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To study long-term clinical and cognitive outcomes of patients with anti-N-methyl-d-aspartate receptor encephalitis (NMDAR-E), an acute autoimmune neurological disease with severe acute presentations.In this French multicentre retrospective observational cohort study, patients no older than 18 years with a follow-up of at least 2 years were included. Data from clinical and cognitive assessments were collected.Eighty-one patients were included (57 females, 24 males; median age 10 years 7 months [range 1-18 years], median follow-up 40 months [range 25-53 months]). At last follow-up, 35 patients (45%) had cognitive impairment, 48 (70%) had academic difficulties, and 65 (92%) needed rehabilitation. Seventy-one patients (88%) had a modified Rankin Scale score of no more than 2. A higher number of symptoms at diagnosis was associated with cognitive impairment (p = 0.01), while an abnormal electroencephalogram at diagnosis increased the risk of academic difficulties (p = 0.03).Although most children with NMDAR-E seemed to recover from motor disabilities, more than 45% had cognitive and academic difficulties. The initial severity of symptoms seems to have an impact on cognition and academic performances.

γ-Aminobutyric acid (GABA)We collected clinical, electrophysiological, therapeutic, and molecular data from patients with GABAWe gathered the reported patients in three epileptic phenotypes: 15 patients with fever-related epilepsy (40%), 11 with early developmental epileptic encephalopathy (30%), 10 with generalized epilepsy spectrum (27%), and 1 patient without seizures (3%). We did not find a specific phenotype for any gene, but we showed that the location of variants on the transmembrane (TM) segment was associated with a more severe phenotype, irrespective of the GABAGABA

Objective Asparagine‐linked glycosylation 13 (ALG13) deficiencies have been repeatedly described in the literature with the clinical phenotype of a developmental and epileptic encephalopathy (DEE). Most cases were females carrying the recurrent ALG13 de novo variant, p.(Asn107Ser), with normal transferrin electrophoresis. Methods We delineate the phenotypic spectrum of 38 individuals, 37 girls and one boy, 16 of them novel and 22 published, with the most common pathogenic ALG13 variant p.(Asn107Ser) and additionally report the phenotype of three individuals carrying other likely pathogenic ALG13 variants. Results The phenotypic spectrum often comprised pharmacoresistant epilepsy with epileptic spasms, mostly with onset within the first 6 months of life and with spasm persistence in one‐half of the cases. Tonic seizures were the most prevalent additional seizure type. Electroencephalography showed hypsarrhythmia and at a later stage of the disease in one‐third of all cases paroxysms of fast activity with electrodecrement. ALG13‐related DEE was usually associated with severe to profound developmental delay; ambulation was acquired by one‐third of the cases, whereas purposeful hand use was sparse or completely absent. Hand stereotypies and dyskinetic movements including dystonia or choreoathetosis were relatively frequent. Verbal communication skills were absent or poor, and eye contact and pursuit were often impaired. Significance X‐linked ALG13‐related DEE usually manifests as West syndrome with severe to profound developmental delay. It is predominantly caused by the recurrent de novo missense variant p.(Asn107Ser). Comprehensive functional studies will be able to prove or disprove an association with congenital disorder of glycosylation.

Purpose. Several weeks after COVID-19 infection, some children report the persistence or recurrence of functional complaints. This clinical presentation has been referred as “long COVID” in the adult population, and an 18F-FDG brain PET hypometabolic pattern has recently been suggested as a biomarker. Herein, we present a retrospective analysis of 7 paediatric patients with suspected long COVID who were explored by 18F-FDG brain PET exam. Metabolic brain findings were confronted to those obtained in adult patients with long COVID, in comparison to their respective age-matched control groups. Methods. Review of clinical examination, and whole-brain voxel-based analysis of 18F-FDG PET metabolism of the 7 children in comparison to 20 paediatric controls, 35 adult patients with long COVID and 44 healthy adult subjects. Results. Paediatric patients demonstrated a similair brain hypometabolic pattern as that found in adult long COVID patients, involving bilateral medial temporal lobes, brainstem and cerebellum (p-voxel < 0.001, p-cluster < 0.05 FWE-corrected), and also the right olfactory gyrus after small volume correction (p-voxel = 0.010 FWE-corrected), with partial recovery in two children at follow-up. Conclusion. These results provide arguments in favour of possible long COVID in children, with a similar functional brain involvement to those found in adults.

International audience; Objective: This longitudinal study aimed to measure the time course of intellectual changes after pediatric focal resective epilepsy surgery and to identify their predictors.Methods: We analyzed a cohort of 81 school-aged children with focal epilepsy and intractable seizures who underwent neurosurgery (focal resection) from 2000 to 2018 in La Timone Hospital (Marseille). Neuropsychological assessments were carried out before and then 1, 2, 3, and 5 years after epilepsy surgery.Results: Eighty-one patients with a median age at surgery of 13.74 years [4.25] were enrolled. Overall, 45 of the 81 (55%) recruited patients were improved after the surgery on at least one of the five domains of the Wechsler Intelligence Scale. Temporal lobe localization and postoperative seizure freedom were the main prognostic factors impacting intellectual outcome (improvement and decline) after epilepsy surgery. Younger patients at surgery were less likely to have a postoperative IQ decline. Intellectual improvement after epilepsy surgery could be delayed for up to 5 years after surgery and concerned all intellectual domains except the Verbal Comprehension Index (VCI). Intellectual decline after epilepsy surgery occurred mainly during the first two years after the surgery and was reflected in full-scale intelligence quotient (FSIQ) and Working Memory Index (WMI).Conclusions: Our study points out that children and adolescents with TLE who achieved freedom from seizure after epilepsy surgery are the leading candidates for achieving postoperative intellectual improvement. This enhancement in intellectual function shows a long time course, whereas intellectual decline is evidenced earlier.

Objective: To assess adverse events (AEs) and efficacy of add-on cannabidiol (CBD) with a slower titration protocol in pediatric clinical practice. Methods: We conducted a prospective, open-label, multicenter study in seven French reference centers for rare epilepsies. Patients had slow titration to reach a target dose of 10 mg/kg/day within at least 1 month and then gradually increased to a maximum dose of 20 mg/kg/day. We analyzed AEs and efficacy at M1 (month 1), M2, and M6, comparing two sets of subgroups: Dravet syndrome (DS) vs. Lennox-Gastaut (LGS) and patients with clobazam (CLB+) vs. patients without (CLB−). Results: One hundred and twenty-five patients were enrolled (62 LGS, 48 DS, 5 Tuberous sclerosis, and 10 other etiologies). Median concomitant antiepileptic drugs (AEDs) was three (25th percentile: 3, 75th percentile: 4). Patients received a dose of 10 (10–12), 14 (10–20), and 15.5 mg/kg/day (10–20) at M1, M2, and M6, respectively. Twenty-six patients discontinued CBD, 19 due to lack of efficacy, 2 due to AEs, 4 for both, and 1 had a sudden unexpected death in epilepsy. AEs were reported in 61 patients (48.8%), mainly somnolence (n = 26), asthenia (n = 20), and behavior disorders (n = 16). Abnormal transaminases (≥3 times) were reported in 11 patients receiving both valproate and clobazam. AEs were significantly higher at M2 (p = 0.03) and increased with the number of AEDs (p = 0.03). At M6, total seizure frequency change from baseline was −41% ± 37.5% (mean ± standard deviation), and 28 patients (37.8%) had a reduction ≥50%. AE and efficacy did not differ between DS vs. LGS and CLB+ vs. CLB– patients. Significance: A slower titration of CBD dose delivered better tolerance with comparable efficacy to previous trials. Concomitant CLB did not increase efficacy rates but in a few cases increased AEs. This slow titration scheme should help guide clinicians prescribing CBD and allow patients to benefit from its potential efficacy.

Purpose Ictal blinking may be observed in various forms of epilepsies. In the context of presurgical assessment of drug-resistant focal epilepsies, its semiological value is poorly understood. Our aims were to determine the prevalence and localizing value of ictal blinking. Methods We reviewed our cohort of more than 300 patients explored by SEEG, searching for ictal blinking. We defined seizure onset zone (SOZ) using visual analysis complemented by a quantified method (epileptogenicity index). We analysed the features of ictal blinking and the associated signs. We tested for statistically significant associations with the underlying SOZ. Results We found that about 8% of our patients exhibited ictal blinking, mostly bilateral. Ictal blinking was seen mostly in four types of SOZ: occipital, occipito-temporal, temporal mesial, and insulo-opercular. It was significantly over-represented in occipito-temporal and occipital SOZ. Eye blinking was fastest in insulo-opercular SOZ and slowest in temporal mesial SOZ. Nystagmus and tonic eye deviation were associated with SOZ involving the occipital lobe. Conclusion Ictal blinking is not uncommon in the population of patients with drug-resistant focal epilepsies. It is mostly associated with four types of SOZ: occipital, occipito-temporal, temporal mesial, and insulo-opercular. Some features of ictal blinking, as well as the analysis of the associated signs, allow to orient clinical hypotheses toward some specific SOZ.

OBJECTIVE Post-stroke epilepsy (PSE) represents a rare etiology in patients undergoing pre-surgical evaluation for epilepsy. Refractory PSE has been traditionally surgically treated with hemispherotomy. The aim of this study was to define the electrophysiological features of epileptogenic zone (EZ) using stereoelectroencephalography (SEEG) recordings in patients with refractory PSE. METHODS We analyzed ictal SEEG recordings from 21 consecutive patients. Epileptogenicity was quantified using the "epileptogenicity index" (EI) method in distant and perilesional cortical structures. We identified different seizure onset patterns (SOP) through a visual and time-frequency analysis. RESULTS We found that 81% of patients showed a complex organization of EZ, involving remote and perilesional structures. EZ involved a significantly (p 0.01) higher number of distant regions displaying a high epileptogenicity (EI ≥ 0.3). Low voltage fast activity (LFA) and high amplitude slow activity (HAS) patterns were observed respectively in 85.7% and 14.3% of patients. Surgery was proposed in 12/21 patients. Good surgical outcome (Engel Class I or II) was observed for all patients who underwent tailored functional disconnection based on SEEG results. Shorter epilepsy duration to surgery was found in the seizure-free group. SIGNIFICANCE Refractory PSE may present a complex organization of EZ. SEEG recordings are warranted to guide tailored hemispherectomy.

International audience; Management of patients after initial epilepsy surgical failure is challenging. In this study, we report our experience in using the stereoelectroencephalography (SEEG) method in the reevaluation of patients after initial epilepsy surgical failure. We selected 28 patients examined through SEEG in our department for drug-resistant focal epilepsy following initial epilepsy surgical failure. For each patient, the residual seizure onset zone (rSOZ) as defined by SEEG was classified as either contiguous if the seizure onset zone (SOZ) was focal and close to the surgical cavity (same lobe) or noncontiguous in cases where the SOZ included site(s) distant from the surgical cavity. The rSOZ was defined according to visual analysis of SEEG traces completed by an estimation of the epileptogenicity index (EI). A second surgical procedure was performed in 12 patients (45%). A favorable outcome (Engel class I or II) was obtained in 9/12 patients (6 in Engel class I, 50%). The proportion of patients that had reoperation was higher in the contiguous group (80%) than in the noncontiguous group (22%) (p = 0.02). A rSOZ localized in close relation to the initial surgical resection zone (contiguous group) was found in 10 patients (35%). Among them, 8 have since undergone reoperation, and a good outcome (Engel class I) was achieved in 5/8 (63%). A rSOZ involving a distant region from the first surgery was observed in 18 patients (65%) (noncontiguous group). Among them, only 4 have undergone reoperation, leading to a failure in 2 (Engel class III or IV) and a good outcome in 2 (IA). Ten patients had a first standard temporal lobectomy, and in 50% of these cases, the insula was involved in the rSOZ. Stereoelectroencephalography offers a unique way to evaluate the rSOZ at the individual level and thus guide further surgical decision-making. The best results are observed in patients having a focal rSOZ close to the site of the surgical resection in the first surgery.

OBJECTIVEHemispherotomy is currently the most frequently performed surgical option for refractory epilepsy associated with large perinatal or childhood ischemic events. Such an approach may lead to good seizure control, but it has inherent functional consequences linked to the disconnection of functional cortices. The authors report on 6 consecutive patients who presented with severe epilepsy associated with hemiplegia due to stroke and who benefitted from a new, stereoelectroencephalography-guided partial disconnection technique.METHODSThe authors developed a new disconnection technique termed “tailored suprainsular partial hemispherotomy” (TSIPH). Disconnection always included premotor and motor cortex with variable anterior and posterior extent.RESULTSAt a mean follow-up of 28 months, there were no deaths and no patient had hydrocephalus. Motor degradation was observed in all patients in the 2 weeks after surgery, but all patients completely recovered. The 6 patients were seizure free (Engel class IA) at the last follow-up. No neuropsychological aggravation was observed.CONCLUSIONSTSIPH appears to be a conservative alternative to classic hemispherotomy, leading to favorable outcome in this series.

Defining the roles of heterotopic and normotopic cortex in the epileptogenic networks in patients with nodular heterotopia is challenging. To elucidate this issue, we compared heterotopic and normotopic cortex using quantitative signal analysis on stereoelectroencephalography (SEEG) recordings.Clinically relevant biomarkers of epileptogenicity during ictal (epileptogenicity index; EI) and interictal recordings (high-frequency oscillation and spike) were evaluated in 19 patients undergoing SEEG. These biomarkers were then compared between heterotopic cortex and neocortical regions. Seizures were classified as normotopic, heterotopic, or normoheterotopic according to respective values of quantitative analysis (EI ≥0.3).A total of 1,246 contacts were analyzed: 259 in heterotopic tissue (heterotopic cortex), 873 in neocortex in the same lobe of the lesion (local neocortex), and 114 in neocortex distant from the lesion (distant neocortex). No significant difference in EI values, high-frequency oscillations, and spike rate was found comparing local neocortex and heterotopic cortex at a patient level, but local neocortex appears more epileptogenic (p0.001) than heterotopic cortex analyzing EI values at a seizure level. According to EI values, seizures were mostly normotopic (48.5%) or normoheterotopic (45.5%); only 6% were purely heterotopic. A good long-term treatment response was obtained in only two patients after thermocoagulation and surgical disconnection.This is the first quantitative SEEG study providing insight into the mechanisms generating seizures in nodular heterotopia. We demonstrate that both the heterotopic lesion and particularly the normotopic cortex are involved in the epileptogenic network. This could open new perspectives on multitarget treatments, other than resective surgery, aimed at modifying the epileptic network.

Summary Objective Rasmussen's encephalitis (RE) is a severe chronic inflammatory brain disease affecting one cerebral hemisphere and leading to drug-resistant epilepsy, progressive neurologic deficit, and unilateral brain atrophy. Hemispherotomy remains the gold standard treatment but causes permanent functional impairment. No standardized medical treatment protocol currently exists for patients prior to indication of hemispherotomy, although some immunotherapies have shown partial efficacy with functional preservation but poor antiseizure effect. Some studies suggest a role for tumor necrosis factor alpha (TNF-α) in RE pathophysiology. Methods We report an open-label study evaluating the efficacy and the safety of anti-TNF-α therapy (adalimumab) in 11 patients with RE. The primary outcome criterion was the decrease of seizure frequency. The secondary outcome criteria were neurologic and cognitive outcomes and existence of side effects. Results Adalimumab was introduced with a median delay of 31 months after seizure onset (range 1 month to 16 years), and follow-up was for a median period of 18 months (range 9–54 months). There was a significant seizure frequency decrease after adalimumab administration (from a median of 360 to a median of 32 seizures per quarter, p ≤ 0.01). Statistical analysis showed that adalimumab had a significant intrinsic effect (p < 0.005) independent from disease fluctuations. Five patients (45%) were found to have sustained improvement over consecutive quarters in seizure frequency (decrease of 50%) on adalimumab. Three of these five patients also had no further neurocognitive deterioration. Adalimumab was well tolerated. Significance Our study reports efficacy of adalimumab in terms of seizure frequency control. In addition, stabilization of functional decline occurred in three patients. This efficacy might be particularly relevant for atypical slowly progressive forms of RE, in which hemispherotomy is not clearly indicated. Due to our study limitations, further studies are mandatory to confirm these preliminary results.

International audience; Early onset epileptic encephalopathies (EOEE) are heterogeneous group of severe epilepsies that still need to be better defined and characterized. On a genetic point of view, several dozen of genes have been associated with EOEE, and to date, it is difficult to find a common mechanism to explain EOEE. In this short review, we show that two mains genes are involved in EOEE: STXBP1 and KCNQ2. Focusing on KCNQ2 related EOEE, we show that a relatively similar phenotype can be related to various consequences of mutations on a single gene. This will probably challenge the treatment of EOEE patients.