We report a retrospective multicenter study on ketogenic diets (KD) administered for at least 3 months in 32 patients under 18 years of age with tuberous sclerosis complex (TSC). The primary endpoint was seizure reduction after 6 months under KD. Secondary endpoints were seizure reduction at other time points, tolerability and retention rate. The KD was administered for a median of 9.2 months (range 3-132 months). After 6 months 27 patients were still on the diet. A relevant reduction of seizure frequency was found in 15 (58%) of 26 analyzable cases and 6 became seizure-free (23%). The efficacy of the KD declined over time. At the end of the observation period the KD had been stopped in 27 patients. The documented reasons were lack of efficacy (6), noncompliance (8), side effects (5) and surgery (3). Mild and/or transient side effects were documented in 8 patients, 5 other patients discontinued KD due to side effects (2 cases of elevated transaminases and 1 case each of pancreatitis, vomiting and kidney stones). Patients in the subgroup with classical KD (N = 19) were significantly younger than those with a modified Atkins diet (N = 13). Efficacy and tolerability did not differ between these subgroups. There was no difference between patients receiving concomitant mTOR inhibition (N = 13) and patients without mTOR inhibition throughout the entire duration of KD (N = 12). KD is an effective and well-tolerated epilepsy therapy in TSC. A combination with mTOR inhibitors is possible. The effectiveness of KD in our cohort is comparable to that generally expected for epilepsy; however, we found no evidence that KD was more effective in patients with TSC than in cohorts with other etiologies.

Es handelt sich um eine retrospektive multizentrische Studie zur ketogenen Ernährungstherapie (KET, Dauer mindestens 3 Monate) bei 32 Patienten mit tuberöse Sklerose-Komplex (TSC) im Alter unter 18 Jahren. Primärer Endpunkt war die Anfallsreduktion nach 6 Monaten unter der KET. Sekundäre Endpunkte waren die Anfallsreduktion zu anderen Zeitpunkten, die Verträglichkeit und die Retentionsrate. Die Dauer der KET betrug im Median 9,2 Monate (3–132). Nach 6 Monaten waren noch 27 Patienten behandelt. Eine relevante Anfallsreduktion zeigte sich in 15 von 26 auswertbaren Fällen (58

The 2017 International League Against Epilepsy (ILAE) classification suggested that the term “genetic generalized epilepsies” (GGEs) should be used for the broad group of epilepsies with so-called “generalized” seizure types and “generalized” spike-wave activity on EEG, based on a presumed genetic etiology. Within this framework, idiopathic generalized epilepsies (IGEs) are described as a subset of GGEs and include only four epileptic syndromes: childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and epilepsy with generalized tonic-clonic seizures alone. The recent 2022 ILAE definition of IGEs is based on the current state of knowledge and reflects a community consensus and is designed to evolve as knowledge advances. The term “frontiers of IGEs” refers to the actual limits of our understanding of these four syndromes. Indeed, among patients presenting with a syndrome compatible with the 2022 definition of IGEs, we still observe a significant proportion of patients presenting with specific clinical features, refractory seizures, or drug-resistant epilepsies. This leads to the discussion of the boundaries of IGEs and GGEs, or what is accepted within a clinical spectrum of a definite IGE. Here, we discuss several entities that have been described in the literature for many years and that may either constitute rare features of IGEs or a distinct differential diagnosis. Their recognition by clinicians may allow a more individualized approach and improve the management of patients presenting with such entities.

BackgroundPrevious studies showed the efficacy of epilepsy surgery in carefully selected children with epilepsy associated with tuberous sclerosis complex. However, how this selection is conducted, and the characteristics of the patients brought to surgery are still poorly described. By conducting a multicentric retrospective cohort study covering the practice of the last twenty years, we describe the paths leading to epilepsy surgery in children with epilepsy associated with tuberous sclerosis complex.MethodsWe identified 84 children diagnosed with tuberous sclerosis complex and epilepsy by matching two exhaustive registries of genetic diseases and subsequent medical records reviews within two French neuropediatric and epilepsy centers. Demographic, clinical, longitudinal, and diagnostic and surgical procedures data were collected.ResultsForty-six percent of the children were initially drug-resistant and 19% underwent resective surgery, most often before the age of four. Stereotactic electroencephalography was performed prior to surgery in 44% of cases. Fifty-seven and 43% of patients remained seizure-free one and ten years after surgery, respectively. In addition, 52% of initially drug-resistant patients who did not undergo surgery were seizure-free at the last follow-up. The number of anti-seizure medications required decreased in 50% of cases after surgery. Infantile spasms, intellectual disability, autism spectrum disorder or severe behavioral disorders were not contraindications to surgery but were associated with a higher rate of complications and a lower rate of seizure freedom after surgery.ConclusionDespite the assumption of complex multifocal epilepsy and practical difficulties in young children with tuberous sclerosis complex, successful surgery results are comparable with other populations of patients with drug-resistant epilepsy, and a spontaneous evolution to drug-sensitive epilepsy may occur in non-operated patients.

Background Epileptic encephalopathy with spike -wave activation in sleep (EE-SWAS) is a rare syndrome associated with cognitive and behavioural regression. On the basis of mostly small observational and retrospective studies, corticosteroids and clobazam are often considered the most effective treatments for this syndrome. We aimed to compare cognitive outcomes of children with EE-SWAS 6 months after starting treatment with either corticosteroids or clobazam. Methods We did a multicentre, randomised controlled trial at eight tertiary referral centres for rare epilepsies in seven European countries. Children were eligible to participate if they were aged 2-12 years, were diagnosed with EE-SWAS within 6 months before inclusion, and had not been treated with corticosteroids or clobazam previously. Participants were randomly assigned (1:1) to treatment with corticosteroids (either continuous treatment with 1-2 mg/kg per day of prednisolone orally or pulse treatment with 20 mg/kg per day of methylprednisolone intravenously for 3 days every 4 weeks) or clobazam (0 center dot 5-1 center dot 2 mg/kg per day orally). The primary outcome was cognitive functioning after 6 months of treatment, which was assessed by either the intelligence quotient (IQ) responder rate (defined as improvement of >= 11 center dot 25 IQ points) or the cognitive sum score responder rate (defined as improvement of >= 0 center dot 75 points). Safety was assessed by number of adverse events and serious adverse events. Data were analysed in the intention -to -treat population, which included all children as randomised who had primary outcome data available at 6 months. The trial is registered with the Dutch Trial Register, Toetsingonline, NL43510.041.13, and the ISRCTN registry, ISRCTN42686094. The trial was terminated prematurely because enrolment of the predefined number of 130 participants was deemed not feasible. Findings Between July 22, 2014, and Sept 3, 2022, 45 children were randomly assigned to either corticosteroids (n=22) or clobazam (n=23); two children assigned clobazam dropped out before 6 months and were excluded from the intentionto -treat analysis. At the 6 -month assessment, an improvement of 11 center dot 25 IQ points or greater was reported for five (25%) of 20 children assigned corticosteroids versus zero (0%) of 18 assigned clobazam (risk ratio [RR] 10 center dot 0, 95% CI 1 center dot 2-1310 center dot 4; p=0 center dot 025). An improvement of 0 center dot 75 points or more in the cognitive sum score was recorded for one (5%) of 22 children assigned corticosteroids versus one (5%) of 21 children assigned clobazam (RR 1 center dot 0, 95% CI 0 center dot 1-11 center dot 7, p=0 center dot 97). Adverse events occurred in ten (45%) of 22 children who received corticosteroids, most frequently weight gain, and in 11 (52%) of 21 children who received clobazam, most often fatigue and behavioural disturbances. Occurrence of adverse events did not differ between groups (RR 0 center dot 8, 95% CI 0 center dot 4-1 center dot 4; p=0 center dot 65). Serious adverse events occurred in one child in the corticosteroid group (hospitalisation due to laryngitis) and in two children in the clobazam group (hospitalisation due to seizure aggravation, and respiratory tract infection). No deaths were reported. Interpretation The trial was terminated prematurely, and the target sample size was not met, so our findings must be interpreted with caution. Our data indicated an improvement in IQ outcomes with corticosteroids compared with clobazam treatment, but no difference was seen in cognitive sum score. Our findings strengthen those from previous uncontrolled studies that support the early use of corticosteroids for children with EE-SWAS. Copyright (c) 2023 Elsevier Ltd. All rights reserved.

Numerous studies showed that epilepsy represents a high burden in Tuberous Sclerosis Complex (TSC), affecting 63 to 78% of the patients. Epilepsy will be refractory to medication in over 60% of cases in early presentations, and accompanied by intellectual disabilities and/or autism spectrum disorders. The emerging experimental and clinical data suggest that the molecular and cellular changes triggered by seizures, particularly during the first weeks of life, can be limited by early action. Making any effort to avoid or delay epilepsy onset is a promising pathway to improve global outcome for TSC patients, although it is not possible to tidy up the specific roles of seizures, interictal abnormalities, and cortical abnormalities upon neurodevelopment. Early diagnosis of epilepsy can be made during a "symptomatic phase," shortly after the onset of seizures (focal seizures or spasms), revealing the TSC in a young infant. As soon as the diagnosis is made, a treatment with Vigabatrin is now recommended. The diagnosis of epilepsy can also be performed during a "presymptomatic phase", with the improvement of fetal and neonatal diagnosis of TSC. Recent studies demonstrated a significant delay of more than 3 months between the detection of EEG abnormalities and the first clinical seizures, which allows to consider a preventive treatment. Beside vigabatrin, mTOR inhibitors may have a place in this early management. The last recommendations about early detection and treatment of epilepsy in TSC will be detailed in this review. © 2022 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.

Introduction: MMPSI or EMFSI was described in 1995. KCNT1 is the major gene causing this rare epilepsy with other causative genes recently reported. However, little is known about the outcome of this syndrome mainly in term of long-term outcome. Methods: We studied medical data of patients with EMFSI due to KCNT1 mutation born before 2013. We completed medical data with a survey sent to the families on the status of their children over the last 6 months. Results: 12 patients were included (sex ratio: 1.4) and one patient was lost to follow-up. All families replied to the questionnaire. Fifty percent were deceased at the time of this study (n=6): 2 during the active epileptic phase in infancy at 0.3 and 1.5 y, 2 from SUDEP at 1.5 and 3 y and 2 from respiratory failure at 15 and 19.5 y after frequent respiratory infections. The other 6 were aged from 3.5 to 16 y (mean 10 ± 5 y). All patients had acquired microcephaly (−4.5 ± 2 SD) and a severe intellectual disability with major hypotonia. None acquired sitting position or language. Four patients were able to hold their head up. Only one patient could hold objects. Patients had eye contact and were able to communicate with their parents by modulating their vocals and crying and one was able to repeat “mama”. Seizures remain very frequent from at least one to 25 seizures a day and occurred in clusters (n=5). Parents describe seizures as hypertonic with a cry, extension of members and facial rictus. Main triggering factors were stress, emotion and pain. For five patients seizures were predominant during night time with no prodromal signs or trigger factors. Conclusion: MPSI is probably one of the most severe epileptic encephalopathies with severe intellectual and motor outcome and persistent active epilepsy.

Objective Antiepileptic drugs (AEDs) have cognitive side effects that, particularly in children, may affect intellectual functioning. With the TimeToStop (TTS) study, we showed that timing of AED withdrawal does not majorly influence long‐term seizure outcomes. We now aimed to evaluate the effect of AED withdrawal on postoperative intelligence quotient (IQ), and change in IQ (delta IQ) following pediatric epilepsy surgery. Methods We collected IQ scores of children from the TTS cohort with both pre‐ and postoperative neuropsychological assessments (NPAs; n = 301) and analyzed whether reduction of AEDs prior to the latest NPA was related to postoperative IQ and delta IQ, using linear regression analyses. Factors previously identified as independently relating to (delta) IQ, and currently identified predictors of (delta) IQ, were considered possible confounders and used for adjustment. Additionally, we adjusted for a compound propensity score that contained previously identified determinants of timing of AED withdrawal. Results Mean interval to the latest NPA was 19.8 ± 18.9 months. Reduction of AEDs at the latest NPA significantly improved postoperative IQ and delta IQ (adjusted regression coefficient [RC] = 3.4, 95% confidence interval [CI] = 0.6–6.2, p = 0.018 and RC = 4.5, 95% CI = 1.7–7.4, p = 0.002), as did complete withdrawal (RC = 4.8, 95% CI = 1.4–8.3, p = 0.006 and RC = 5.1, 95% CI = 1.5–8.7, p = 0.006). AED reduction also predicted ≥10‐point IQ increase ( p = 0.019). The higher the number of AEDs reduced, the higher was the IQ (gain) after surgery (RC = 2.2, 95% CI = 0.6–3.7, p = 0.007 and RC = 2.6, 95% CI = 1.0–4.2, p = 0.001, IQ points per AED reduced). Interpretation Start of AED withdrawal, number of AEDs reduced, and complete AED withdrawal were associated with improved postoperative IQ scores and gain in IQ, independent of other determinants of cognitive outcome. Ann Neurol 2015;78:104–114

Le virus varicella-zoster (VZV) occupe une place prépondérante parmi les facteurs infectieux à l’origine de vasculopathies cérébrales et d’accidents vasculaires cérébraux (AVC) pédiatriques. Une atteinte virale directe de la paroi vasculaire a été démontrée dans de rares observations neuropathologiques ainsi que la présence de marqueurs viraux dans le LCR. Cela témoigne d’un processus infectieux localisé probablement associé à des phénomènes inflammatoires indirects. Cependant, l’utilité d’un bilan biologique (ponction lombaire [PL]) et d’un traitement antiviral ou anti-inflammatoire reste incertaine au vu de l’évolution souvent monophasique de l’artériopathie cérébrale post-varicelleuse chez l’enfant, expliquant les divergences d’attitude thérapeutique observées. Ce travail présente un état des lieux des modalités pédiatriques de prise en charge diagnostique et thérapeutique des AVC post-varicelleux à partir de l’analyse de 26 observations de la littérature depuis l’année 2000, auxquelles s’ajoutent 3 observations personnelles. L’AVC post-varicelleux est classiquement due à une artériopathie du segment initial de l’artère cérébrale moyenne (ACM) entraînant un infarctus du territoire lenticulo-strié et touche de jeunes enfants immunocompétents. La recherche d’une thrombophilie est en général négative. Une PL a été réalisée dans 17/29 cas. La présence de marqueurs viraux n’a été cherchée que dans 14 cas et ne s’est avérée positive que chez 8 enfants. Un traitement antiviral a été administré dans 11 cas. Sous réserve d’un échantillonnage rétrospectif et de petite taille, les enfants traités n’ont ni une meilleure évolution de la vasculopathie ni un moindre risque des séquelles neurologiques, comparativement à l’évolution spontanée.Among infectious factors, varicella-zoster virus (VZV) is a leading cause of central nervous system vasculopathy and stroke in childhood. Not only have viral markers been detected in the cerebrospinal fluid of affected patients, but also direct evidence of viral particles in the wall of cerebral arteries has been demonstrated in rare pathological specimens. This certainly reflects a localized infectious process likely associated with variable indirect inflammatory responses. Yet the usefulness in this setting of a lumbar puncture as well as of subsequent targeted antiviral and/or anti-inflammatory therapies is uncertain. Indeed, in the majority of cases, the so-called post-varicella angiopathy has a monophasic evolution with spontaneous resolution or stabilization, explaining diverging diagnostic and treatment approaches. In this paper, we have addressed this problematic area by reviewing 26 published cases from the year 2000 and three unpublished cases. Post-varicella stroke is typically associated with angiopathy most often involving the initial portion of the middle cerebral artery, causing a basal ganglia stroke. It tends to occur in young immunocompetent children. Thrombophilia work-up is in general negative. Lumbar puncture was performed in 17 out of 29 cases. Viral markers were examined in 14 cases, but were positive in only eight cases. Antiviral therapy was administrated in 11 children. In this small retrospective study, the treated children's vasculopathy did not progress more favorably nor was there a better outcome compared with untreated subjects.