetic N = 3, metabolic N = 4). Of 107 patients followed >2 years, 38 (35.5%) developed drug‐resistant epilepsy (DRE). DRE was more likely with younger age at onset, known etiology, and presence of epileptic spasms. Sixty‐eight (63.0% of those with follow‐up) were developmentally delayed at last follow‐up, and known etiology, DRE, and presence of epileptic spasms were significantly associated with delay (p <.001 for all). Fifteen patients (12.0%) died at a median age of 7.1 years (IQR 1.7, 21.7), but only one death was seizure related (suspected sudden unexpected death in epilepsy [SUDEP]). Of 20 infants with normal development at onset and no known etiology with >2 years follow‐up, none developed DRE, all were seizure‐free at last follow‐up (95% off antiseizure medications [ASMs]), and all remained developmentally normal. Significance: Infantile‐onset focal epilepsy accounts for 18% of all epilepsy in childhood, is frequently due to known etiologies, and has a high rate of DRE. However, developmentally normal infants without a known cause appear to have a very favorable course. [ABSTRACT FROM AUTHOR]

Introduction: This study was designed to assess current recommendations from child neurologists and epileptologists on masking for school-age children with epilepsy. Methods: A 7-item survey was created and sent out to members of the Child Neurology Society and Pediatric Epilepsy Research Consortium in August of 2021 to assess current practice and provider recommendations on masking. Results: One hundred four individuals participated with representation from all regions of the United States. Masking was recommended by 95.1%, with 63.4% (n = 66) noting exception of those with severe intellectual disability, autism, and behavioral problems. Of those who write exemption letters, 54% write these <5% of the time. Only 3% reported potential adverse events associated with masking. Conclusion: Nearly all respondents recommended masking for school-age children with epilepsy. Potential risks of masking and adverse events were low. Improved guidance on masking is needed to ensure academic success of our patients with epilepsy. [ABSTRACT FROM AUTHOR]

Developmental and epileptic encephalopathies (DEEs) are among the most challenging of all epilepsies to manage, given the exceedingly frequent and often severe seizure types, pharmacoresistance to conventional antiseizure medications, and numerous comorbidities. During the past decade, efforts have focused on development of new treatment options for DEEs, with several recently approved in the United States or Europe, including cannabidiol as an orphan drug in Dravet and Lennox–Gastaut syndromes and everolimus as a possible antiepileptogenic and precision drug for tuberous sclerosis complex, with its impact on the mammalian target of rapamycin pathway. Furthermore, fenfluramine, an old drug, was repurposed as a novel therapy in the treatment of Dravet syndrome. The evolution of new insights into pathophysiological processes of various DEEs provides possibilities to investigate novel and repurposed drugs and to place them into the context of their role in future management of these patients. The purpose of this review is to provide an overview of these new medical treatment options for the DEEs and to discuss the clinical implications of these results for improved treatment. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effect of the COVID-19 pandemic on global access to care and practice patterns for children with epilepsy. Methods: We conducted a cross-sectional, online survey of pediatric neurologists across the world affiliated with the International Child Neurology Association, the Chinese Child Neurology Society, the Child Neurology Society, and the Pediatric Epilepsy Research Consortium. Results were analyzed in relation to regional burden of COVID-19 disease. Results: From April 10 to 24, 2020, a sample of 212 respondents from 49 countries indicated that the COVID-19 pandemic has dramatically changed many aspects of pediatric epilepsy care, with 91.5% reporting changes to outpatient care, 90.6% with reduced access to electroencephalography (EEG), 37.4% with altered management of infantile spasms, 92.3% with restrictions in ketogenic diet initiation, 93.4% with closed or severely limited epilepsy monitoring units, and 91.3% with canceled or limited epilepsy surgery. Telehealth use had increased, with 24.7% seeing patients exclusively via telehealth. Changes in practice were related both to COVID-19 burden and location. Conclusions: In response to COVID-19, pediatric epilepsy programs have implemented crisis standards of care that include increased telemedicine, decreased EEG use, changes in treatments of infantile spasms, and cessation of epilepsy surgery. The long-term impact of these abrupt changes merit careful study. [ABSTRACT FROM AUTHOR]

Objective: Whereas studies in adult epilepsy patients have shown higher rates of suicidal ideation and attempt, such studies in children are limited. Using the Rochester Epidemiology Project database, we compared the risk of self‐injurious behavior and suicidal ideation in a population‐based cohort of childhood epilepsy to controls. Methods: We studied 339 cases with epilepsy and 678 age‐ and sex‐matched controls followed to a median age of 24.7 and 23.4 years, and identified 98 subjects with self‐injurious behavior or suicidal ideation (43 with epilepsy and 55 controls). All behaviors were categorized using the Columbia Suicide Severity Rating Scale. Results: Those with epilepsy had a significantly higher rate of any self‐injurious behavior and suicidal ideation (hazard ratio [HR] = 1.56, 95% confidence interval [CI] = 1.04‐2.35) and tended to have an increased risk of suicidal ideation and attempt (HR = 1.48, 95% CI = 0.93‐2.37). The prevalence of preceding mood and substance abuse disorders was similarly high in both cases and controls with self‐injurious behavior or suicidal ideation; however, preceding attention‐deficit/hyperactivity disorder was more than twice as common in the epilepsy cases. Among cases with epilepsy, we did not identify any specific epilepsy‐related variable that was significantly correlated with risk of self‐injurious behavior or suicidal ideation. Significance: Children, teens, and young adults with a history of childhood epilepsy are at greater risk of self‐injurious behavior, highlighting the need for careful screening of mental health concerns as part of routine epilepsy care. [ABSTRACT FROM AUTHOR]

Febrile infection-related epilepsy syndrome (FIRES) is a rare and devastating epileptic encephalopathy with historically abysmal neurocognitive outcomes, including a high incidence of mortality. It tends to affect children and young adults and is characterized by superrefractory status epilepticus following a recent febrile illness. Growing evidence suggests a heterogeneous etiology resulting in fulminant nonantibody-mediated neuroinflammation. For some children with FIRES, this aberrant neuroinflammation appears secondary to a functional deficiency in the endogenous interleukin-1 receptor antagonist. A precise etiology has not been identified in all FIRES patients, and current treatments are not always successful. Limited treatment evidence exists to guide choice, dosing, and duration of therapies. However, the ketogenic diet and certain targeted immunomodulatory treatments, including anakinra, appear safe and have been associated with relatively excellent clinical outcomes in some FIRES patients. Future prospective multicenter collaborative studies are needed to further delineate the FIRES heterogeneous disease pathophysiology and to determine the safety and efficacy of treatment strategies through a robust measurement of neurocognitive outcomes. [ABSTRACT FROM AUTHOR]

Dravet syndrome is a rare but severe epilepsy syndrome that begins in the first year of life with recurrent seizures triggered by fever that are typically prolonged and hemiclonic. The epilepsy is highly drug resistant. Although development is normal at onset, over time, most patients develop moderate-to-severe intellectual disability, behavior disorders, and a characteristic crouch gait. There is a significant mortality, predominantly owing to sudden unexpected death in epilepsy. Complete seizure control is rarely attainable. Initial therapy includes valproic acid and clobazam, but response is typically inadequate. The results of new drugs for Dravet syndrome, including stiripentol, cannabidiol, and fenfluramine, are very promising. Stiripentol was associated with a greater than 50% reduction in convulsive seizure frequency in 71% of cases, when added to valproic acid and clobazam, and also markedly reduced status epilepticus. Pharmaceutical-grade cannabidiol resulted in a median change in monthly motor seizures from baseline of - 36.5%. Fenfluramine was associated with a greater than 50% reduction in seizures of 70%, with one quarter of cases achieving near seizure freedom over the duration of the trial. These agents are generally well tolerated, with few patients discontinuing for adverse effects. There is limited evidence to date regarding improvement in cognition with these newer agents; however, a meaningful change is challenging to assess over short trial periods and requires longer follow-up studies. While current treatments focus predominantly on seizure control, newer therapies including genetic treatments and antisense oligonucleotides can target the SCN1A channelopathy, and thus, may also significantly impact the important co-morbidities associated with this syndrome. [ABSTRACT FROM AUTHOR]

Background: The dynamin 1-like gene (DNM1L) encodes a GTPase that mediates mitochondrial and peroxisomal fission and fusion. We report a new clinical presentation associated with a DNM1L pathogenic variant and review the literature. Results: A 13-year-old boy with mild developmental delays and paroxysmal dystonia presented acutely with multifocal myoclonic super-refractory status epilepticus. Despite sustained and aggressive treatment, seizures persisted and care was ultimately withdrawn in the context of extensive global cortical atrophy. Rapid trio-whole exome sequencing revealed a de novo heterozygous c.1207C>T (p.R403C) pathogenic variant in DNM1L. Immunofluorescence staining of fibroblast mitochondria revealed abnormally elongated and tubular morphology. Conclusions: This case highlights the diagnostic importance of rapid whole exome sequencing within a critical care setting and reveals the expanding phenotypic spectrum associated with DNM1L variants. This now includes progressive paroxysmal dystonia and adolescent-onset super-refractory myoclonic status epilepticus contributing to strikingly rapid and progressive cortical atrophy and death. [ABSTRACT FROM AUTHOR]

The clinical phenotype of leucine-rich glioma-inactivated protein 1 (LGI1) and contactin-associated proteinlike 2 (CASPR2) autoimmunity is well defined in adults. Data for children are limited (<10 cases). Among 13,319 pediatric patients serologically tested for autoimmune neurological disorders (2010-2017), 264 were seropositive for voltage-gated potassium channel-complex-IgG (radioimmunoprecipitation). Only 13 (4.9%) were positive by transfected cell-binding assay for LGI1-IgG (n = 7), CASPR2-IgG (n = 3), or both (n = 3). This is significantly less than in adults. Encephalopathy, seizures, and peripheral nerve hyperexcitability were common, as was coexisting autoimmunity. No faciobrachial dystonic seizures or cancers were identified. Functional neurologic disorders were frequently the initial diagnosis, and immunotherapy appeared beneficial. Ann Neurol 2018;84:473-480. [ABSTRACT FROM AUTHOR]

Dravet syndrome (DS) is a medically refractory epilepsy that onsets in the first year of life with prolonged seizures, often triggered by fever. Over time, patients develop other seizure types (myoclonic, atypical absences, drops), intellectual disability, crouch gait and other co-morbidities (sleep problems, autonomic dysfunction). Complete seizure control is generally not achievable with current therapies, and the goals of treatment are to balance reduction of seizure burden with adverse effects of therapies. Treatment of co-morbidities must also be addressed, as they have a significant impact on the quality of life of patients with DS. Seizures are typically worsened with sodium-channel agents. Accepted first-line agents include clobazam and valproic acid, although these rarely provide adequate seizure control. Benefit has also been noted with stiripentol, topiramate, levetiracetam, the ketogenic diet and vagal nerve stimulation. Several agents presently in development, specifically fenfluramine and cannabidiol, have shown efficacy in clinical trials. Status epilepticus is a recurring problem for patients with DS, particularly in their early childhood years. All patients should be prescribed a home rescue therapy (usually a benzodiazepine) but should also have a written seizure action plan that outlines when rescue should be given and further steps to take in the local hospital if the seizure persists despite home rescue therapy. [ABSTRACT FROM AUTHOR]

Infantile spasms are the defining seizures of West syndrome, a severe form of early life epilepsy with poorly-understood pathophysiology. We present a novel comparative analysis of infants with spasms versus other seizure-types and identify clinical, etiological, and molecular-genetic factors preferentially predisposing to spasms. We compared ages, clinical etiologies, and associated-genes between spasms and non-spasms groups in a multicenter cohort of 509 infants (<12months) with newly-diagnosed epilepsy. Gene ontology and pathway enrichment analysis of clinical laboratory-confirmed pathogenic variant-harboring genes was performed. Pathways, functions, and cellular compartments between spasms and non-spasms groups were compared. Spasms onset age was similar in infants initially presenting with spasms (6.1 months) versus developing spasms as a later seizure type (6.9 months) but lower in the non-spasms group (4.7 months, p<0.0001). This pattern held across most etiological categories. Gestational age negatively correlated with spasms onset-age (r = -0.29, p<0.0001) but not with non-spasm seizure age. Spasms were significantly preferentially associated with broad developmental and regulatory pathways, whereas motor functions and pathways including cellular response to stimuli, cell motility and ion transport were preferentially enriched in non-spasms. Neuronal cell-body organelles preferentially associated with spasms, while, axonal, dendritic, and synaptic regions preferentially associated with other seizures. Spasms are a clinically and biologically distinct infantile seizure type. Comparative clinical-epidemiological analyses identify the middle of the first year as the time of peak expression regardless of etiology. The inverse association with gestational age suggests the preterm brain must reach a certain post-conceptional, not just chronological, neurodevelopmental stage before spasms manifest. Clear differences exist between the biological pathways leading to spasms versus other seizure types and suggest that spasms result from dysregulation of multiple developmental pathways and involve different cellular components than other seizure types. This deeper level of understanding may guide investigations into pathways most critical to target in future precision medicine efforts. [ABSTRACT FROM AUTHOR]

Stiripentol is a structurally unique antiepileptic drug that has several possible mechanisms of action, including diverse effects on the gamma-aminobutyric acid (GABA)-A receptor and novel inhibition of lactate dehydrogenase. Because of its inhibition of several cytochrome P450 enzymes, it has extensive pharmacokinetic interactions, which often necessitates reduction in doses of certain co-therapies, particularly clobazam. Stiripentol also has a neuroprotective action, by reducing calcium-mediated neurotoxicity. Evidence of its efficacy is most robust for Dravet syndrome, where stiripentol added to clobazam and valproic acid reduces seizure frequency and severity in the majority of cases. Small case series have also suggested benefit for malignant migrating partial seizures in infancy, super-refractory status epilepticus, and intractable focal epilepsy, although larger prospective studies are needed in these disorders. [ABSTRACT FROM AUTHOR]

Febrile infection-related epilepsy syndrome (FIRES) is a devastating epileptic encephalopathy with limited treatment options and an unclear etiology. Anakinra is a recombinant version of the human interleukin-1 receptor antagonist used to treat autoinflammatory disorders. This is the first report of anakinra for treatment of a child with super-refractory status epilepticus secondary to FIRES. Anakinra was well tolerated and effective. Cerebral spinal fluid analysis revealed elevated levels of proinflammatory cytokines before treatment that normalized on anakinra, suggesting a potential pathogenic role for neuroinflammation in FIRES. Further studies are required to assess anakinra efficacy and dosing, and to further delineate disease etiology. Ann Neurol 2016;80:939-945. [ABSTRACT FROM AUTHOR]

Electrical status epilepticus in slow-wave sleep ( ESES) is characterized by nearly continuous spike-wave discharges during non-rapid eye movement ( REM) sleep. ESES is present in Landau-Kleffner syndrome ( LKS) and continuous spike and wave in slow-wave sleep ( CSWS). Sulthiame has demonstrated reduction in spike-wave index ( SWI) in ESES, but is not available in the United States. Acetazolamide ( AZM) is readily available and has similar pharmacologic properties. Our aims were to assess the effect of AZM on SWI and clinical response in children with LKS and CSWS. Children with LKS or CSWS treated with AZM at our institution were identified retrospectively. Pre- and posttherapy electroencephalography ( EEG) studies were evaluated for SWI. Parental and teacher report of clinical improvement was recorded. Six children met criteria for inclusion. Three children (50%) demonstrated complete resolution or SWI <5% after AZM. All children had improvement in clinical seizures and subjective improvement in communication skills and school performance. Five of six children had subjective improvement in hyperactivity and attention. AZM is a potentially effective therapy for children with LKS and CSWS. This study lends to the knowledge of potential therapies that can be used for these disorders, which can be challenging for families and providers. [ABSTRACT FROM AUTHOR]

Objective Infantile spasms ( IS) are a severe form of childhood epilepsy associated with autism spectrum disorders ( ASD) in up to 35% of cases. The objective of this post hoc analysis of our randomized control trial was to determine whether rapid diagnosis and treatment of IS could limit the incidence of ASD while identifying risk factors related to ASD outcome. Methods Patients with IS were randomized in a standardized diagnostic and treatment protocol. Clinical and electroencephalogram ( EEG) evaluations were completed at all eight visits over 5 years, while cognitive evaluations were administered at 0, 6, 24 and 60 months, respectively. Autism was initially screened by means of the Checklist for Autism in Toddlers ( CHAT) at 24 months, and formally assessed at the 30-and 60-month follow-ups using the Autism Diagnostic Observation Schedule-Generic ( ADOS-G). Results Of the 69 patients included in the study, 25 could not be assessed due to severe delay or death. Eleven of the 42 patients screened with CHAT, were found to be at risk of an ASD outcome. ADOS was performed in 44 and 10 were diagnosed with ASD. The CHAT proved to correlate highly with the ADOS (80% ppv). Only patients with symptomatic IS developed ASD (p = 0.003). Earlier diagnosis or successful treatment did not correlate with a reduced rate of ASD. Other risk factors were identified such as having chronic epileptic discharges in the frontotemporal areas after disappearance of hypsarrhythmia (p = 0.005 and p = 0.007) and being of nonwhite origin (p = 0.009). Significance ASD was only observed in children with sympyomatic IS. Other clinical risk factors include chronic frontotemporal epileptic activity and being of non-white origin. Early diagnosis and treatment did not prevent ASD as an outcome of IS. However, patients at risk for ASD could be identified early on and should in the future benefit from early intervention to potentially improve their long-term outcome. [ABSTRACT FROM AUTHOR]

Objective To prospectively evaluate the etiology of new-onset infantile spasms and evaluate the yield of genetic and metabolic investigations in those without obvious cause after initial clinical evaluation and magnetic resonance imaging ( MRI). Methods Twenty-one U.S. pediatric epilepsy centers prospectively enrolled infants with newly diagnosed West syndrome in a central database. Etiology and investigations performed within 3 months of diagnosis were documented. Results From June 2012 to June 2014, a total of 251 infants were enrolled (53% male). A cause was identified in 161 (64.4%) of 250 cases (genetic,14.4%; genetic-structural, 10.0%; structural-congenital, 10.8%; structural-acquired, 22.4%; metabolic, 4.8%; and infectious, 2.0%). An obvious cause was found after initial clinical assessment (history and physical examination) and/or MRI in 138 of 161, whereas further genetic and metabolic studies were revealing in another 23 cases. Of 112 subjects without an obvious cause after initial evaluation and MRI, 81 (72.3%) had undergone genetic testing, which showed a causal abnormality in 23.5% and a variant of unknown significance in 14.8%. Although metabolic studies were done in the majority (serum, 79.5%; urine, 69.6%; and cerebrospinal fluid [ CSF], 38.4%), these revealed an etiology in only five cases (4.5%). No correlation was found between type of health insurance (public vs. private) and either genetic or metabolic testing. Significance Clinical evaluation and MRI provide a specific diagnosis in 55% of children presenting with West syndrome. We propose that a cost-effective workup for those without obvious cause after initial clinical evaluation and MRI includes an array comparative genomic hybridization ( aCGH) followed by an epilepsy gene panel if the microarray is not definitive, serum lactate, serum amino acids, and urine organic acids. [ABSTRACT FROM AUTHOR]

Objective To determine the outcome of implanting fewer electrodes over the hemisphere with less supporting presurgical localizing data. Methods We retrospectively reviewed our epilepsy surgery database at Mayo Clinic, Rochester, Minnesota, between January 1, 1999, and December 31, 2011, to identify patients who had an asymmetric number of electrode contacts implanted in each hemisphere for seizure localization. We scored each presurgical noninvasive data point (0, 0.5, or 1) to predict the likelihood of identifying seizure onset in the hemisphere with fewer intracranial electrode contacts ( HFEC). An aggregate score was obtained for each patient. Results Thirteen (37%) of 35 patients had HFEC-onset seizures on intracranial electroencephalography (i EEG). The following factors predicted HFEC-onset seizures: (1) temporal lobe epilepsy (p = 0.02); (2) interictal scalp electroencephalographic discharges at the HFEC (p = 0.04); and (3) both interictal and ictal scalp EEG discharges at the HFEC (p = 0.01). The median (range) aggregate score was 2 (1-3) for patients with HFEC-onset seizures recorded on i EEG and 1 (0-3) for patients without HFEC-onset seizures (p = 0.001). Using this scoring model, the odds ratio of identifying HFEC-onset seizures on i EEG was 6.4 for each one-point increment in the aggregate score. The area under the receiver operating characteristic curve for this model was 0.84, suggesting excellent ability of the aggregate score to discriminate between patients with and without HFEC-onset seizures on i EEG. Significance Implanting electrodes on the basis of limited supporting presurgical data may be useful in selected patients, especially those with temporal lobe epilepsy, interictal scalp discharges involving the HFEC, or both interictal and ictal scalp discharges involving the HFEC. In addition, our proposed scoring system may be helpful in selecting patients with complicated epilepsy for implantation of an asymmetric number of intracranial electrodes in the hemispheres. [ABSTRACT FROM AUTHOR]

This chapter covers the syndromes of benign epilepsy with centrotemporal spikes ( BECTS), nonlesional focal epilepsy in otherwise normal children ( NLFN), and the genetic generalized epilepsies. BECTS is an epilepsy syndrome that always enters terminal remission before the general age of a planned transition of adolescents. This is also the case for the majority (65%) of those with childhood absence epilepsy ( CAE). Approximately 15% of patients with CAE who initially remit during their childhood years later develop juvenile myoclonic epilepsy ( JME) as teenagers. They will have many issues for continuing medical care and transition, because their seizure disorder generally persists into adulthood. A significant minority of NLFN (~35%) and most patients with JME continue to have active epilepsy into adulthood. In addition, CAE, JME, and NLFN patients are at risk of a number of significant adverse social outcomes that require ongoing advice and counseling. [ABSTRACT FROM AUTHOR]

Medically refractory epilepsy remains a major medical problem worldwide. Although some patients are eligible for surgical resection of seizure foci, a proportion of patients are ineligible for a variety of reasons. One such reason is that the foci reside in eloquent cortex of the brain and therefore resection would result in significant morbidity. This retrospective study reports our experience with a novel neurostimulation technique for the treatment of these patients. We identified three patients who were ineligible for surgical resection of the intracranially identified seizure focus because it resided in eloquent cortex, who underwent therapeutic trial of focal cortical stimulation delivered through the subdural monitoring grid. All three patients had a significant reduction in seizures, and two went on to permanent implantation, which resulted in long-term reduction in seizure frequency. In conclusion, this small case report provides some evidence of proof of concept of the role of targeted continuous neocortical neurostimulation in the treatment of medically refractory focal epilepsy, and provides support for ongoing investigations into this treatment modality. A PowerPoint slide summarizing this article is available for download in the Supporting Information section . [ABSTRACT FROM AUTHOR]

Purpose To review the efficacy and tolerability of stiripentol in the treatment of U. S. children with Dravet syndrome. Methods U. S. clinicians who had prescribed stiripentol for two or more children with Dravet syndrome between March 2005 and 2012 were contacted to request participation in this retrospective study. Data collected included overall seizure frequency, frequency of prolonged seizures, and use of rescue medications and emergency room ( ER)/hospital visits in the year preceding stiripentol initiation, and with stiripentol therapy. We separately assessed efficacy in the following treatment groups: group A, stiripentol without clobazam or valproate; group B, stiripentol with clobazam but without valproate; group C, stiripentol with valproate but without clobazam; and group D, stiripentol with clobazam and valproate. In addition, adverse effects were recorded. Key Findings Thirteen of 16 clinicians contacted for study participated and provided data on 82 children. Stiripentol was initiated a median of 6.0 years after seizure onset and 1.2 years after diagnosis of Dravet syndrome. Compared to baseline, overall seizure frequency was reduced in 2/6 in group A, 28/35 in group B, 8/14 in group C, and 30/48 in group D. All children with prolonged seizure frequency greater than quarterly during the baseline period experienced a reduction in this frequency on the various treatment arms with stiripentol. Similarly, 2/4 patients in group A, 25/25 in group B, 5/10 in group C, and 26/33 in group D experienced reduction in frequency of rescue medication use and 1/1 in group A, 12/12 in group B, 3/5 in group C, and 18/19 in group D had reduction in frequency of ER/hospital visits. Adverse effects were reported in 38, most commonly sedation and reduced appetite. Four patients (5%) discontinued stiripentol for adverse effects and two (2%) for lack of efficacy. Significance Stiripentol is an effective and well-tolerated therapy that markedly reduced frequency of prolonged seizures in Dravet syndrome. [ABSTRACT FROM AUTHOR]

Mutations of the SCN1A subunit of the sodium channel is a cause of genetic epilepsy with febrile seizures plus ( GEFS+) in multiplex families and accounts for 70-80% of Dravet syndrome ( DS). DS cases without SCN1A mutation inherited have predicted SCN9A susceptibility variants, which may contribute to complex inheritance for these unexplained cases of DS. Compared with controls, DS cases were significantly enriched for rare SCN9A genetic variants. None of the multiplex febrile seizure or GEFS+ families could be explained by highly penetrant SCN9A mutations. [ABSTRACT FROM AUTHOR]