Wirrell, Elaine C

Abstract Objective We analyzed the long‐term safety and effectiveness of fenfluramine (FFA) in patients with Dravet syndrome (DS) in an open‐label extension (OLE) study after participating in randomized controlled trials (RCTs) or commencing FFA de novo as adults. Methods Patients with DS who participated in one of three RCTs or were 19 to 35 years of age and started FFA de novo were included. Key endpoints were: incidence of treatment‐emergent adverse events (TEAEs) in the safety population, and median percentage change in monthly convulsive seizure frequency (MCSF) from the RCT baseline to end of study (EOS) in the modified intent‐to‐treat (mITT) population. Post hoc analyses compared effectiveness in patients on concomitant stiripentol (STP) vs those not taking STP, and assessed safety (TEAEs) and effectiveness (Clinical Global Impression‐Improvement [CGI‐I] scale ratings) in patients enrolled as adults. Results A total of 374 patients, including 45 adults, received ≥1 FFA dose. Median FFA exposure was 824 days (range, 7–1280). TEAEs occurring in ≥10% of patients were pyrexia, nasopharyngitis, decreased appetite, seizure, decreased blood glucose, diarrhea, abnormal echocardiography (only physiologic regurgitation), upper respiratory tract infection, influenza, vomiting, and ear infection; no valvular heart disease or pulmonary arterial hypertension was observed over the OLE. In the mITT population ( n = 324), median percentage change in MCSF from baseline to EOS was −66.8% ( p < .001). The post hoc analyses of MCSF change from baseline to EOS in patients on concomitant STP ( n = 75) was −36.2% vs −71.6% in those not on concomitant STP ( n = 234) ( p < .0001). In adult patients, 29 of 41 (70.7%) and 29 of 42 patients (69.1%) demonstrated clinically meaningful improvement on CGI‐I at last visit as rated by caregivers and investigators, respectively. Significance Our OLE study of FFA in patients with DS confirmed previous positive findings and extended the exposure up to 3.5 years. No new or unexpected safety signals were observed and FFA demonstrated sustained and clinically meaningful reduction in MCSF.

AbstractThe aim of this study is to report three cases of epilepsy with eyelid myoclonia (EEM) with CHD2 pathogenic variants. A database of 134 patients with EEM evaluated at Mayo Clinic sites was searched to identify patients with CHD2 variants. The medical records of those identified were reviewed to describe their presentation, treatment, and clinical course. Three patients (2 males, 1 female) with EEM were found to harbor de novo CHD2 pathogenic variants (c.2636C>T p.(Ala879Val), c.3734delA p. (Lys1245Asnfs*4), and c.3896delTinsCG p. (Val1299Alafs*5)). All three patients had comorbid autism spectrum disorder (ASD), intellectual disability (ID), and attention deficit disorder (ADHD). Eyelid myoclonia was a prominent seizure type that persisted in the three patients despite trials of multiple antiseizure medications. Generalized tonic–clonic seizures occurred in two of the patients but were controlled with antiseizure medications. Genetic testing should be considered in patients presenting with EEM, especially when ADHD, ID, ASD, and drug‐resistant seizures are present. Further understanding of the relationship between CHD2 variants and epileptogenesis may provide important insights into the pathogenesis of EEM.

AbstractThe Psychiatric Pediatric Issues Task Force of the International League Against Epilepsy (ILAE) aimed to develop recommendations for the diagnosis and treatment of anxiety and depression in children and adolescents with epilepsy. The Task Force conducted a systematic review and identified two studies that assessed the accuracy of four screening measures for depression and anxiety symptoms compared with a psychiatric interview. Nine studies met the eligibility criteria for treatment of anxiety and depressive disorders or symptoms. The risk of bias and certainty of evidence were assessed. The evidence generated by this review followed by consensus where evidence was missing generated 47 recommendations. Those with a high level of agreement (≥80%) are summarized. Diagnosis: (1) Universal screening for anxiety and depression is recommended. Closer surveillance is recommended for children after 12 years, at higher risk (e.g., suicide‐related behavior), with subthreshold symptoms, and experiencing seizure worsening or therapeutic modifications. (2) Multiple sources of ascertainment and a formal screening are recommended. Clinical interviews are recommended whenever possible. The healthcare provider must always explain that symptom recognition is essential to optimize treatment outcomes and reduce morbidity. (3) Questioning about the relationship between symptoms of anxiety or depression with seizure worsening/control and behavioral adverse effects of antiseizure medications is recommended. Treatment: (1) An individualized treatment plan is recommended. (2) For mild depression, active monitoring must be considered. (3) Referral to a mental health care provider must be considered for moderate to severe depression and anxiety. (4) Clinical care pathways must be developed. (5) Psychosocial interventions must be tailored and age‐appropriate. (6) Healthcare providers must monitor children with epilepsy who are prescribed antidepressants, considering symptoms and functioning that may not improve simultaneously. (7) Caregiver education is essential to ensure treatment adherence. (8) A shared‐care model involving all healthcare providers is recommended for children and adolescents with epilepsy and mental health disorders. We identified clinical decisions in the management of depression and anxiety that lack solid evidence and provide consensus‐based guidance to address the care of children and adolescents with epilepsy.

AbstractFenfluramine (FFA), an antiseizure medication (ASM) with serotonergic and sigma‐1 receptor activity, is used to manage patients with developmental and epileptic encephalopathies (DEEs). It is approved in the US for treating seizures associated with Dravet syndrome (DS) and Lennox–Gastaut syndrome (LGS) in patients ≥2 years old and as add‐on therapy for seizures associated with DS and LGS in the EU, UK, and Japan in similarly aged patients. Consensus guidelines for treatment of DS have recommended FFA to be an early‐line ASM, and it has also shown efficacy in managing seizures associated with LGS. DS and LGS are DEEs associated with a range of seizure types, developmental impairments, and multiple comorbidities. Here we provide case vignettes describing 4 patients (3 DS and 1 LGS) aged 4–29 years old in whom up to 14 ASMs had previously failed, to illustrate real‐world practice issues encountered by neurologists. This review provides guidance on the use of FFA in the context of ASM polytherapy and drug–drug interactions (DDIs), behavioral issues, dose titration, and adverse events. Along with data from the clinical trial program, these case vignettes emphasize the low risk of DDIs, a generally well‐tolerated safety profile, and other seizure and nonseizure benefits (eg, improved cognition and sleep) associated with the use of FFA in DS or LGS.Plain Language SummaryFenfluramine is used to treat seizures in individuals with Dravet syndrome and Lennox–Gastaut syndrome, but there are a range of issues that clinicians may face when treating patients. This review highlights four patients from the authors’ everyday clinical work and offers guidance and practical considerations by neurologists with expertise in managing these complex conditions related to drug interactions, dosing, and side effects associated with fenfluramine.

AbstractObjectivesWe aimed to develop consensus on comorbidities (frequency, severity, and prognosis) and overall outcomes in epilepsy, development, and cognition for the five phenotypes of SCN8A‐related disorders.MethodsA core panel consisting of 13 clinicians, 1 researcher, and 6 caregivers was formed and split into three workgroups. One group focused on comorbidities and prognosis. All groups performed a literature review and developed questions for use in a modified‐Delphi process. Twenty‐eight clinicians, one researcher, and 13 caregivers from 16 countries participated in three rounds of the modified‐Delphi process. Consensus was defined as follows: strong consensus ≥80% fully agree; moderate consensus ≥80% fully or partially agree, <10% disagree; and modest consensus 67%–79% fully or partially agree, <10% disagree.ResultsConsensus was reached on the presence of 14 comorbidities in patients with Severe Developmental and Epileptic Encephalopathy (Severe DEE) spanning non‐seizure neurological disorders and other organ systems; impacts were mostly severe and unlikely to improve or resolve. Across Mild/Moderate Developmental and Epileptic Encephalopathy (Mild/Moderate DEE), Neurodevelopmental Delay with Generalized Epilepsy (NDDwGE), and NDD without Epilepsy (NDDwoE) phenotypes, cognitive and sleep‐related comorbidities as well as fine and gross motor delays may be present but are less severe and more likely to improve compared to Severe DEE. There was no consensus on comorbidities in the SeL(F)IE phenotype but strong conesensus that seizures would largely resolve. Seizure freedom is rare in patients with Severe DEE but may occur in some with Mild/Moderate DEE and NDDwGE.SignificanceSignificant comorbidities are present in most phenotypes of SCN8A‐related disorders but are most severe and pervasive in the Severe DEE phenotype. We hope that this work will improve recognition, early intervention, and long‐term management for patients with these comorbidities and provide the basis for future evidence‐based studies on optimal treatments of SCN8A‐related disorders. Identifying the prognosis of patients with SCN8A‐related disorders will also improve care and quality‐of‐life for patients and their caregivers.

AbstractObjectiveWe aimed to develop consensus for diagnosis/management of SCN8A‐related disorders. Utilizing a modified Delphi process, a global cohort of experienced clinicians and caregivers provided input on diagnosis, phenotypes, treatment, and management of SCN8A‐related disorders.MethodsA Core Panel (13 clinicians, one researcher, six caregivers), divided into three subgroups (diagnosis/phenotypes, treatment, comorbidities/prognosis), performed a literature review and developed questions for the modified Delphi process. Twenty‐eight expert clinicians, one researcher, and 13 caregivers from 16 countries participated in the subsequent three survey rounds. We defined consensus as follows: strong consensus, ≥80% fully agree; moderate consensus, ≥80% fully/partially agree, <10% disagree; and modest consensus, 67%–79% fully/partially agree, <10% disagree.ResultsEarly diagnosis is important for long‐term clinical outcomes in SCN8A‐related disorders. There are five phenotypes: three with early seizure onset (severe developmental and epileptic encephalopathy [DEE], mild/moderate DEE, self‐limited (familial) infantile epilepsy [SeL(F)IE]) and two with later/no seizure onset (neurodevelopmental delay with generalized epilepsy [NDDwGE], NDD without epilepsy [NDDwoE]). Caregivers represented six patients with severe DEE, five mild/moderate DEE, one NDDwGE, and one NDDwoE. Phenotypes vary by age at seizures/developmental delay onset, seizure type, electroencephalographic/magnetic resonance imaging findings, and first‐line treatment. Gain of function (GOF) versus loss of function (LOF) is valuable for informing treatment. Sodium channel blockers are optimal first‐line treatment for GOF, severe DEE, mild/moderate DEE, and SeL(F)IE; levetiracetam is relatively contraindicated in GOF patients. First‐line treatment for NDDwGE is valproate, ethosuximide, or lamotrigine; sodium channel blockers are relatively contraindicated in LOF patients.SignificanceThis is the first‐ever global consensus for the diagnosis and treatment of SCN8A‐related disorders. This consensus will reduce knowledge gaps in disease recognition and inform preferred treatment across this heterogeneous disorder. Consensus of this type allows more clinicians to provide evidence‐based care and empowers SCN8A families to advocate for their children.

Abstract A variety of terms, such as “antiepileptic,” “anticonvulsant,” and “antiseizure” have been historically applied to medications for the treatment of seizure disorders. Terminology is important because using terms that do not accurately reflect the action of specific treatments may result in a misunderstanding of their effects and inappropriate use. The present International League Against Epilepsy (ILAE) position paper used a Delphi approach to develop recommendations on English‐language terminology applicable to pharmacological agents currently approved for treating seizure disorders. There was consensus that these medications should be collectively named “antiseizure medications”. This term accurately reflects their primarily symptomatic effect against seizures and reduces the possibility of health care practitioners, patients, or caregivers having undue expectations or an incorrect understanding of the real action of these medications. The term “antiseizure” to describe these agents does not exclude the possibility of beneficial effects on the course of the disease and comorbidities that result from the downstream effects of seizures, whenever these beneficial effects can be explained solely by the suppression of seizure activity. It is acknowledged that other treatments, mostly under development, can exert direct favorable actions on the underlying disease or its progression, by having “antiepileptogenic” or “disease‐modifying” effects. A more‐refined terminology to describe precisely these actions needs to be developed.

Abstract Objective Dravet syndrome (DS) is a developmental and epileptic encephalopathy characterized by high seizure burden, treatment‐resistant epilepsy, and developmental stagnation. Family members rate communication deficits among the most impactful disease manifestations. We evaluated seizure burden and language/communication development in children with DS. Methods ENVISION was a prospective, observational study evaluating children with DS associated with SCN1A pathogenic variants ( SCN1A + DS) enrolled at age ≤5 years. Seizure burden and antiseizure medications were assessed every 3 months and communication and language every 6 months with the Bayley Scales of Infant and Toddler Development 3rd edition and the parent‐reported Vineland Adaptive Behavior Scales 3rd edition. We report data from the first year of observation, including analyses stratified by age at Baseline: 0:6–2:0 years:months (Y:M; youngest), 2:1–3:6 Y:M (middle), and 3:7–5:0 Y:M (oldest). Results Between December 2020 and March 2023, 58 children with DS enrolled at 16 sites internationally. Median follow‐up was 17.5 months (range = .0–24.0), with 54 of 58 (93.1%) followed for at least 6 months and 51 of 58 (87.9%) for 12 months. Monthly countable seizure frequency (MCSF) increased with age (median [minimum–maximum] = 1.0 in the youngest [1.0–70.0] and middle [1.0–242.0] age groups and 4.5 [.0–2647.0] in the oldest age group), and remained high, despite use of currently approved antiseizure medications. Language/communication delays were observed early, and developmental stagnation occurred after age 2 years with both instruments. In predictive modeling, chronologic age was the only significant covariate of seizure frequency (effect size = .52, p = .024). MCSF, number of antiseizure medications, age at first seizure, and convulsive status epilepticus were not predictors of language/communication raw scores. Significance In infants and young children with SCN1A + DS, language/communication delay and stagnation were independent of seizure burden. Our findings emphasize that the optimal therapeutic window to prevent language/communication delay is before 3 years of age.