UNASSIGNED: Pediatric video-EEG monitoring is a standard procedure in epilepsy clinics, typically conducted in in-hospital settings.However, hospitalizationis sometimesunnecessary and imposes a burden on children and their families. In response to the rise of telehealth, home video-EEG monitoring has emerged, utilizing portable EEG equipment and video-cameras.
UNASSIGNED: The aim of this study was to assess the feasibility of home video-EEGin a pediatric population.
UNASSIGNED: We conducteda prospective pilot study of twentyhome video-EEG tests in children. We evaluated the quality of EEG and video recordings using a 5-point scale.Demographic, clinical and quality data were comparedto a similar group undergoing in-hospital video-EEG monitoring.
UNASSIGNED: Twenty children aged 2.1-17.2 years (mean 9.57 ± 1.01), 12 females (60 %), underwent home video-EEG. A higher proportion of children with intellectual disability/autism were observed in the home-EEG group compared to the in-hospital group: 12 patients (60 %) vs. 5 (25 %) (p < 0.05*, Fisher exact test). In the ambulatory group patients with developmental and epileptic encephalopathy were overrepresented (7 i.e., 35 % vs. 0), while those withself-limited childhood epilepsy were more prevalent in the in-hospital group (5 i.e., 25 % vs 0) (p < 0.05*, Chi square). In the ambulatory group the reasons for referral were seizure localization/classification in 11 patients (55 %), paroxysmal event classification in 5 (25 %) and quantification of sleep epileptic activity in 4(20 %),similar to the in-hospital group (40 %, 40 % and 20 % respectively, p > 0.05, Chi square). The quality of the EEG recording was higher compared to in-hospital tests: median 5 [IQR 3.25-5] vs 4[IQR 3-4] (p < 0.05*, Mann-Whitney U test), while the quality of video recording was lower compared to in-hospital recordings: median 3[IQR 2.25-4] vs 5[IQR4-5] (p < 0.01**, Mann-Whitney U test).
UNASSIGNED: Home video-EEG monitoring is apromising option forlong-termpediatric EEG monitoring, particularlyfor children with special needs.

The genetic causes of epilepsies and developmental and epileptic encephalopathies (DEE) with onset in early childhood are increasingly recognized. Their outcomes vary from benign to severe disability. In this paper, we wished to retrospectively review the clinical, genetic, EEG, neuroimaging, and outcome data of patients experiencing the onset of epilepsy in the first three years of life, diagnosed and followed up in four Italian epilepsy centres (Epilepsy Centre of San Paolo University Hospital in Milan, Child Neurology and Psychiatry Unit of AUSL-IRCCS di Reggio Emilia, Pediatric Neurology Unit of Vittore Buzzi Children\'s Hospital, Milan, and Child Neurology and Psychiatry Unit, IRCCS Mondino Foundation, Pavia). We included 168 patients (104 with monogenic conditions, 45 with copy number variations (CNVs) or chromosomal abnormalities, and 19 with variants of unknown significance), who had been followed up for a mean of 14.75 years. We found a high occurrence of generalized seizures at onset, drug resistance, abnormal neurological examination, global developmental delay and intellectual disability, and behavioural and psychiatric comorbidities. We also documented differing presentations between monogenic issues versus CNVs and chromosomal conditions, as well as atypical/rare phenotypes. Genetic early-childhood-onset epilepsies and DEE show a very wide phenotypic and genotypic spectrum, with a high risk of complex neurological and neuropsychiatric phenotypes.

UNASSIGNED: The recent evolution of genomics has led to the development of targeted therapeutics, revolutionizing medical approaches. This study aimed to assess the impact of genetic testing on the current epilepsy management paradigm with a specific focus on the variability of outcomes subsequent to genetic diagnoses.
UNASSIGNED: Data were collected retrospectively from a cohort of children aged 1-18 years, diagnosed with refractory epilepsy of confirmed genetic origin. The participants received care at a quaternary care center\'s pediatric neurology clinic from August 2019 to June 2021. The collected information included demographic characteristics, seizure types, EEG findings, imaging abnormalities, genetic diagnoses, attempted treatments, and seizure outcomes.
UNASSIGNED: Among the 210 children with confirmed genetic diagnoses, 74 were included in the study. The gender distribution comprised 45 males and 29 females. Within the cohort, 68/74 exhibited single gene variations, with 23 cases associated with sodium/potassium/calcium channelopathies. Precision medicine could be applied to 25/74 cases. 17/74 children (22.97%) experienced a reduction of up to 50% in seizure frequency due to precision medicine implementation.
UNASSIGNED: While our study indicates the significance of genetic insights in adapting treatment approaches for pediatric epilepsy, it is important to temper our conclusions. The retrospective nature of our study confines our ability to definitively gauge the extent of precision medicine\'s utility. Our findings suggest the potential of genetic information to enhance epilepsy management, but the true impact of precision medicine can only be established through prospective investigations.

OBJECTIVE: There is growing evidence that ketogenic dietary therapy (KDT) can be safely and efficiently used in young children, but little evidence exists on its use in newborns. Developmental and epileptic encephalopathies starting in the neonatal period or early infancy usually present a poor prognosis. The aim of this study was to evaluate effectiveness, safety, and survival of infants younger than 3 months of age with drug-resistant epilepsy in whom KDT was used.
METHODS: A retrospective study was conducted to evaluate neonates and infants younger than 3 months who started KDT for drug-resistant developmental and epileptic encephalopathies at three referral centers. Data were collected on demographic features, time of epilepsy onset, epilepsy syndrome, seizure type, seizure frequency at diet onset, etiology, details regarding diet initiation, type of ketogenic formula, breastfeeding, route of administration, blood ketones, growth, length of NICU stay, and survival.
RESULTS: Nineteen infants younger than 12 weeks of life who received KDT with a minimum follow-up of 1 month were included; 13 had early-infantile developmental and epileptic encephalopathy, four epilepsy of infancy with migrating focal seizures, and two focal epilepsy. A >50% response was observed in 73.7% at 1 month on the diet; 37% achieved a > 75% seizure reduction, and 10.5% became seizure free. At 3 months, a >50% decrease in seizure frequency was observed in 72.2%; 15.8% had a >75% reduction; 21% became seizure free. Overall survival was 76% at 1 year on diet. Incidence of acute and late adverse effects was low and most adverse effects were asymptomatic and manageable.
CONCLUSIONS: Our experience suggests that KDT is safe and effective in newborns and very young infants; however, further studies on the management of the diet in this vulnerable age group are necessary.

Developmental and epileptic encephalopathies (DEEs) are rare neurodevelopmental disorders characterised by early-onset and often intractable seizures and developmental delay/regression, and include Dravet syndrome and Lennox-Gastaut syndrome (LGS). Rufinamide, fenfluramine, stiripentol, cannabidiol and ganaxolone are antiseizure medications (ASMs) with diverse mechanisms of action that have been approved for treating specific DEEs. Rufinamide is thought to suppress neuronal hyperexcitability by preventing the functional recycling of voltage-gated sodium channels from the inactivated to resting state. It is licensed for adjunctive treatment of seizures associated with LGS. Fenfluramine increases extracellular serotonin levels and may reduce seizures via activation of specific serotonin receptors and positive modulation of the sigma-1 receptor. Fenfluramine is licensed for adjunctive treatment of seizures associated with Dravet syndrome and LGS. Stiripentol is a positive allosteric modulator of type-A gamma-aminobutyric acid (GABAA) receptors. As a broad-spectrum inhibitor of cytochrome P450 enzymes, its antiseizure effects may additionally arise through pharmacokinetic interactions with co-administered ASMs. Stiripentol is licensed for treating seizures associated with Dravet syndrome in patients taking clobazam and/or valproate. The mechanism(s) of action of cannabidiol remains largely unclear although multiple targets have been proposed, including transient receptor potential vanilloid 1, G protein-coupled receptor 55 and equilibrative nucleoside transporter 1. Cannabidiol is licensed as adjunctive treatment in conjunction with clobazam for seizures associated with Dravet syndrome and LGS, and as adjunctive treatment of seizures associated with tuberous sclerosis complex. Like stiripentol, ganaxolone is a positive allosteric modulator at GABAA receptors. It has recently been licensed in the USA for the treatment of seizures associated with cyclin-dependent kinase-like 5 deficiency disorder. Greater understanding of the causes of DEEs has driven research into the potential use of other novel and repurposed agents. Putative ASMs currently in clinical development for use in DEEs include soticlestat, carisbamate, verapamil, radiprodil, clemizole and lorcaserin.

Ion channels modulate cellular excitability by regulating ionic fluxes across biological membranes. Pathogenic mutations in ion channel genes give rise to epileptic disorders that are among the most frequent neurological diseases affecting millions of individuals worldwide. Epilepsies are triggered by an imbalance between excitatory and inhibitory conductances. However, pathogenic mutations in the same allele can give rise to loss-of-function and/or gain-of-function variants, all able to trigger epilepsy. Furthermore, certain alleles are associated with brain malformations even in the absence of a clear electrical phenotype. This body of evidence argues that the underlying epileptogenic mechanisms of ion channels are more diverse than originally thought. Studies focusing on ion channels in prenatal cortical development have shed light on this apparent paradox. The picture that emerges is that ion channels play crucial roles in landmark neurodevelopmental processes, including neuronal migration, neurite outgrowth, and synapse formation. Thus, pathogenic channel mutants can not only cause epileptic disorders by altering excitability, but further, by inducing morphological and synaptic abnormalities that are initiated during neocortex formation and may persist into the adult brain.

Biallelic variants of RARS1, a gene that encodes the cytoplasmic tRNA synthetase for arginine (ArgRS), are associated with central nervous system (CNS) manifestations, such as hypomyelinating leukodystrophy-9 and developmental and epileptic encephalopathy (DEE). This study aimed to better understand the RARS1 biallelic mutations and the associated phenotypes, particularly in patients with DEE.
We identified two patients with RARS1 biallelic mutations and functionally validated these mutations in vitro. Furthermore, we performed a review of the literature.
Two patients with hypomyelinating leukodystrophy were found to have RARS1 biallelic variants (Patient 1: c.1535G>A (p.Arg512Gln) and c.1382G>A (p.Arg461His); Patient 2: homozygous variants c.5A>T (p.Asp2Val)). Patient 2 had a severe clinical manifestation of DEE. A review of the literature identified 27 patients from five studies. Among the 29 patients, intellectual disability, developmental delay, and hypomyelination were the common symptoms, while 13 of them exhibited DEE and malformations of cortical development. Of the 25 variants identified, c.5A>G (p.Asp2Gly) was identified in 10 patients. ArgRS protein expression and stability were substantially reduced in the two newly identified patients.
Patients with RARS1 biallelic mutations frequently exhibit DEE, a severe phenotype, along with hypomyelinating leukodystrophy. Besides its effects on the white matter, this mutation also influences cortical development. Moreover, the variants c.5A>T (p.Asp2Val), c.1382G>A (p.Arg461His), and c.1535G>A (p.Arg512Gln) are pathogenic and affect the expression of ArgRS by reducing the protein stability.

Variants of SEMA6B have been identified in an increasing number of patients, often presenting with progressive myoclonus epilepsy (PME), and to lesser extent developmental encephalopathy, with or without epilepsy. The exon 17 is mainly involved, with truncating mutations causing the production of aberrant proteins with toxic gain of function. Herein, we describe three adjunctive patients carrying de novo truncating SEMA6B variants in this exon (c.1976delC and c.2086C > T novel; c.1978delC previously reported). These subjects presented with PME preceded by developmental delay, motor and cognitive impairment, worsening myoclonus, and epilepsy with polymorphic features, including focal to bilateral seizures in two, and non-convulsive status epilepticus in one. The evidence of developmental delay in these cases suggests their inclusion in the \"PME plus developmental delay\" nosological group. This work further expands our knowledge of SEMA6B variants causing PMEs. However, the data to date available confirms that phenotypic features do not correlate with the type or location of variants, aspects that need to be further clarified by future studies.

This study was undertaken to evaluate the long-term safety and effectiveness of fenfluramine in patients with Lennox-Gastaut syndrome (LGS).
Eligible patients with LGS who completed a 14-week phase 3 randomized clinical trial enrolled in an open-label extension (OLE; NCT03355209). All patients were initially started on .2 mg/kg/day fenfluramine and after 1 month were titrated by effectiveness and tolerability, which were assessed at 3-month intervals. The protocol-specified treatment duration was 12 months, but COVID-19-related delays resulted in 142 patients completing their final visit after 12 months.
As of October 19, 2020, 247 patients were enrolled in the OLE. Mean age was 14.3 ± 7.6 years (79 [32%] adults) and median fenfluramine treatment duration was 364 days; 88.3% of patients received 2-4 concomitant antiseizure medications. Median percentage change in monthly drop seizure frequency was -28.6% over the entire OLE (n = 241) and -50.5% at Month 15 (n = 142, p < .0001); 75 of 241 patients (31.1%) experienced ≥50% reduction in drop seizure frequency. Median percentage change in nondrop seizure frequency was -45.9% (n = 192, p = .0038). Generalized tonic-clonic seizures (GTCS) and tonic seizures were most responsive to treatment, with median reductions over the entire OLE of 48.8% (p < .0001, n = 106) and 35.8% (p < .0001, n = 186), respectively. A total of 37.6% (95% confidence interval [CI] = 31.4%-44.1%, n = 237) of investigators and 35.2% of caregivers (95% CI = 29.1%-41.8%, n = 230) rated patients as Much Improved/Very Much Improved on the Clinical Global Impression of Improvement scale. The most frequent treatment-emergent adverse events were decreased appetite (16.2%) and fatigue (13.4%). No cases of valvular heart disease (VHD) or pulmonary arterial hypertension (PAH) were observed.
Patients with LGS experienced sustained reductions in drop seizure frequency on fenfluramine treatment, with a particularly robust reduction in frequency of GTCS, the key risk factor for sudden unexpected death in epilepsy. Fenfluramine was generally well tolerated; VHD or PAH was not observed long-term. Fenfluramine may provide an important long-term treatment option for LGS.

UNASSIGNED: The appropriate management of patients with Dravet Syndrome (DS) is challenging, given the severity of symptoms and the burden of the disease for patients and caregivers. This study aimed to identify, through a qualitative methodology and a Delphi consensus-driven process, a set of recommendations for the management of DS to guide clinicians in the assessment of the clinical condition and quality of life (QoL) of DS patients, with a special focus on patient- and caregiver-reported outcomes (PROs).
UNASSIGNED: This study was conducted in five phases, led by a multidisciplinary scientific committee (SC) including pediatric neurologists, epileptologists, a neuropsychologist, an epilepsy nurse, and members of DS patient advocates. In phases 1 and 2, a questionnaire related to patients\' QoL was prepared and answered by caregivers and the SC. In phase 3, the SC generated, based on these answers and on a focus group discussion, a 70-item Delphi questionnaire, covering six topic categories on a nine-point Likert scale. In phase 4, 32 panelists, from different Spanish institutions and with a multidisciplinary background, answered the questionnaire. Consensus was obtained and defined as strong or moderate if ≥80% and 67-79% of panelists, respectively, rated the statement with ≥7. Phase 5 consisted of the preparation of the manuscript.
UNASSIGNED: The panelists agreed on a total of 69 items (98.6%), 54 (77.14%), and 15 (21.43%) with strong and moderate consensus, respectively. The experts\' recommendations included the need for frequent assessment of patient and caregivers QoL parameters. The experts agreed that QoL should be assessed through specific questionnaires covering different domains. Likewise, the results showed consensus regarding the regular evaluation of several clinical parameters related to neurodevelopment, attention, behavior, other comorbidities, and sudden unexpected death in epilepsy (SUDEP). A consensus was also reached on the instruments, specific parameters, and caregivers\' education in the routine clinical management of patients with DS.
UNASSIGNED: This consensus resulted in a set of recommendations for the assessment of clinical and QoL parameters, including PROs, related to the general evaluation of QoL, neurodevelopment, attention, behavior, other comorbidities affecting QoL, SUDEP, and QoL of caregivers/relatives and patients with DS.