Control of disease activity with large extended-interval dosing of rituximab/ocrelizumab in highly active pediatric multiple sclerosis.

Recent studies in adults suggested that extended-interval dosing of rituximab/ocrelizumab (RTX/OCR) larger than 12 months was safe and could improve safety. This was an observational cohort study of very active pediatric-onset multiple sclerosis (PoMS) (median (range) age, 16 (12-17) years) treated with RTX/OCR with 6 month standard-interval dosing (n = 9) or early extended-interval dosing (n = 12, median (range) interval 18 months (12-25)). Within a median (range) follow-up of 31 (12-63) months after RTX/OCR onset, one patient (standard-interval) experienced relapse and no patient showed disability worsening or new T2-weighted lesions. This study suggests that the effectiveness of RTX/OCR is maintained with a median extended-interval dosing of 18 months in patients with very active PoMS.

Efficacy and tolerance of cannabidiol in the treatment of epilepsy in patients with Rett syndrome.

We aim to assess the efficacy and tolerance of cannabidiol as adjunctive therapy for Rett syndrome (RTT) patients with epilepsy. We conducted a longitudinal observational study through a monocentric cohort of 46 patients with RTT. Patients were recruited from March 2020 to October 2022 and were treated with Epidyolex® (cannabidiol, CBD, 100 mg/mL oral solution). In our cohort, 26 patients had associated epilepsy (26/46 [56%]), and 10/26 (38%) were treated with CBD, in combination with clobazam in 50% of cases. The median dose at their last follow-up was 15 mg/kg/day. The median treatment duration was 13 months (range: 1-32 months). CBD reduced the incidence of seizures in seven out of 10 patients (70%) with one seizure-free patient, two patients with a reduction of seizures of more than 75%, and four patients with a decrease of more than 50%. No aggravation of symptoms or adverse effects were observed. Only one patient experienced a transitory drooling and somnolence episode at the CBD initiation. Half of the patients showed a reduction in agitation and/or anxiety attacks, and an improvement in spasticity was reported in 4/10 (40%) of patients. CBD appears to have potential therapeutic value for the treatment of drug-resistant epilepsy in Rett syndrome. CBD is well tolerated and, when used in combination with clobazam, may increase the effectiveness of clobazam alone.

Exome sequencing of ATP1A3-negative cases of alternating hemiplegia of childhood reveals SCN2A as a novel causative gene.

Alternating hemiplegia of childhood (AHC) is a rare neurodevelopment disorder that is typically characterized by debilitating episodic attacks of hemiplegia, seizures, and intellectual disability. Over 85% of individuals with AHC have a de novo missense variant in ATP1A3 encoding the catalytic α3 subunit of neuronal Na+/K+ ATPases. The remainder of the patients are genetically unexplained. Here, we used next-generation sequencing to search for the genetic cause of 26 ATP1A3-negative index patients with a clinical presentation of AHC or an AHC-like phenotype. Three patients had affected siblings. Using targeted sequencing of exonic, intronic, and flanking regions of ATP1A3 in 22 of the 26 index patients, we found no ultra-rare variants. Using exome sequencing, we identified the likely genetic diagnosis in 9 probands (35%) in five genes, including RHOBTB2 (n = 3), ATP1A2 (n = 3), ANK3 (n = 1), SCN2A (n = 1), and CHD2 (n = 1). In follow-up investigations, two additional ATP1A3-negative individuals were found to have rare missense SCN2A variants, including one de novo likely pathogenic variant and one likely pathogenic variant for which inheritance could not be determined. Functional evaluation of the variants identified in SCN2A and ATP1A2 supports the pathogenicity of the identified variants. Our data show that genetic variants in various neurodevelopmental genes, including SCN2A, lead to AHC or AHC-like presentation. Still, the majority of ATP1A3-negative AHC or AHC-like patients remain unexplained, suggesting that other mutational mechanisms may account for the phenotype or that cases may be explained by oligo- or polygenic risk factors.

GluK2 Is a Target for Gene Therapy in Drug-Resistant Temporal Lobe Epilepsy.

OBJECTIVE: Temporal lobe epilepsy (TLE) is characterized by recurrent seizures generated in the limbic system, particularly in the hippocampus. In TLE, recurrent mossy fiber sprouting from dentate gyrus granule cells (DGCs) crea an aberrant epileptogenic network between DGCs which operates via ectopically expressed GluK2/GluK5-containing kainate receptors (KARs). TLE patients are often resistant to anti-seizure medications and suffer significant comorbidities; hence, there is an urgent need for novel therapies. Previously, we have shown that GluK2 knockout mice are protected from seizures. This study aims at providing evidence that downregulating KARs in the hippocampus using gene therapy reduces chronic epileptic discharges in TLE. METHODS: We combined molecular biology and electrophysiology in rodent models of TLE and in hippocampal slices surgically resected from patients with drug-resistant TLE. RESULTS: Here, we confirmed the translational potential of KAR suppression using a non-selective KAR antagonist that markedly attenuated interictal-like epileptiform discharges (IEDs) in TLE patient-derived hippocampal slices. An adeno-associated virus (AAV) serotype-9 vector expressing anti-grik2 miRNA was engineered to specifically downregulate GluK2 expression. Direct delivery of AAV9-anti grik2 miRNA into the hippocampus of TLE mice led to a marked reduction in seizure activity. Transduction of TLE patient hippocampal slices reduced levels of GluK2 protein and, most importantly, significantly reduced IEDs. INTERPRETATION: Our gene silencing strategy to knock down aberrant GluK2 expression demonstrates inhibition of chronic seizure in a mouse TLE model and IEDs in cultured slices derived from TLE patients. These results provide proof-of-concept for a gene therapy approach targeting GluK2 KARs for drug-resistant TLE patients. ANN NEUROL 2023;94:745-761.

Long-term outcome of paediatric anti-N-methyl-D-aspartate receptor encephalitis.

AIM: 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. METHOD: 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. RESULTS: 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). INTERPRETATION: 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. WHAT THIS PAPER ADDS: Forty-five per cent of patients had cognitive impairment at ≥2 years diagnosis of anti-N-methyl-d-aspartate receptor encephalitis (NMDAR-E). Seventy per cent of patients had academic difficulties at ≥2 years diagnosis of NMDAR-E. Ninety-two per cent of patients needed rehabilitative care at ≥2 years diagnosis of NMDAR-E. A high number of symptoms at diagnosis were associated with cognitive impairment.

Molecular and clinical descriptions of patients with GABAA receptor gene variants (GABRA1, GABRB2, GABRB3, GABRG2): A cohort study, review of literature, and genotype-phenotype correlation.

OBJECTIVE: γ-Aminobutyric acid (GABA)A -receptor subunit variants have recently been associated with neurodevelopmental disorders and/or epilepsy. The phenotype linked with each gene is becoming better known. Because of the common molecular structure and physiological role of these phenotypes, it seemed interesting to describe a putative phenotype associated with GABAA -receptor-related disorders as a whole and seek possible genotype-phenotype correlations. METHODS: We collected clinical, electrophysiological, therapeutic, and molecular data from patients with GABAA -receptor subunit variants (GABRA1, GABRB2, GABRB3, and GABRG2) through a national French collaboration using the EPIGENE network and compared these data to the one already described in the literature. RESULTS: We 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 GABAA -receptor subunit gene, whereas N-terminal variants seemed to be related to milder phenotypes. SIGNIFICANCE: GABAA -receptor subunit variants are associated with highly variable phenotypes despite their molecular and physiological proximity. None of the genes described here was associated with a specific phenotype. On the other hand, it appears that the location of the variant on the protein may be a marker of severity. Variant location may have important weight in the development of targeted therapeutics.

Increased Gray Matter Density in the Right Mesencephalic Tegmentum Is Associated With Better Engel Classes I and II After Radiosurgery for Hypothalamic Hamartomas.

BACKGROUND: Hypothalamic hamartomas (HHs) are disabling congenital lesions, responsible for gelastic seizures frequently associated with catastrophic epilepsies, epileptogenic encephalopathy, and cognitive and psychiatric severe comorbidities. Stereotactic radiosurgery (SRS) is a well-established minimally invasive therapeutic approach. OBJECTIVE: To assess whether pretherapeutic gray matter density (GMD) correlates with seizure outcome. METHODS: We used voxel-based morphometry at whole-brain level, as depicted on pretherapeutic standard structural magnetic resonance neuroimaging. We examined 24 patients (10 male patients, 14 female patients; mean age, 12.7 yr; median, 9; range, 5.9-50) treated in Marseille University Hospital, France, between May 2001 and August 2018. RESULTS: Most relevant anatomic area predicting postoperative Engel classes I and II vs III and IV after SRS for HHs was mesencephalic tegmentum. Higher pretherapeutic GMD in this area was associated with better outcomes for seizure cessation. The only other statistically significant clusters were right cerebellar lobule VIIIb and VIIIa. Lower pretherapeutic GMD in both clusters correlated with better Engel class outcomes. GMD decreased with age in the left mediodorsal thalamus. CONCLUSION: Seizure cessation after SRS for HHs was associated with higher GMD in mesencephalic tegmental area, acknowledged to be involved in the neural control of explosive vocal behavior in animals. This area is connected by the mamillotegmental bundle to the lateral tuberal nucleus area of the hypothalamus, where HHs are known to rise. In the future, the detection of more gray matter in this "laugh" tegmental area based on pretherapeutic routine structural neuroimaging might help in patient selection for minimally invasive radiosurgery for HH.

Similar patterns of [18F]-FDG brain PET hypometabolism in paediatric and adult patients with long COVID: a paediatric case series.

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 21 paediatric controls, 35 adult patients with long COVID and 44 healthy adult subjects. RESULTS: Despite lower initial severity at the acute stage of the infection, paediatric patients demonstrated on average 5 months later a similar 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 PET 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, regardless of age and initial severity.

Intellectual outcome from 1 to 5 years after epilepsy surgery in 81 children and adolescents: A longitudinal study.

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.

The phenotypic spectrum of X-linked, infantile onset ALG13-related developmental and epileptic encephalopathy.

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.

Clinical Features and Risk of Relapse in Children and Adults with Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease.

OBJECTIVE: The main objective was to compare clinical features, disease course, and myelin oligodendrocyte glycoprotein (MOG) antibody (Ab) dynamics between children and adults with MOG-Ab-associated disease (MOGAD). METHODS: This retrospective multicentric, national study included 98 children and 268 adults with MOGAD between January 2014 and September 2019. Cox regression model for recurrent time-to-event data and Kaplan-Meier curves for time to antibody negativity were performed for the objectives. RESULTS: Isolated optic neuritis was the most frequent clinical presentation in both children (40.8%) and adults (55.9%, p = 0.013), and acute disseminated encephalomyelitis syndrome was more frequent in children (36.7% vs 5.6%, p < 0.001). Compared to adults, children displayed better recovery (Expanded Disability Status Scale ≥ 3.0 at last follow-up reached only by 10 of 97 [10.3%] vs 66/247 [26.7%], p < 0.001). In the multivariate analysis, adults were at higher risk of relapse than children (hazard ratio = 1.41, 95% confidence interval [CI] = 1.12-1.78, p = 0.003). At 2 years, 64.2% (95% CI = 40.9-86.5) of nonrelapsing children became MOG-Ab negative compared to 14.1% (95% CI = 4.7-38.3) of relapsing children (log-rank p < 0.001), with no differences observed in adults (log-rank p = 0.280). INTERPRETATION: MOGAD patients differ in the clinical presentation at onset, showing an age-related shift in the clinical features across age groups. Compared to children, adults have a higher risk of relapse and worse functional recovery. Finally, children with monophasic disease become MOG-Ab negative earlier than relapsing children, but this is not true in adults. Considering these differences, management and treatment guidelines should be considered independently in children and adults. ANN NEUROL 2021;89:30-41.

Anatomical electroclinical correlations during an SEEG-recorded seizure with autoscopic hallucination.

Autoscopic phenomena (AP) are characterized by seeing an image of oneself in extra-personal space. These phenomena are rare and the anatomy of brain regions producing these phenomena is not well defined. We report anatomical electroclinical correlations during a stereoelectroencephalography-recorded seizure with autoscopic hallucination (a form of AP in which the double of oneself is seen from an internal point of view). Seizure onset zone was quantified using the epileptogenicity index method (EI). Maximal EI values were obtained in the left lateral parietal cortex (supramarginal gyrus) and high values were also found in the left posterior-superior insular cortex, left temporo-occipital junction and contralateral inferior parietal lobule. Our case confirms the involvement of the inferior parietal lobule, temporo-parieto-occipital junction and posterior insula in the genesis of autoscopic hallucination.

Slow Titration of Cannabidiol Add-On in Drug-Resistant Epilepsies Can Improve Safety With Maintained Efficacy in an Open-Label Study.

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.

Ictal blinking in focal seizures: Insights from SEEG recordings.

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.

[Effect of activities profile variations on health-related quality of life among breast cancer patients: Secondary exploratory analysis from PASAPAS study data]. / Effet de l'évolution du profil d'activité quotidienne sur la qualité de vie chez des femmes atteintes de cancers du sein : analyse exploratoire secondaire des données de l'étude PASAPAS.

INTRODUCTION: Lifestyle changes in breast cancer patients, by physical activity increasing, are becoming a main objective in supportive care. The objective of this study was to explore the impact of the daily activity profile evolution on the quality of life among this public. METHODS: Sixty patients (18 to 75 years) with non-metastatic breast cancer were randomized to a 2:1 ratio (physical activity intervention; control) in the PASAPAS randomized clinical trial. Multiple linear regression analyzes were computed to explain quality of life scores 6 months after the start of adjuvant therapy. Variables retained were the baseline quality of life scores, the anxiety trait, the randomization arm, the variations of time spent in different physical activity classes ([3-4 [MET, [4-6 [MET, ≥6 MET) and in sedentary behaviors. RESULTS: Only the decrease in time spent in sedentary behaviors really appeared as a predictor of the quality of physical life. Participation in the intervention group appeared as a predictor of quality of mental life. DISCUSSION: Results plead in favor of sedentary life style decrease as part of the objectives of care program for women with breast cancer. It also highlights the need of collective supervised sessions implemented by competent staff. This research also suggests that the dynamics of daily activity profile variations should be studied further in association to quality of life.

Anatomoelectroclinical features of SEEG-confirmed pure insular-onset epilepsy.

PURPOSE: In this study, we aimed to improve our knowledge of insular epilepsy by studying anatomoelectroclinical correlations in pure insular-onset epilepsy and characterizing differences between anterior and posterior insular-onset seizures. METHODS: Patients in whom seizure-onset zone was confined to the insula and peri-insular sulcus were selected from 301 consecutive presurgical stereo-electroencephalography (EEG) recordings performed between years 2010 and 2017 in two epilepsy centers. Ictal-onset zone in stereo-EEG was delineated visually and quantitatively using epileptogenic index method. Seizure characteristics were reanalyzed, and anatomoelectroclinical correlations were assessed. Characteristics of posterior and anterior insular-onset seizures were compared. RESULTS: Eleven insular cases were identified, five of them with an anterior insular seizure onset and six with a posterior one. Nonpainful somatosensory symptoms and autonomic symptoms were the most common symptoms (73% of patients) followed by speech-related symptoms (55%) and ipsilateral eye blinking (45%). Six patients had seizures restricted to somatosensory or viscerosensory symptoms. In all patients, seizures progressed to motor symptoms. Somatosensory symptoms did not differentiate anterior from posterior insular seizures. However, hyperkinetic signs, speech modifications, and viscerosensory symptoms were related to an anterior insular seizure-onset zone. Pain, asymmetric tonic, focal clonic, and tonic symptoms were more frequent in patients with a posterior insular seizure onset. CONCLUSIONS: Seizure semiology is heterogeneous in pure insular-onset epilepsy. Differences between the anterior and posterior insular seizures reflect the functional organization of the insula. Particularly, the different types of motor symptoms may help to distinguish anterior from posterior insular seizure onset.

Cost-effectiveness of an exercise and nutritional intervention versus usual nutritional care during adjuvant treatment for localized breast cancer: the PASAPAS randomized controlled trial.

We undertook a cost-effectiveness analysis (CEA) to compare an exercise and nutritional program with the usual nutritional care concomitant to adjuvant chemotherapy in localized breast cancer patients. The CEA was designed as part of the interventional, controlled, randomized, single-center, open-label PASAPAS study. Breast cancer patients receiving first-line adjuvant chemotherapy at a French Comprehensive Cancer Center were randomized 2:1 to a 6-month exercise program of supervised indoor and outdoor group sessions in addition to usual nutritional care (exercise arm) or a usual nutritional care group receiving dietary and physical activity counseling (control arm). Costs were assessed from the French national insurance perspective (in Euros, 2012). Incremental cost-effectiveness ratios (ICERs) were calculated for four criteria: body mass index, waist circumference, body fat percentage, and estimated aerobic capacity. Uncertainty around the ICERs was captured by a probabilistic analysis using a non-parametric bootstrap method. The analysis was based on 60 patients enrolled between 2011 and 2013. Average intervention costs per participant were €412 in the exercise arm (n = 41) and €117 (n = 19) in the control arm. Total mean costs were €17,344 (standard deviation 9,928) and €20,615 (standard deviation 14,904), respectively, did not differ significantly (p = 0.51). The 6-month exercise program was deemed to be cost-effective compared with usual care for the estimated aerobic capacity. Multicenter randomized studies with long-term costs and outcomes should be done to provide additional evidence. Clinical trial: The PASAPAS study is registered under ClinicalTrials.gov. Trial registration ID: NCT01331772.

Re-annotation of 191 developmental and epileptic encephalopathy-associated genes unmasks de novo variants in SCN1A.

The developmental and epileptic encephalopathies (DEE) are a group of rare, severe neurodevelopmental disorders, where even the most thorough sequencing studies leave 60-65% of patients without a molecular diagnosis. Here, we explore the incompleteness of transcript models used for exome and genome analysis as one potential explanation for a lack of current diagnoses. Therefore, we have updated the GENCODE gene annotation for 191 epilepsy-associated genes, using human brain-derived transcriptomic libraries and other data to build 3,550 putative transcript models. Our annotations increase the transcriptional 'footprint' of these genes by over 674 kb. Using SCN1A as a case study, due to its close phenotype/genotype correlation with Dravet syndrome, we screened 122 people with Dravet syndrome or a similar phenotype with a panel of exon sequences representing eight established genes and identified two de novo SCN1A variants that now - through improved gene annotation - are ascribed to residing among our exons. These two (from 122 screened people, 1.6%) molecular diagnoses carry significant clinical implications. Furthermore, we identified a previously classified SCN1A intronic Dravet syndrome-associated variant that now lies within a deeply conserved exon. Our findings illustrate the potential gains of thorough gene annotation in improving diagnostic yields for genetic disorders.

Screening for depression in youth with epilepsy: Psychometric analysis of NDDI-E-Y and NDDI-E in a French population.

OBJECTIVES: The objective of this study was to evaluate the Neurological Disorders Depression Inventory-Epilepsy (NDDI-E) for Youth (NDDI-E-Y) for screening for major depressive disorder (MDD) in French youth with epilepsy (YWE), in order to (1) validate this tool in a separate population; (2) determine whether the 12-item NDDI-E-Y affords advantages over the 6-item adult NDDI-E; (3) measure psychometric performance of each item. METHODS: Youth with epilepsy aged 11-17 years completed a 15-item questionnaire to calculate total scores for NDDI-E-Y (12 items) and NDDI-E (6 items). Gold standard for MDD was Children's Depression Inventory (CDI). Receiver operator characteristic (ROC) analyses for total NDDI-E-Y and NDDI-E scores were compared. Psychometric properties of each item were analyzed for: floor/ceiling effect, item-internal consistency, and ROC curve. RESULTS: Ninety-seven YWE were included; 21.6% had MDD (CDI > 15). Correlation was very high between total NDDI-E-Y and NDDI-E scores, and high between NDDI-E-Y and CDI. Cutoff point for the NDDI-E-Y maximizing both sensitivity and specificity was 23 (original study cutoff 32). The ROC analysis of the NDDI-E-Y showed an area under the curve (AUC) 0.967 (95% confidence intervals [CI] 0.909-0.992); (p < 0.0001). Sensitivity, specificity, and positive (PPV) and negative predictive values (NPV) were 100% [83.9; 100], 82.9% [72.5; 90.6], 61.8 [43.6; 77.8], and 100% [94.3; 100], respectively. The NDDI-E-Y was not superior to NDDI-E according to pairwise comparison of ROC (p = 0.07). Psychometric analysis revealed marked differences between items. After eliminating items with poorer performance, a 6-item version of the NDDI-E-Y showed sensitivity, specificity, PPV, and NPV of 100% [85.5; 100], 85.5% [75.6; 92.5], 65.6 [46.8; 81.4], and 100% [94.5; 100], respectively. This was significantly better than the adult NDDI-E (p = 0.03) though not NDDI-E-Y (p = 0.07). SIGNIFICANCE: Significant difference in cutoff indicates that the NDDI-E-Y cannot yet be recommended for widespread screening of MDD in YWE. Discrepancies in psychometric performance between items suggest that further work is needed to examine both validation of the original 12-item NDDI-E-Y and comparison with a shorter version.

Epileptogenicity and surgical outcome in post stroke drug resistant epilepsy in children and adults.

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.