To review the evolution of the concept of epileptic encephalopathy during the course of past years and analyze how the current definition might impact on both clinical practice and research.
...Developmental delay in children with epilepsy could be the expression of the cause, consequence of intense epileptiform activity (seizures and EEG abnormalities), or because of the combination of both factors. Therefore, the current International League Against Epilepsy classification identified three electroclinical entities that are those of developmental encephalopathy, epileptic encephalopathy, and developmental and epileptic encephalopathy (DEE). Many biological pathways could be involved in the pathogenesis of DEEs. DNA repair, transcriptional regulation, axon myelination, metabolite and ion transport, and peroxisomal function could all be involved in DEE. Also, epilepsy and epileptiform discharges might impact on cognition via several mechanisms, although they are not fully understood.
The correct and early identification of cause in DEE might increase the chances of a targeted treatment regimen. Interfering with neurobiological processes of the disease will be the most successful way in order to improve both the cognitive disturbances and epilepsy that are the key features of DEE.
Mutations in SCN2A, a gene encoding the voltage-gated sodium channel Nav1.2, have been associated with a spectrum of epilepsies and neurodevelopmental disorders. Here, we report the phenotypes of 71 ...patients and review 130 previously reported patients. We found that (i) encephalopathies with infantile/childhood onset epilepsies (≥3 months of age) occur almost as often as those with an early infantile onset (<3 months), and are thus more frequent than previously reported; (ii) distinct phenotypes can be seen within the late onset group, including myoclonic-atonic epilepsy (two patients), Lennox-Gastaut not emerging from West syndrome (two patients), and focal epilepsies with an electrical status epilepticus during slow sleep-like EEG pattern (six patients); and (iii) West syndrome constitutes a common phenotype with a major recurring mutation (p.Arg853Gln: two new and four previously reported children). Other known phenotypes include Ohtahara syndrome, epilepsy of infancy with migrating focal seizures, and intellectual disability or autism without epilepsy. To assess the response to antiepileptic therapy, we retrospectively reviewed the treatment regimen and the course of the epilepsy in 66 patients for which well-documented medical information was available. We find that the use of sodium channel blockers was often associated with clinically relevant seizure reduction or seizure freedom in children with early infantile epilepsies (<3 months), whereas other antiepileptic drugs were less effective. In contrast, sodium channel blockers were rarely effective in epilepsies with later onset (≥3 months) and sometimes induced seizure worsening. Regarding the genetic findings, truncating mutations were exclusively seen in patients with late onset epilepsies and lack of response to sodium channel blockers. Functional characterization of four selected missense mutations using whole cell patch-clamping in tsA201 cells-together with data from the literature-suggest that mutations associated with early infantile epilepsy result in increased sodium channel activity with gain-of-function, characterized by slowing of fast inactivation, acceleration of its recovery or increased persistent sodium current. Further, a good response to sodium channel blockers clinically was found to be associated with a relatively small gain-of-function. In contrast, mutations in patients with late-onset forms and an insufficient response to sodium channel blockers were associated with loss-of-function effects, including a depolarizing shift of voltage-dependent activation or a hyperpolarizing shift of channel availability (steady-state inactivation). Our clinical and experimental data suggest a correlation between age at disease onset, response to sodium channel blockers and the functional properties of mutations in children with SCN2A-related epilepsy.
Summary
We report the proceedings of the First International new‐onset refractory status epilepticus (NORSE) and febrile infection‐related epilepsy syndrome (FIRES) Symposium. To promote awareness of ...this condition and foster research efforts, we conveyed the First International new‐onset refractory status epilepticus (NORSE) and febrile infection‐related epilepsy syndrome (FIRES) Symposium. The conference was supported by The NORSE Institute (http://www.norseinstitute.org). This article summarizes the discussions that were held during the Symposium and presents our strategy to unravel the cause of these disorders and to improve patient care. The standardized definitions for these disorders that have been developed, are required to improve communication and facilitate the development of multicenter registries and biobanks. A distinction between childhood‐ and adult‐onset forms of the syndrome is not supported by strong scientific evidence and it is argued that both should be studied together. Although the pathophysiology remains elusive, nascent evidence suggests a role for a postinfectious cytokine‐mediated mechanism, which should be further investigated. It also appears important to develop tools for their early recognition and prompt treatment. Recent evidence suggests that specific electroencephalography (EEG) features might be helpful. The optimal treatment options remain to be determined; immune therapies are usually disappointing, but the ketogenic diet has proved effective in uncontrolled trials. NORSE and FIRES represent a very delicate clinical situation with specific communication issues between physicians and with patients and families. Standardized consensus definitions and a multidisciplinary multicenter strategy will help research efforts and improve clinical care for patients with NORSE and FIRES.
In 2017, the International League Against Epilepsy (ILAE) Classification of Epilepsies described the “genetic generalized epilepsies” (GGEs), which contained the “idiopathic generalized epilepsies” ...(IGEs). The goal of this paper is to delineate the four syndromes comprising the IGEs, namely childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and epilepsy with generalized tonic–clonic seizures alone. We provide updated diagnostic criteria for these IGE syndromes determined by the expert consensus opinion of the ILAE’s Task Force on Nosology and Definitions (2017–2021) and international external experts outside our Task Force. We incorporate current knowledge from recent advances in genetic, imaging, and electroencephalographic studies, together with current terminology and classification of seizures and epilepsies. Patients that do not fulfill criteria for one of these syndromes, but that have one, or a combination, of the following generalized seizure types: absence, myoclonic, tonic‐clonic and myoclonic‐tonic‐clonic seizures, with 2.5–5.5 Hz generalized spike‐wave should be classified as having GGE. Recognizing these four IGE syndromes as a special grouping among the GGEs is helpful, as they carry prognostic and therapeutic implications.
Summary
We convened an international group of experts to standardize definitions of New‐Onset Refractory Status Epilepticus (NORSE), Febrile Infection‐Related Epilepsy Syndrome (FIRES), and related ...conditions. This was done to enable improved communication for investigators, physicians, families, patients, and other caregivers. Consensus definitions were achieved via email messages, phone calls, an in‐person consensus conference, and collaborative manuscript preparation. Panel members were from 8 countries and included adult and pediatric experts in epilepsy, electroencephalography (EEG), and neurocritical care. The proposed consensus definitions are as follows: NORSE is a clinical presentation, not a specific diagnosis, in a patient without active epilepsy or other preexisting relevant neurological disorder, with new onset of refractory status epilepticus without a clear acute or active structural, toxic or metabolic cause. FIRES is a subcategory of NORSE, applicable for all ages, that requires a prior febrile infection starting between 2 weeks and 24 hours prior to onset of refractory status epilepticus, with or without fever at onset of status epilepticus. Proposed consensus definitions are also provided for Infantile Hemiconvulsion‐Hemiplegia and Epilepsy syndrome (IHHE) and for prolonged, refractory and super‐refractory status epilepticus. This document has been endorsed by the Critical Care EEG Monitoring Research Consortium. We hope these consensus definitions will promote improved communication, permit multicenter research, and ultimately improve understanding and treatment of these conditions.
Close to one-third of patients with epilepsies are refractory to current anti-seizure medications; however, trials with cenobamate suggest effectiveness in such patients with focal onset seizures. We ...searched for data published or otherwise reported on cenobamate and outlined these here. Despite being marketed in the USA, few studies are yet published in full, and trials are ongoing. Nevertheless, cenobamate showed potential for a high degree of efficacy in reducing seizures with an unprecedented seizure-free rate of up to 28%. Rare cases of hypersensitivity reactions seen in early trials seem to be avoided by the current recommended titration schedule. Other adverse events were rated mild-to-moderate and most commonly included dizziness, drowsiness, and headache. If data are confirmed in further published trials, cenobamate will be a welcome new treatment and further analyses may identify those that will benefit the most.
Objective
Dravet syndrome (DS) is a drug‐resistant, infantile onset epilepsy syndrome with multiple seizure types and developmental delay. In recently published randomized controlled trials, ...fenfluramine (FFA) proved to be safe and effective in DS.
Methods
DS patients were treated with FFA in the Zogenix Early Access Program at four Italian pediatric epilepsy centers. FFA was administered as add‐on, twice daily at an initial dose of 0.2 mg/kg/d up to 0.7 mg/kg/d. Seizures were recorded in a diary. Adverse events and cardiac safety (with Doppler echocardiography) were investigated every 3 to 6 months.
Results
Fifty‐two patients were enrolled, with a median age of 8.6 years (interquartile range IQR = 4.1‐13.9). Forty‐five (86.5%) patients completed the efficacy analysis. The median follow‐up was 9.0 months (IQR = 3.2‐9.5). At last follow‐up visit, there was a 77.4% median reduction in convulsive seizures. Thirty‐two patients (71.1%) had a ≥50% reduction of convulsive seizures, 24 (53.3%) had a ≥75% reduction, and five (11.1%) were seizure‐free. The most common adverse event was decreased appetite (n = 7, 13.4%). No echocardiographic signs of cardiac valvulopathy or pulmonary hypertension were observed. There was no correlation between type of genetic variants and response to FFA.
Significance
In this real‐world study, FFA provided a clinically meaningful reduction in convulsive seizure frequency in the majority of patients with DS and was well tolerated.
Objective
This study was undertaken to develop consensus‐based recommendations for the management of adult and pediatric patients with new onset refractory status epilepticus (NORSE)/febrile ...infection‐related epilepsy syndrome (FIRES) based on best evidence and experience.
Methods
The Delphi methodology was followed. A facilitator group of nine experts was established, who defined the scope, users, and suggestions for recommendations. Following a review of the current literature, recommendation statements concerning diagnosis, treatment, and research directions were generated, which were then rated on a scale of 1 (strongly disagree) to 9 (strongly agree) by a panel of 48 experts in the field. Consensus that a statement was appropriate was reached if the median score was ≥7 and inappropriate if the median score was ≤3. The analysis of evidence was mapped to the results of each statement included in the Delphi survey.
Results
Overall, 85 recommendation statements achieved consensus. The recommendations are divided into five sections: (1) disease characteristics; (2) diagnostic testing and sampling; (3) acute treatment; (4) treatment in the postacute phase; and (5) research, registries, and future directions in NORSE/FIRES. The detailed results and discussion of all 85 statements are outlined herein. A corresponding summary of findings and practical flowsheets are presented in a companion article.
Significance
This detailed analysis offers insight into the supporting evidence and the current gaps in the literature that are associated with expert consensus statements related to NORSE/FIRES. The recommendations generated by this consensus can be used as a guide for the diagnosis, evaluation, and management of patients with NORSE/FIRES, and for planning of future research.
Developmental encephalopathies, including intellectual disability and autistic spectrum disorder, are frequently associated with infant epilepsy. Epileptic encephalopathy is used to describe an ...assumed causal relationship between epilepsy and developmental delay. Developmental encephalopathies pathogenesis more independent from epilepsy is supported by the identification of several gene variants associated with both developmental encephalopathies and epilepsy, the possibility for gene-associated developmental encephalopathies without epilepsy, and the continued development of developmental encephalopathies even when seizures are controlled. Hence, 'developmental and epileptic encephalopathy' may be a more appropriate term than epileptic encephalopathy. This update considers the best studied 'developmental and epileptic encephalopathy' gene variants for illustrative support for 'developmental and epileptic encephalopathy' over epileptic encephalopathy. Moreover, the interaction between epilepsy and developmental encephalopathies is considered with respect to influence on treatment decisions. Continued research in genetic testing will increase access to clinical tests, earlier diagnosis, better application of current treatments, and potentially provide new molecular-investigated treatments.
Summary
Objective
PCDH19‐related epilepsy is an epileptic syndrome with infantile onset, characterized by clustered and fever‐induced seizures, often associated with intellectual disability (ID) and ...autistic features. The aim of this study was to analyze a large cohort of patients with PCDH19‐related epilepsy and better define the epileptic phenotype, genotype‐phenotype correlations, and related outcome‐predicting factors.
Methods
We retrospectively collected genetic, clinical, and electroencephalogram (EEG) data of 61 patients with PCDH19‐related epilepsy followed at 15 epilepsy centers. All consecutively performed EEGs were analyzed, totaling 551. We considered as outcome measures the development of ID, autistic spectrum disorder (ASD), and seizure persistence. The analyzed variables were the following: gender, age at onset, age at study, genetic variant, fever sensitivity, seizure type, cluster occurrence, status epilepticus, EEG abnormalities, and cognitive and behavioral disorders. Receiver operating characteristic curve analysis was performed to evaluate the age at which seizures might decrease in frequency.
Results
At last follow‐up (median = 12 years, range = 1.9‐42.1 years), 48 patients (78.7%) had annual seizures/clusters, 13 patients (21.3%) had monthly to weekly seizures, and 12 patients (19.7%) were seizure‐free for ≥2 years. Receiver operating characteristic analysis showed a significant decrease of seizure frequency after the age of 10.5 years (sensitivity = 81.0%, specificity = 70.0%). Thirty‐six patients (59.0%) had ID and behavioral disturbances. ASD was present in 31 patients. An earlier age at epilepsy onset emerged as the only predictive factor for ID (P = 0.047) and ASD (P = 0.014). Conversely, age at onset was not a predictive factor for seizure outcome (P = 0.124).
Significance
We found that earlier age at epilepsy onset is related to a significant risk for ID and ASD. Furthermore, long‐term follow‐up showed that after the age of 10 years, seizures decrease in frequency and cognitive and behavioral disturbances remain the primary clinical problems.
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