Pathogenic variants in SLC6A1 cause a neurodevelopmental disorder characterized by developmental delay with behavioral disturbances, seizures, often pharmacoresistant, and a spectrum of movement disorders such as ataxia. A similar triad is observed in other monogenic conditions, such as SLC2A1, CHD2, and CACNA1A-related disorders, where acetazolamide (ACZ) has shown beneficial effects. We assessed the efficacy of ACZ as an adjunctive treatment in patients with SLC6A1-related neurodevelopmental disorder (SLC6A1-NDD) and drug-resistant seizures. We recruited patients with genetically confirmed pathogenic SLC6A1 variants and drug-resistant seizures treated with add-on ACZ. The medical records were reviewed to evaluate changes in seizure frequency and severity, and to document adverse events. Improvements in ataxia and social interaction were determined by clinical judgment together with caregiver reports. Six patients with a mean age of 7 years were included. The mean dose of ACZ was 16.2 mg/kg/day, and the mean treatment duration was 30 months. Three (50%) patients achieved full seizure remission, and the remaining three patients had a reduction in seizure frequency ranging from 50 to 90%. Except for weight loss in one patient, no serious adverse effects were reported. Three out of four patients with baseline ataxia showed improvement. Caregivers noted improvement in social interaction and school engagement in five out of six patients. ACZ may offer a promising therapeutic option for drug-resistant SLC6A1-related seizures. Prospective studies with larger cohorts and standardized outcome measures are necessary to confirm the efficacy and long-term safety of ACZ in this population. PLAIN LANGUAGE SUMMARY: Pathogenic SLC6A1 variants in children cause developmental delay with behavioral issues, seizures, and often ataxia. In six children with drug-resistant seizures, adjunctive acetazolamide (ACZ) led to seizure freedom in three and a 50-90% reduction in the others. Improvement in ataxia and behavior, with better social and school performances, was reported. One child had mild weight loss. These early findings suggest ACZ may be a safe, effective, and affordable option for SLC6A1-related neurodevelopmental disorder when standard treatments fail, warranting further study.

OBJECTIVE:To determine the etiology of Infantile Epileptic Spasms Syndrome (IESS) in Azerbaijan, and to evaluate treatment response and outcome. METHODS:For the seventy children referred for ongoing IESS over a 3-year period, we studied medical history, physical examination, EEG, neuroimaging and genetic testing. RESULTS:37.1% were born to consanguineous parents. The etiology was genetic in 50.0% of cases and brain injury in 17.1%. Epileptic spasms persisted for a median of 11.5 months. 72.9% of children experienced additional seizure types. Consanguinity, genetic etiology, and conventional treatment were significant predictors of mortality (p = 0.016, p = 0.034, and p = 0.002, respectively), with a 7.7-fold increased risk of death in children of consanguineous parents. In multivariate analysis, genetic etiology and treatment regimens that did not include first-line therapies such as vigabatrin and hormones remained significant risk factors. The mean duration of epileptic spasms was shortest with hormonal therapy (5.8 months), compared to vigabatrin (14.8 months), or other anti-seizure medications alone (30.6months). The risk of global developmental delay was 3.4 times higher in children with additional seizure types, and 37-times higher in those with neurological signs. SIGNIFICANCE:Genetic etiology, parental consanguinity, and treatment response that are correlated with increased mortality, are modifiable factors requiring education.

Abstract CHD2‐related epilepsy is characterized by early‐onset photosensitive myoclonic epilepsy with developmental delay and a high rate of pharmacoresistance. We sought to evaluate the efficacy of acetazolamide (ACZ) in CHD2‐related epilepsy, due to ACZ's unexpected efficacy in our first patient harboring a pathogenic CHD2 variant. We collected patients from different Eastern European countries with drug‐resistant CHD2‐related epilepsy who were then treated with ACZ. Patients underwent video EEG before and during ACZ treatment. In a zebrafish model of CHD2‐related epilepsy, ictal‐like events were recorded 5 days post‐fertilization after overnight ACZ exposure. Developmental delay preceded the onset of seizures in 10 of the 12 patients. Four had ataxia, and 6 exhibited autistic features. Seizures, primarily myoclonic, began at an average age of 3.4 years and were photosensitive in all 12 patients. Add‐on ACZ treatment controlled photosensitive seizures in all patients: 6 became seizure‐free, and in the remaining 6, seizure frequency decreased by over 75%. Four patients transitioned to ACZ monotherapy. The median follow‐up was 13 months. In the zebrafish model, ACZ exposure reduced ictal‐like events by 72%. ACZ, a well‐tolerated and cost‐effective medication, could be a good option for CHD2‐related epilepsy, predominantly manifesting with myoclonic seizures and photosensitivity. Plain Language Summary Epilepsy associated with CHD2 mutations is often pharmacoresistant and associated with developmental delay and eventually ataxia. There are several generalized seizure types, including generalized tonic–clonic seizures, but the most characteristic are jerks triggered by light stimulation. We collected 12 patients who received acetazolamide, a drug usually given as a diuretic and registered as a mild antiseizure medication. All jerks triggered by light disappeared while the frequency of spontaneous seizures decreased by over 75%. Further studies are needed to confirm this promising finding and identify the mechanism by which an old compound seems to have such a specific antiseizure effect.

Most cases of herpes simplex virus 1 (HSV-1) encephalitis (HSE) remain unexplained1,2. Here, we report on two unrelated people who had HSE as children and are homozygous for rare deleterious variants of TMEFF1, which encodes a cell membrane protein that is preferentially expressed by brain cortical neurons. TMEFF1 interacts with the cell-surface HSV-1 receptor NECTIN-1, impairing HSV-1 glycoprotein D- and NECTIN-1-mediated fusion of the virus and the cell membrane, blocking viral entry. Genetic TMEFF1 deficiency allows HSV-1 to rapidly enter cortical neurons that are either patient specific or derived from CRISPR-Cas9-engineered human pluripotent stem cells, thereby enhancing HSV-1 translocation to the nucleus and subsequent replication. This cellular phenotype can be rescued by pretreatment with type I interferon (IFN) or the expression of exogenous wild-type TMEFF1. Moreover, ectopic expression of full-length TMEFF1 or its amino-terminal extracellular domain, but not its carboxy-terminal intracellular domain, impairs HSV-1 entry into NECTIN-1-expressing cells other than neurons, increasing their resistance to HSV-1 infection. Human TMEFF1 is therefore a host restriction factor for HSV-1 entry into cortical neurons. Its constitutively high abundance in cortical neurons protects these cells from HSV-1 infection, whereas inherited TMEFF1 deficiency renders them susceptible to this virus and can therefore underlie HSE.

Background and purposeKetogenic diet (KD) is an emerging treatment option for super-refractory status epilepticus (SRSE). We evaluated the effectiveness of KD in patients presenting SRSE including NORSE (and its subcategory FIRES).MethodsA retrospective review of the medical records was performed at the Necker Enfants Malades Hospital. All children with SRSE in whom KD was started during the last 10 years were included. A systematic search was carried out for all study designs, including at least one patient of any age with SRSE in whom KD was started. The primary outcome was the responder rate and Kaplan–Meier survival curves were generated for the time-to-KD response. As secondary outcomes, Cox proportional hazard models were created to assess the impact of NORSE-related factors on KD efficacy.ResultsSixteen children received KD for treatment of SRSE, and three had NORSE presentation (one infectious etiology, two FIRES). In medical literature, 1,613 records were initially identified, and 75 were selected for review. We selected 276 patients receiving KD during SRSE. The most common etiology of SRSE was acute symptomatic (21.3%), among these patients, 67.7% presented with NORSE of immune and infectious etiologies. Other etiologies were remote symptomatic (6.8%), progressive symptomatic (6.1%), and SE in defined electroclinical syndromes (14.8%), including two patients with genetic etiology and NORSE presentation. The etiology was unknown in 50.7% of the patients presenting with cryptogenic NORSE, of which 102 presented with FIRES. Overall, most patients with NORSE benefit from KD (p < 0.004), but they needed a longer time to achieve RSE resolution after starting KD compared with other non-NORSE SRSE (p = 0.001). The response to KD in the NORSE group with identified etiology compared to the cryptogenic NORSE was significantly higher (p = 0.01), and the time to achieve SE resolution after starting KD was shorter (p = 0.04).ConclusionsThe search for underlying etiology should help to a better-targeted therapy. KD can have good efficacy in NORSE; however, the time to achieve SE resolution seems to be longer in cryptogenic cases. These findings highlight the therapeutic role of KD in NORSE, even though this favorable response needs to be better confirmed in prospective controlled studies.

Study Objectives:To describe early diagnostic clues in Cyclin-Dependent Kinase-Like 5 (CDKL5) refractory encephalopathy, to improve treatment strategies.Methods:We retrospectively studied 35 patients (25 females, 10 males) with CDKL5 gene mutations or deletion, focusing on their early seizure semiology, the electroencephalogram (EEG) pattern, the effect of treatment, and developmental outcome.Results:The first seizures were recognizable and consisted of tonic, then clonic, and spasms phases, occurring in sleep at a median age of 6 weeks. Clusters of spasms were observed in quiet sleep or slow-wave sleep (SWS), with screaming, staring, and arms' extension that mimicked sleep terror in 28 of 35 patients (80%). Programmed awakening prevented these spasms in 9 of 16 patients and small doses of clonazepam given at night improved epilepsy in 14 of 23 patients.Conclusions:Peculiar seizures with spasms starting in SWS are an early diagnostic clue in infants with CDKL5 encephalopathy. Sleep video-EEG polygraphy is an easy tool to disclose these early seizures and epileptic spasms in infants during the first months of life while polysomnography is unlikely to give a contribution at that early age. While conventional antiepileptic treatment and corticosteroids are poorly, transiently, or not efficient, therapeutic strategy used for sleep terror could help, although the mechanism of spasms generation in SWS needs to be elucidated.

OBJECTIVE:Many early-onset epilepsies present as developmental and epileptic encephalopathy associated with refractory seizures, altered psychomotor development, and disorganized interictal cortical activity. Abnormal upregulation of specific N-methyl-d-aspartate receptor (NMDA-R) subunits is being disentangled as one of the mechanisms of severe early-onset epilepsies. In tuberous sclerosis complex (TSC), upregulation of the GluN2C subunit of the NMDA-R with slow deactivation kinetic results in increased neuronal excitation and synchronization.METHODS:Starting from an available GluN2C/D antagonist, NMDA-R-modulating compounds were developed and screened using a patch clamp on neuronal culture to select those with the strongest inhibitory effect on glutamatergic NMDA currents. For these selected compounds, blood pharmacokinetics and passage through the blood-brain barrier were studied. We tested the effect of the most promising compounds on epileptic activity in Tsc1+/- mice brain slices with multielectrode array, and then in vivo at postnatal ages P14-P17, comparable with the usual age at epilepsy onset in human TSC.RESULTS:Using a double-electrode voltage clamp on isolated NMDA currents, we identified the most prominent antagonists of the GluN2C subunit with no effect on GluN2A as a means of preventing side effects. The best compound passing through the blood-brain barrier was selected. Applied in vivo in six Tsc1+/- mice at P14-P17, this compound reduced or completely stopped spontaneous seizures in four of them, and decreased the background activity disorganization. Furthermore, ictal-like discharges stopped on a human brain sample from an infant with epilepsy due to TSC.INTERPRETATION:Subunit-selective inhibition is a valuable target for developing drugs for severe epilepsies resulting from an upregulation of NMDA-R subunit-mediated transmission.

Objective Aiming to detect associations between neuroradiologic and EEG evaluations and long-term clinical outcome in order to detect possible prognostic factors, a detailed clinical and neuroimaging characterization of 67 cases of Aicardi syndrome (AIC), collected through a multicenter collaboration, was performed. Methods Only patients who satisfied Sutton diagnostic criteria were included. Clinical outcome was assessed using gross motor function, manual ability, and eating and drinking ability classification systems. Brain imaging studies and statistical analysis were reviewed. Results Patients presented early-onset epilepsy, which evolved into drug-resistant seizures. AIC has a variable clinical course, leading to permanent disability in most cases; nevertheless, some cases presented residual motor abilities. Chorioretinal lacunae were present in 86.56% of our patients. Statistical analysis revealed correlations between MRI, EEG at onset, and clinical outcome. On brain imaging, 100% of the patients displayed corpus callosum malformations, 98% cortical dysplasia and nodular heterotopias, and 96.36% intracranial cysts (with similar rates of 2b and 2d). As well as demonstrating that posterior fossa abnormalities (found in 63.63% of cases) should also be considered a common feature in AIC, our study highlighted the presence (in 76.36%) of basal ganglia dysmorphisms (never previously reported). Conclusion The AIC neuroradiologic phenotype consists of a complex brain malformation whose presence should be considered central to the diagnosis. Basal ganglia dysmorphisms are frequently associated. Our work underlines the importance of MRI and EEG, both for correct diagnosis and as a factor for predicting long-term outcome. Classification of Evidence This study provides Class II evidence that for patients with AIC, specific MRI abnormalities and EEG at onset are associated with clinical outcomes.

Purpose: To report the effect of the ketogenic diet (KD) on non-convulsive status epilepticus (NCSE) due to Angelman syndrome (AS) in two members of a large Georgian family affected by a novel frameshift variant in the UBE3A gene (NM_000462.3). Methods: We evaluated two members of this family who were affected with clinical and EEG features of AS. Clinical history with special emphasis on development, seizure type, frequency, and treatment was reviewed. Routine and long-term video EEG monitoring were conducted, particularly during NCSE. A non-fasting inpatient KD protocol was implemented using blended food orally with full administration of 4:1 (fat to non-fat) ratio. Urine ketone bodies (KBs), measured with urine ketone acetone strips readings, reached 150 mg/dL in both patients. Results: Patients had characteristic signs of AS and presented with epilepsy between the age of 2-4 years. As methylation tests were negative, next generation sequencing disclosed a c.2365del variant. For both, NCSE was revealed by cognitive deterioration and did not respond to anti-seizure medication. As recommended, IV pyridoxine, benzodiazepines, and valproic acid were administered, but without success. For both patients, NCSE resolved on the second-third day of KD initiation, before the appearance of ketonuria and resulting in improved communication, mood and sleep. Conclusion: KD is safe and effective for the treatment of NCSE due to AS. Resolution before the appearance of ketone bodies points to a possible mechanism of action of KD.

A child with a de novo STXBP1 heterozygous missense mutation, believed to be a pathogenic variant, presented with clustering focal seizures affecting both hemispheres. These had begun at the age of 10 months with a phenotype similar to that of PCDH19 encephalopathy. MRI suggested a similarity to focal cortical dysplasia, though further research is needed. There was no evidence of either suppression-bursts or infantile spasms. This new case adds to the few other cases of patients with STXBP1 mutation in whom imaging features of focal cortical dysplasia on MRI have been reported, implying a possible role of STXBP1 mutation in neuronal migration disorders. If such a mutation with focal seizures is suspected, the possibility of focal cortical dysplasia should be investigated. [Published with video sequences].

L’encéphalopathie CDKL5 est une pathologie génétique produisant une épilepsie pharmacorésistante avec un retard psychomoteur. Il n’y a pas été rapporté de troubles de sommeil auparavant. Nous avons mis en évidence des crises nocturnes particulières, rappelant les terreurs nocturnes, comme critère diagnostique de la maladie. Nous avons réalisé une étude rétrospective incluant 10 patients (âge moyen de diagnostic = 3 mois, 8 filles et 2 garçons), suivis jusqu’à 14 ans, et analysé l’histoire, les caractéristiques des crises, ainsi que les données de la polygraphie EEG vidéo. Les crises nocturnes ont été le premier signe à apparaître. Elles persistaient au cours de l’évolution sous forme de spasmes épileptiques très particuliers car ils survenaient au cours du sommeil nocturne ou diurne chez 100 % de patients, apparaissant de 30 min à 4 heures après l’endormissement. Chez 50 % des enfants, ces événements ressemblaient à des terreurs nocturnes. Les polygraphies EEG ont montré leur origine épileptique. Pour 3 patients les crises pouvaient être prévenues ou atténuées par des réveils programmés pratiqués par les parents. L’encéphalopathie CDKL5 doit être envisagée dans le diagnostic différentiel des terreurs nocturnes. Les spasmes nocturnes sont un symptôme clé pour un diagnostic précoce. L’approche thérapeutique de cette pathologie devrait être réévaluée, ciblant le lien avec le sommeil. Les réveils programmés peuvent alléger les crises. Des enregistrements par PSG vidéo seraient utiles pour comprendre le mécanisme de ces événements et leur lien avec les stades de sommeil.

Two patients with insular and striatal postnatal scar had epileptic spasms (ES) that were asymmetrical and the only seizure type, whereas none of the usual ictal symptoms of insular seizures occurred. Ictal electroencephalography (EEG) showed the high-amplitude slow-wave characteristic of ES. Vigabatrin remained efficient for over 4 years for one patient and right into the third decade for the other one. Such ES are distinct from infantile and late onset spasms. Furthermore, these observations suggest that in ES insular epilepsy triggers paroxysmal activation of the striatum, and that vigabatrin inhibits the striatal startle motor program, thus interrupting the corticostriatal loop.

Introduction: Sodium voltage-gated channel alpha subunit 2 (SCN2A) gene encodes the Nav1.2 subunit of voltage-gated sodium channel in pyramidal neurons. SCN2A gain-of-function mutations are identified more and more often with gene panels and whole exome sequencing. Phenotype ranges from benign neonatal or infantile seizures to severe epileptic encephalopathy. Although large series of patients targeting genetic background point out two main phenotypes with SCN2A encephalopathy, Ohtahara syndrome and malignant migrating partial seizures in infancy (EMPSI), we noticed that in fact, a peculiar clinical and electroencephalogram (EEG) sequence distinct from these syndromes should suggest the diagnosis early. Patients and methods: We report three new cases with de novo SCN2A mutations - 166237617C>A p. (Asp1487Glu), c.407T>G p.(Met136Arg), and c.4633A>G p.(Met1545Val) - diagnosed by direct sequencing or genes panel, their follow-up ranging from 4 to 5 years. Results: For all three patients, seizures started at two days of life and consisted of apnea and cyanosis with partial clonic or tonic, alternating on both sides with, up to 100/day, evolving to generalized tonic-clonic seizures (GTCS) and epileptic spasms by three months. First EEG showed a discontinuous pattern, evolving to multifocal spikes, by 3 (two patients) and 6 months (one). Seizure frequency decreased progressively by the middle or end of the first year of life. Only less frequent GTCS persisted during the second year of life for two patients. Improvement was observed in two patients with sodium channel blocker (phenytoin) used at age of 1 month for one patient and at 2 years for another one. All patients remained with severe psychomotor delay. Discussion: All three infants share a condition different from Ohtahara syndrome in which tonic spasms predominate and suppression-burst pattern is obvious, and from EMPSI, in which partial migrating discharges involve successively the various parts of the brain including occipital regions with oculoclonic seizures, but there is neither discontinuous pattern nor therapeutic response to sodium channel blockers. Conclusion: Neonatal SCN2A encephalopathy has a recognizable phenotype starting soon after birth with alternating partial motor seizures evolving to infantile spasms and a discontinuous EEG pattern. Seizures improve spontaneously in the first year of life. This electroclinical sequence should indicate the search of SCN2A mutation and suggest the administration of sodium channel blockers. (C) 2020 Elsevier Inc. All rights reserved.

Vigabatrin is indicated as adjunctive therapy for refractory focal seizures. For children, European recommendations indicate maintenance doses varying from 30 to 100 mg/kg/day for this indication. Since cumulated dose was associated with retinal toxicity, it is essential to administrate the lowest effective dose to patients. This work was conducted with the purpose to determine the pediatric doses of vigabatrin that allow a similar exposure than effective doses in adults (2-3 g/day) through a pharmacokinetic (PK) study, using both pediatric and adult data. For this study, we focused on the active S(+) enantiomer of vigabatrin. First, the adult effective exposition range of vigabatrin-S was determined from an adult PK model. Then, this same model was scaled to the pediatric population using allometry and maturation principles to account for growth and development. The ability of the model to predict pediatric data was assessed by comparing population predictions with observed pediatric data. Finally, the extrapolated pediatric model was used to simulate pediatric expositions which were compared to the adult exposition range (36.5-77.9 mg.h/L). From those simulations, we determined that, for children aged between 3 months and 18 years, doses between 40 and 50 mg/kg/day allow vigabatrin-S expositions similar to those found in adults at the recommended posology. We proposed those doses as optimal maintenance doses that may be increased, if necessary, by slow titration.

The aim of this study was to disentangle mechanisms of epileptogenesis in monogenic epilepsies in children. We reviewed paediatric monogenic epilepsies excluding brain malformation or an inborn error of metabolism, but including the gene function whether there is loss‐of‐function or gain‐of‐function, age at gene expression when available, and associated epilepsy syndrome. Genes for which at least five patients with similar epilepsy phenotype had been reported were selected. Three mechanisms are shared by most monogenic epilepsies: (1) excess of N‐methyl‐d‐aspartate (NMDA) transmission activation (NMDA‐pathies); (2) abnormal gamma‐aminobutyric acid (GABA) transmission with reduced inhibition (phasic GABA‐pathies); and (3) tonic activation of extrasynaptic GABAA receptors by extracellular GABA (tonic GABA‐pathies). NMDA‐pathies comprise early epileptic encephalopathy with suppression‐burst, neonatal/infantile benign seizures, West and Lennox–Gastaut syndromes, and encephalopathy with continuous spike waves in slow sleep, thus brief seizures with major interictal spiking. Phasic GABA‐pathies comprise mostly generalized epilepsy with febrile seizures plus and Dravet syndrome, thus long‐lasting seizures with mild interictal spiking. Tonic GABA‐pathies cause epilepsy with myoclonic–atonic seizures and Angelman syndrome, thus major high‐amplitude slow‐wave activity. This pathophysiological approach to monogenic epilepsies provides diagnostic clues and helps to guide treatment strategy.What this paper adds In paediatric monogenic epilepsies, electroclinical patterns point to three main mechanisms: NMDA‐pathies, and phasic and tonic GABA‐pathies. Antiepileptic treatment choice could be guided by each of these mechanisms.

SummaryObjectiveTo describe the mode of onset of SCN8A‐related severe epilepsy in order to facilitate early recognition, and eventually early treatment with sodium channel blockers.MethodsWe reviewed the phenotype of patients carrying a mutation in the SCN8A gene, among a multicentric cohort of 638 patients prospectively followed by several pediatric neurologists. We focused on the way clinicians made the diagnosis of epileptic encephalopathy, the very first symptoms, electroencephalography (EEG) findings, and seizure types. We made genotypic/phenotypic correlation based on epilepsy‐associated missense variant localization over the protein.ResultsWe found 19 patients carrying a de novo mutation of SCN8A, representing 3% of our cohort, with 9 mutations being novel. Age at onset of epilepsy was 1 day to 16 months. We found two modes of onset: 12 patients had slowly emerging onset with rare and/or subtle seizures and normal interictal EEG (group 1). The first event was either acute generalized tonic–clonic seizure (GTCS; Group 1a, n = 6) or episodes of myoclonic jerks that were often mistaken for sleep‐related movements or other movement disorders (Group 1b, n = 6). Seven patients had a sudden onset of frequent tonic seizures or epileptic spasms with abnormal interictal EEG leading to rapid diagnosis of epileptic encephalopathy. Sodium channel blockers were effective or nonaggravating in most cases.SignificanceSCN8A is the third most prevalent early onset epileptic encephalopathy gene and is associated with two modes of onset of epilepsy.