Search

Abstract Background In juvenile systemic lupus erythematosus (j-SLE) with neuropsychiatric (NP) symptoms, there is a lack of diagnostic biomarkers. Thus, we study whether PET-FDG may identify any metabolic dysfunction in j-NPSLE. Methods A total of 19 18FDG-PET exams were consecutively performed using PET-MRI system in 11 non-sedated patients presenting with j-NPSLE (11-18y) for less than 18 months (m) and without any significant lesion at MRI. Psychiatric symptoms were scored from 0 (none) to 3 (severe) at PET time. PET images were visually analyzed and voxel-based analyses of cerebral glucose metabolism were performed using statistical parametric mapping (spm) with an age-matched control group, at threshold set > 50 voxels using both p

Abstract Status epilepticus (SE) is a life‐threatening emergency with high morbidity and mortality. In people with epilepsy, the management of SE is focused on early medical treatment. Stiripentol is a third‐generation antiseizure medication (ASM) approved for refractory generalized tonic–clonic seizures in Dravet syndrome. The aim of this systematic review was to evaluate the effectiveness and safety of stiripentol in reducing the incidence of SE in patients with Dravet syndrome or any epilepsy characterized by recurrent SE. The PubMed and Cochrane databases were systematically searched, and gray literature was hand‐searched. Search results were screened by title and abstract; studies with data on the effect of stiripentol on SE outcomes, including the cessation of SE, reduction in number of SE episodes, or reduction in hospitalizations, were included. Of 66 records identified, 17 studies were eligible for inclusion, of which 15 were human studies (n = 474; aged 1.1–78 years), and two were animal experiments. Results of retrospective or prospective observational studies showed that stiripentol as add‐on therapy to ASMs such as clobazam or valproate reduced the incidence of SE in patients with Dravet syndrome or other developmental and epileptic encephalopathies (DEEs). A mean of 68% of patients (range 41%–100%) had a ≥50% reduction in SE episodes from baseline, and 26%–100% of patients (mean 77%) became SE‐free after stiripentol initiation. Moreover, this review found stiripentol, used as acute treatment, may also be effective for the cessation of super‐refractory SE, but data are limited to three retrospective case series. Stiripentol was generally well‐tolerated. In conclusion, stiripentol reduces the incidence of SE episodes in patients with Dravet syndrome and potentially other DEEs, and it promotes cessation of super‐refractory SE in patients with and without a history of seizures. Plain Language Summary Status epilepticus (SE) is a life‐threatening, long‐lasting seizure occurring in patients with/without epilepsy. This article analyzed 15 published studies that investigated the effects and safety of the anti‐seizure medication stiripentol for preventing SE in epilepsy patients (prevention) or stopping an SE episode (cessation), and two animal studies that investigated how stiripentol works. In epilepsy patients, stiripentol halved the number of SE episodes in 41–100% of patients, 26–100% of patients became SE‐free, and stiripentol was considered to be well tolerated. In patients with/without epilepsy, stiripentol may stop the SE episode after other drugs like anesthetics have not worked.

Abstract Background Attention‐deficit hyperactivity disorder (ADHD) is a frequent comorbidity in children with epilepsy, which management mostly relies on the usual treatments of ADHD, especially methylphenidate. Supplementation with polyunsaturated n‐3 Fatty Acid (PUFA) has been proposed as an alternative therapeutic approach in ADHD without epilepsy but has never been evaluated in epilepsy‐associated ADHD. Methods A multicenter double blind randomized placebo‐controlled trial evaluating supplementation with PUFA, in eicosapentaenoic‐ and docosahexaenoic‐acid form, conjugated to a phospholipid vector (PS‐Omega3) in children aged >6 and

Summary: Background: Variants in GABRB2, encoding the β2 subunit of the γ-aminobutyric acid type A (GABAA) receptor, can result in a diverse range of conditions, ranging from febrile seizures to severe developmental and epileptic encephalopathies. However, the mechanisms underlying the risk of developing milder vs more severe forms of disorder remain unclear. In this study, we conducted a comprehensive genotype–phenotype correlation analysis in a cohort of individuals with GABRB2 variants. Methods: Genetic and electroclinical data of 42 individuals harbouring 26 different GABRB2 variants were collected and accompanied by electrophysiological analysis of the effects of the variants on receptor function. Findings: Electrophysiological assessments of α1β2γ2 receptors revealed that 25/26 variants caused dysfunction to core receptor properties such as GABA sensitivity. Of these, 17 resulted in gain-of-function (GOF) while eight yielded loss-of-function traits (LOF). Genotype-phenotype correlation analysis revealed that individuals harbouring GOF variants suffered from severe developmental delay/intellectual disability (DD/ID, 74%), movement disorders such as dystonia or dyskinesia (59%), microcephaly (50%) and high risk of early mortality (26%). Conversely, LOF variants were associated with milder disease manifestations. Individuals with these variants typically exhibited fever-triggered seizures (92%), milder degrees of DD/ID (85%), and maintained ambulatory function (85%). Notably, severe movement disorders or microcephaly were not reported in individuals with loss-of-function variants. Interpretation: The data reveals that genetic variants in GABRB2 can lead to both gain and loss-of-function, and this divergence is correlated with distinct disease manifestations. Utilising this information, we constructed a diagnostic flowchart that aids in predicting the pathogenicity of recently identified variants by considering clinical phenotypes. Funding: This work was funded by the Australian National Health & Medical Research Council, the Novo Nordisk Foundation and The Lundbeck Foundation.

A case study of a child with childhood absence epilepsy and hyperactivity introduces the discussion around the psychiatric diagnosis, differential considerations, and pharmacologic treatment options for ADHD/hyperactivity in children with epilepsy. Most of the time, ADHD in children with epilepsy is an inattentive form.The assessment emphasizes the need to differentiate ADHD symptoms from other psychiatric comorbidities. This is also crucial to evaluate when symptoms emerged, their impact on daily life, and if it could be a potential medication side effect. Speaking about hyperactivity signs, differential diagnoses include anxiety disorders, autism spectrum disorders, learning disabilities, and thyroid disorders. Valproate use is associated with an exacerbation of attentional issues in childhood absence epilepsy, but there are also studies suggesting its possible role in hyperactivity symptoms.Regarding pharmacologic treatment, limited studies exist on ADHD management in children with epilepsy. Methylphenidate shows effectiveness without significant risk of epilepsy worsening. Atomoxetine and clonidine, usually use in ADHD, lack sufficient data for efficacy and safety in children with epilepsy and ADHD. Pharmacologic treatment should be a part of a global management plan that involves psychoeducation, environmental adaptations, and collaborative efforts between healthcare providers, caregivers, and schools.

Introduction Severe sialorrhoea is a common, distressing problem in children/adolescents with neurodisabilities, which has adverse health and social consequences. The SALIVA trial is designed to evaluate the efficacy and safety of a paediatric-specific oral solution of glycopyrronium along with its impact on quality-of-life (QoL), which has been lacking from previous trials of sialorrhoea treatments.Methods and analysis A double-blind, placebo-controlled, randomised phase IV trial is ongoing in several centres across France. Eighty children aged 3–17 years with severe sialorrhoea (≥6 on the modified Teachers Drooling Scale) related to chronic neurological disorders in whom non-pharmacological standard of care has already been implemented or has failed, will be recruited. Patients will be randomised 1:1 to receive a 2 mg/5 mL solution of glycopyrronium bromide (Sialanar 320 µg/mL glycopyrronium) or placebo three times daily during a 3-month blinded period. After Day 84, participants will be invited into a 6-month, open-label study extension period, where they will all receive glycopyrronium. The primary endpoint of the double-blind period will be the change from baseline to Day 84 in the Drooling Impact Scale (DIS), a validated measure to assess sialorrhoea. A series of secondary efficacy endpoints involving change in total DIS, specific DIS items and response (DIS improvement ≥13.6 points) will be analysed in a prespecified hierarchy. QoL data will be collected from parents, caregivers and patients where possible using specific DIS questions and DISABKIDS questionnaires. Safety endpoints, including adverse events, will be assessed throughout the trial periods.Ethics and dissemination In total, 87 children have been recruited and recruitment is now complete. Final results are expected by the end of 2023. Findings will be presented at conferences and published in peer-reviewed journals.Trial registration number EudraCT 2020-005534-15.

Abstract Objective Antiseizure medications (ASMs) remain the mainstay of epilepsy treatment. These ASMs have mainly been tested in trials in adults with epilepsy, which subsequently led to market authorization (MA). For treatment of – especially young – children with epilepsy, several ASMs do not have a MA and guidelines are lacking, subsequently leading to “off‐label” use of ASMs. Even though “off‐label” ASM prescriptions for children could lead to more adverse events, it can be clinically appropriate and rational if the benefits outweigh the risks. This could be the case if “on‐label” ASM, in mono‐ or polytherapy, fails to achieve adequate seizure control. Methods The Medical Therapies Task Force of the International League Against Epilepsy (ILAE) Commission for Pediatrics performed a survey to study the current treatment practices in six classic, early life epilepsy scenarios. Our aim was not only to study first‐ and second‐line treatment preferences but also to illustrate the use of “off‐label” drugs in childhood epilepsies. Results Our results reveal that several ASMs (e.g. topiramate, oxcarbazepine, benzodiazepines) are prescribed “off‐label” in distinct scenarios of young children with epilepsy. In addition, recent scientific guidelines were not always adopted by several survey respondents, suggesting a potential knowledge gap. Significance We report the relatively common use of “off‐label” prescriptions that underlines the need for targeted and appropriately designed clinical trials, including younger patients, which will also result in the ability to generate evidence‐based guidelines.

GRN mutations are among the main genetic causes of frontotemporal dementia (FTD). Considering the progranulin involvement in lysosomal homeostasis, we aimed to evaluate if plasma lysosphingolipids (lysoSPL) are increased in GRN mutation carriers, and whether they might represent relevant fluid-based biomarkers in GRN-related diseases.We analyzed four lysoSPL levels in plasmas of 131 GRN carriers and 142 non-carriers, including healthy controls and patients with frontotemporal dementias (FTD) carrying a C9orf72 expansion or without any mutation. GRN carriers consisted of 102 heterozygous FTD patients (FTD-GRN), three homozygous patients with neuronal ceroid lipofuscinosis-11 (CLN-11) and 26 presymptomatic carriers (PS-GRN), the latter with longitudinal assessments. Glucosylsphingosin d18:1 (LGL1), lysosphingomyelins d18:1 and isoform 509 (LSM18:1, LSM509) and lysoglobotriaosylceramide (LGB3) were measured by electrospray ionization-tandem mass spectrometry coupled to ultraperformance liquid chromatography.Levels of LGL1, LSM18:1 and LSM509 were increased in GRN carriers compared to non-carriers (p

Abstract Dravet syndrome (DS) is a severe, rare, and complex developmental and epileptic encephalopathy affecting 1 in 16 000 live births and characterized by a drug‐resistant epilepsy, cognitive, psychomotor, and language impairment, and behavioral disorders. Evidence suggests that optimal treatment of seizures in DS may improve outcomes, even though neurodevelopmental impairments are the likely result of both the underlying genetic variant and the epilepsy. We present an updated guideline for DS diagnosis and treatment, taking into consideration care of the adult patient and nonpharmaceutical therapeutic options for this disease. This up‐to‐date guideline, which is based on an extensive review of the literature and culminates with a new treatment algorithm for DS, is a European consensus developed through a survey involving 29 European clinical experts in DS. This guideline will serve professionals in their clinical practice and, as a consequence, will benefit DS patients and their families.

IntroductionThe PERMIT study is the largest pooled analysis of perampanel (PER) clinical practice data conducted to date.MethodsThis post-hoc analysis of PERMIT investigated the effectiveness, safety and tolerability of PER when used as early add-on therapy (after failure of one or two previous antiseizure medications) in comparison with late add-on therapy (after failure of three or more previous antiseizure medications). Retention and effectiveness were assessed after 3, 6, and 12 months, and at the last visit (last observation carried forward). Effectiveness was assessed by seizure type (total seizures, focal seizures, generalized tonic-clonic seizures [GTCS]) and assessments included seizure freedom rate and responder rate. Safety and tolerability were assessed by evaluating adverse events (AEs) and discontinuation due to AEs.ResultsThe Full Analysis Set included 1184 and 2861 PWE treated with PER as early and late add-on therapy, respectively. Compared to the late add-on subgroup, the early add-on subgroup was characterized by later mean age at epilepsy onset, shorter mean duration of epilepsy, lower rates of intellectual disability and psychiatric comorbidity, and lower frequency of seizures per month, suggesting a less severe form of epilepsy in this subgroup. After 12 months, retention was significantly higher in the early versus late add-on subgroup (67.7% vs. 62.4%; p = 0.004). At the last visit, responder rates in the early versus late add-on subgroup were significantly higher for total seizures (68.2% vs. 39.3%; p < 0.001), focal seizures (65.0% vs. 36.8%; p < 0.001) and GTCS (83.7% vs. 67.2%; p < 0.001), as were seizure freedom rates (total seizures, 35.9% vs. 11.9% [p < 0.001]; focal seizures, 29.4% vs. 8.7% [p < 0.001]; GTCS, 69.0% vs. 48.1% [p < 0.001]). Incidence of AEs was significantly lower in the early versus late add-on subgroup (42.1% vs. 54.7%; p < 0.001), as was the rate of discontinuation due to AEs over 12 months (15.0% vs. 18.1%; p = 0.031).DiscussionThis study demonstrated that PER was effective and generally well tolerated when initiated as early or late add-on therapy, but it was significantly more effective and better tolerated when initiated early. These findings support PER's use as a broad-spectrum, early add-on therapy for use in PWE with focal and generalized seizures.

Abstract Background Many initiatives have emerged worldwide to handle the surge of hospitalizations during the SARS-CoV-2 pandemic. In France, the University of Paris North called on its medical students, whose status makes them integral members of the healthcare staff, to volunteer in their capacity of medical students and/or as nurses/nursing aids in understaffed intensive care units and other Covid-19 services. We attempted to evaluate their commitment, whether the pandemic affected their certainty for the medical profession and career choices, and how they scored their sadness and anxiety levels. Methods The University of Paris North took a weekly official census of the involvement of 1205 4th–6th year medical students during the first lockdown in France. Six weeks after the lockdown began (May 4th), an e-questionnaire was sent to 2145 2nd-6th year medical students. The survey lasted 4 weeks and documented volunteering by medical students, the association between the pandemic and certainty for their profession, their choice of medical specialty and factors that influenced sadness and anxiety scores. Results 82% of 4th–6th year medical students volunteered to continue their internship or be reassigned to COVID-19 units. Of 802 2nd-6th year students who completed the e-questionnaire, 742 (93%) volunteered in Covid-19 units, of which half acted as nurses. This engagement reinforced the commitment of 92% of volunteers to become physicians. However, at the peak of the outbreak, 17% had doubts about their ability to be physicians, while 12% reconsidered their choice of future specialty. Finally, 38% of students reported a score of 7/10 or more on the sadness scale, and 43% a score of 7/10 or more for anxiety. Neither study year nor service influenced sadness or anxiety scores. However, gender influenced both, with women scoring significantly higher than men (p

Abstract Background Tuberous sclerosis complex (TSC) is a rare, genetic, multisystem disorder characterized by the growth of hamartomas in several organs, including the brain, kidneys, heart, eyes, and lungs. Even though over 90% of patients will have some form of TSC-associated neuropsychiatric disorder (TAND), there is an apparent lack of involvement of mental health professionals (MHPs) in the care of patients with TSC. The aim of this study was to determine the current level of TAND awareness in the TSC community and to identify possible barriers to effective multidisciplinary collaboration between MHPs and other healthcare providers (HCPs) in TAND management. Methods An electronic survey on current TSC and TAND management was conducted, targeting TSC caregivers/families, psychiatrists, neurologists, TSC specialists, and primary care physicians. Results The invitation to participate in the survey was emailed to 659 HCPs and was disseminated through social media channels of patient advocacy groups. The survey was open for 4 months, with 359 responses collected. The majority of participants were TSC caregivers/families (73.3% of all responses). Of the 96 HCPs who participated, most were neurologists (61.5%) or TSC specialists (28.1%). Only 6 psychiatrists and 4 primary care physicians participated. Approximately half of patients have never had a neuropsychiatric assessment, and it was their caregivers/families who initiated the discussion of TAND with their providers. Almost 70% of TSC caregivers/families believed that psychiatric treatment could improve their quality of life. However, 54% of patients had difficulty obtaining psychiatric assessment. In turn, only 21% of HCPs believed that psychiatric therapy would help and 74% were concerned that their patients would be stigmatized by psychiatric referral. Conclusions This study focused on European healthcare systems suggests that current care for mental health issues in patients with TSC is inadequate, despite guideline recommendations for regular neuropsychiatric assessments. This appears to be due to a combination of gaps in diagnosis and surveillance, low frequency of psychiatric referrals, insufficient resources, and stigmatization of mental healthcare. There is a pressing need for further initiatives to study and address the mechanisms underlying the mental health treatment gap. The importance of MHP support must be recognized to optimize TSC management.

Anti-seizure medications (ASMs) are the first line of treatment for seizure control in children with epilepsy. Cumulative evidence suggests an imbalanced gut microbiota in refractory epilepsy patients. We systematically investigated the differential antimicrobial impacts of nine ASM active ingredients, seven common excipients of ASMs, and four syrup formulations on core early-life gut microbiota strains. Additionally, we evaluated the toxicity and gene expression profiles of HT-29 colon epithelial cells when exposed to active ingredients with or without bacterial supernatants. The physicochemical structure of ASM active ingredients and bacterial phylogeny were found to be related to ASM toxicity. Carbamazepine, lamotrigine, and topiramate reduced the growth of more than ten strains along with syrup excipient propyl-paraben. Various artificial sweeteners present in ASM formulations stimulated the growth of gut bacterial strains. The active ingredients that were more toxic to bacterial strains also exhibited toxicity towards HT-29 cells, yet Bifidobacterium longum supernatant reduced cytotoxic effects of carbamazepine and lamotrigine. Akkermansia muciniphila or mixed community supernatants reduced the expression of drug resistance genes in HT-29 cell lines. In summary, our results indicate that several ASM active ingredients and their excipients regulate the growth of gut bacterial strains in a species-specific manner. Interactions between ASMs and gut epithelial cells might be modulated by gut microbial metabolites.

Abstract Glut1 deficiency syndrome (Glut1DS) is a brain energy failure syndrome caused by impaired glucose transport across brain tissue barriers. Glucose diffusion across tissue barriers is facilitated by a family of proteins including glucose transporter type 1 (Glut1). Patients are treated effectively with ketogenic diet therapies (KDT) that provide a supplemental fuel, namely ketone bodies, for brain energy metabolism. The increasing complexity of Glut1DS, since its original description in 1991, now demands an international consensus statement regarding diagnosis and treatment. International experts (n = 23) developed a consensus statement utilizing their collective professional experience, responses to a standardized questionnaire, and serial discussions of wide‐ranging issues related to Glut1DS. Key clinical features signaling the onset of Glut1DS are eye‐head movement abnormalities, seizures, neurodevelopmental impairment, deceleration of head growth, and movement disorders. Diagnosis is confirmed by the presence of these clinical signs, hypoglycorrhachia documented by lumbar puncture, and genetic analysis showing pathogenic SLC2A1 variants. KDT represent standard choices with Glut1DS‐specific recommendations regarding duration, composition, and management. Ongoing research has identified future interventions to restore Glut1 protein content and function. Clinical manifestations are influenced by patient age, genetic complexity, and novel therapeutic interventions. All clinical phenotypes will benefit from a better understanding of Glut1DS natural history throughout the life cycle and from improved guidelines facilitating early diagnosis and prompt treatment. Often, the presenting seizures are treated initially with antiseizure drugs before the cause of the epilepsy is ascertained and appropriate KDT are initiated. Initial drug treatment fails to treat the underlying metabolic disturbance during early brain development, contributing to the long‐term disease burden. Impaired development of the brain microvasculature is one such complication of delayed Glut1DS treatment in the postnatal period. This international consensus statement should facilitate prompt diagnosis and guide best standard of care for Glut1DS throughout the life cycle.

Abstract Objective Infantile spasm syndrome (ISS) is an epileptic encephalopathy without established treatment after the failure to standard of care based on steroids and vigabatrin. Converging lines of evidence indicating a role of NR2B subunits of the N‐methyl‐D‐aspartate (NMDA) receptor on the onset of spams in ISS patients, prompted us to test radiprodil, a negative allosteric NR2B modulator in preclinical seizure models and in infants with ISS. Methods Radiprodil has been tested in three models, including pentylenetetrazole‐induced seizures in rats across different postnatal (PN) ages. Three infants with ISS have been included in a phase 1b escalating repeated dose study. Results Radiprodil showed the largest protective seizure effects in juvenile rats (maximum at PN12, corresponding to late infancy in humans). Three infants resistant to a combination of vigabatrin and prednisolone received individually titrated doses of radiprodil for up to 34 days. Radiprodil was safe and well tolerated in all three infants, and showed the expected pharmacokinetic profile. One infant became spasm‐free and two showed clinical improvement without reaching spasm‐freedom. After radiprodil withdrawal, the one infant continued to be spasm‐free, while the two others experienced seizure worsening requiring the use of the ketogenic diet and other antiepileptic drugs. Interpretation Radiprodil showed prominent anti‐seizure effect in juvenile animals, consistent with the prevalent expression of NR2B subunit of the NMDA receptor at this age in both rodents and humans. The clinical testing, although preliminary, showed that radiprodil is associated with a good safety and pharmacokinetic profile, and with the potential to control epileptic spasms.

Abstract High‐quality placebo‐controlled drug trials for focal‐onset seizures in infants and children younger than 4 years have become increasingly difficult to perform because of eligibility constraints and onerous study designs. Traditional designs used in these populations require a high baseline seizure frequency, two hospitalizations for video‐electroencephalography (video‐EEG) monitoring, and willingness to accept potential exposure to placebo when the drugs to be tested are usually already available for off‐label prescription. To address these constraints, the International League Against Epilepsy (ILAE) regulatory taskforce and the ILAE pediatric commission, in collaboration with the Pediatric Epilepsy Research Consortium (PERC), propose a novel trial design which involves seizure counting by caregivers based on previous video‐EEG/video validation of specific seizure semiologies. We present a novel randomized placebo‐controlled trial design intended to be used for studying new antiseizure medications (ASMs) for focal‐onset seizures (FOS) in children aged one month to four years. This design uses “time to Nth seizure” as the primary outcome and incorporates a new element of variable baseline duration. This approach permits enrollment of infants with lower seizure burden, who might not have video‐EEG‐recorded seizures within 2‐3 days of monitoring. Repeated hospitalizations for video‐EEG recordings are avoided, and duration of baseline and exposure to placebo or ineffective treatment(s) are minimized. By broadening eligibility criteria, reducing risks from prolonged placebo exposure, and relying on validated recording of seizure counting by caregivers, clinical trials will be likely to be completed more efficiently than in the recent past.

Summary Objective Drug development for patients with Lennox‐Gastaut syndrome (LGS) is based on clinical trials that use drop seizure counts. However, such counts do not assess total seizure burden and affect a patient's quality of life (QoL). In this post hoc analysis, we evaluated two novel seizure efficacy parameters related to QoL in pediatric patients with LGS, using seizure diary data from rufinamide Study 303 (NCT01405053). Methods Study 303 was a phase III, multicenter, randomized, controlled, open‐label study involving patients aged ≥1 to

Abstract Background Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disorder associated with mutations in TSC1 and TSC2 genes, upregulation of mammalian target of rapamycin signaling, and subsequent tumor formation in various organs. Due to the many manifestations of TSC and their potential complications, management requires the expertise of multiple medical disciplines. A multidisciplinary care approach is recommended by consensus guidelines. Use of multidisciplinary teams (MDTs) has been shown to be beneficial in treating other complex diseases, such as cancer. In a lifelong disease such as TSC, an MDT may facilitate the transition from pediatric to adult care. However, little guidance exists in the literature regarding how to organize an MDT in TSC. Methods To discuss the best approach to assembling an MDT, this project was initiated in October 2017 with a meeting of 12 physicians from various specialties and various countries. Following this first meeting, the experts generated statements on the most important aspects to implement in establishing an MDT for TSC by 3 rounds of selection using a Delphi process via electronic correspondence. Finally, TSC patient advocates reviewed the findings and provided additional insights from a patient perspective. Results A 3-step roadmap was recommended, starting with identifying a single individual to begin organizing care (Step 1), then establishing a small core team (Step 2), and finally, establishing a larger multi-disciplinary team (Step 3). Because of the multisystemic nature of TSC, the MDT should include specialists such as a neurologist, a neurosurgeon, a nephrologist, a urologist, a pulmonologist, an ophthalmologist, a cardiologist, a dermatologist, a geneticist, and a psychiatrist/psychologist. The MDT should recommend a care plan for each patient based on the individual’s needs and in consultation with him/her or his/her family. Some of the most important aspects of an MDT that were agreed upon included identifying a case manager to help coordinate care, providing access to health care professionals of varying specialties, and including a lead physician who takes medical responsibility for patients’ overall care. Conclusions The results of our consensus provide guidance to support the initiation of an MDT in TSC.

Organophosphate pesticides and nerve agents (OPs), are characterized by cholinesterase inhibition. In addition to severe peripheral symptoms, high doses of OPs can lead to seizures and status epilepticus (SE). Long lasting seizure activity and subsequent neurodegeneration promote neuroinflammation leading to profound pathological alterations of the brain.The aim of this study was to characterize neuroinflammatory responses at key time points after SE induced by the OP, diisopropylfluorophosphate (DFP). Immunohistochemistry (IHC) analysis and RT-qPCR on cerebral tissue are often insufficient to identity and quantify precise neuroinflammatory alterations. To address these needs, we performed RT-qPCR quantification after whole brain magnetic-activated cell-sorting (MACS) of CD11B (microglia/infiltrated macrophages) and GLAST (astrocytes)-positive cells at 1, 4, 24 h and 3 days post-SE. In order to compare these results to those obtained by IHC, we performed, classical Iba1 (microglia/infiltrated macrophages) and GFAP (astrocytes) IHC analysis in parallel, focusing on the hippocampus, a brain region affected by seizure activity and neurodegeneration.Shortly after SE (1–4 h), an increase in pro-inflammatory (M1-like) markers and A2-specific markers, proposed as neurotrophic, were observed in CD11B and GLAST-positive isolated cells, respectively. Microglial cells successively expressed immuno-regulatory (M2b-like) and anti-inflammatory (M2a-like) at 4 h and 24 h post-SE induction. At 24 h and 3 days, A1-specific markers, proposed as neurotoxic, were increased in isolated astrocytes. Although IHC analysis presented no modification in terms of percentage of marked area and cell number at 1 and 4 h after SE, at 24 h and 3 days after SE, microglial and astrocytic activation was visible by IHC as an increase in Iba1 and GFAP-positive area and Iba1-positive cells in DFP animals when compared to the control.Our work identified sequential microglial and astrocytic phenotype activation. Although the role of each phenotype in SE cerebral outcomes requires further study, targeting specific markers at specific time point could be a beneficial strategy for DFP-induced SE treatment.

Background: Knowledge is increasing about TSC-Associated Neuropsychiatric Disorders (TAND), but little is known about the potentially confounding effects of intellectual ability (IA) on the rates of TAND across age, sex, and genotype. We evaluated TAND in (a) children vs. adults, (b) males vs. females, and (c) TSC1 vs. TSC2 mutations, after stratification for levels of IA, in a large, international cohort.Methods: Individuals of any age with a documented visit for TSC in the 12 months prior to enrolment were included. Frequency and percentages of baseline TAND manifestations were presented by categories of IA (no intellectual disability [ID, intelligence quotient (IQ)>70]; mild ID [IQ 50–70]; moderate-to-profound ID [IQ

Abstract Epilepsy is a neurological condition that affects 1% of the world population. Conventional treatments of epilepsy use drugs targeting neuronal excitability, inhibitory or excitatory transmission. Yet, one third of patients presents an intractable form of epilepsy and fails to respond to pharmacological anti-epileptic strategies. The ketogenic diet is a well-established non-pharmacological treatment that has been proven to be effective in reducing seizure frequency in the pharmaco-resistant patients. This dietary solution is however extremely restrictive and can be associated with complications caused by the high [fat]:[carbohydrate + protein] ratio. Recent advances suggest that the traditional 4:1 ratio of the ketogenic diet is not a requisite for its therapeutic effect. We show here that combining nutritional strategies targeting specific amino-acids, carbohydrates and fatty acids with a low [fat]:[proteins + carbohydrates] ratio also reduces excitatory drive and protects against seizures to the same extent as the ketogenic diet. Similarly, the morphological and molecular correlates of temporal lobe seizures were reduced in animals fed with the combined diet. These results provide evidence that low-fat dietary strategies more palatable than the ketogenic diet could be useful in epilepsy.

Perinatal arterial stroke is the most frequent form of cerebral infarction in children. Neonatal seizures are the most frequent symptom during the neonatal period. The current management of perinatal stroke is based on supportive care. It is currently unknown if treatment of the seizures modifies the outcome, and no clinical studies have focused on seizures during neonatal stroke. We studied the effect of phenobarbital and levetiracetam on an ischemic-reperfusion stroke model in P7 rats using prolonged electroencephalographic recordings and a histologic analysis of the brain (24 h after injury). The following two types of epileptic events were observed: 1) bursts of high amplitude spikes during ischemia and the first hours of reperfusion and 2) organized seizures consisting in discharges of a 1–2 Hz spike-and-wave. Both phenobarbital and levetiracetam decreased the total duration of the bursts of high amplitude spikes. Phenobarbital also delayed the start of seizures without changing the total duration of epileptic discharges. The markedly limited efficacy of the antiepileptic drugs studied in our neonatal stroke rat model is frequently observed in human neonatal seizures. Both drugs did not modify the stroke volume, which suggests that the modification of the quantity of bursts of high amplitude spikes does not influence the infarct size. In the absence of a reduction in seizure burden by the antiepileptic drugs, we increased the seizure burden and stroke volume by combining our neonatal stroke model with a lithium-pilocarpine-induced status epilepticus. Our data suggest that the reduction of burst of spikes did not influence the stroke volume. The presence of organized seizure with a pattern close to what is observed in human newborns seems related to the presence of the infarct. Further research is required to determine the relationship between seizure burden and infarct volume.

Epileptic encephalopathies are a group of diseases in which epileptic activity itself contributes to severe cognitive and behavioral impairments above and beyond what might be expected from the underlying pathology alone. These impairments can worsen over time. This concept has been continually redefined since its introduction. A few syndromes are considered epileptic encephalopathies: early myoclonic encephalopathy and Ohtahara syndrome in the neonatal period, epilepsy of infancy with migrating focal seizures, West syndrome or infantile spasms, Dravet syndrome during infancy, Lennox-Gastaut syndrome, epileptic encephalopathy with continuous spikes-and-waves during sleep, and Landau-Kleffner syndrome during childhood. The inappropriate use of this term to refer to all severe epilepsy syndromes with intractable seizures and severe cognitive dysfunction has led to confusion regarding the concept of epileptic encephalopathy. Here, we review our current understanding of those epilepsy syndromes considered to be epileptic encephalopathies. Genetic studies have provided a better knowledge of neonatal and infantile epilepsy syndromes, while neuroimaging studies have shed light on the underlying causes of childhood-onset epileptic encephalopathies such as Lennox-Gastaut syndrome. Apart from infantile spasm models, we lack animal models to explain the neurobiological mechanisms at work in these conditions. Experimental studies suggest that neuroinflammation may be a common neurobiological pathway that contributes to seizure refractoriness and cognitive involvement in the developing brain.

Lennox–Gastaut syndrome (LGS) is a severe epileptic and developmental encephalopathy that is associated with a high rate of morbidity and mortality. It is characterized by multiple seizure types, abnormal electroencephalographic features, and intellectual disability. Although intellectual disability and associated behavioral problems are characteristic of LGS, they are not necessarily present at its outset and are therefore not part of its diagnostic criteria. LGS is typically treated with a variety of pharmacological and non-pharmacological therapies, often in combination. Management and treatment decisions can be challenging, due to the multiple seizure types and comorbidities associated with the condition. A panel of five epileptologists met to discuss consensus recommendations for LGS management, based on the latest available evidence from literature review and clinical experience. Treatment algorithms were formulated. Current evidence favors the continued use of sodium valproate (VPA) as the first-line treatment for patients with newly diagnosed de novo LGS. If VPA is ineffective alone, evidence supports lamotrigine, or subsequently rufinamide, as adjunctive therapy. If seizure control remains inadequate, the choice of next adjunctive antiepileptic drug (AED) should be discussed with the patient/parent/caregiver/clinical team, as current evidence is limited. Non-pharmacological therapies, including resective surgery, the ketogenic diet, vagus nerve stimulation, and callosotomy, should be considered for use alongside AED therapy from the outset of treatment. For patients with LGS that has evolved from another type of epilepsy who are already being treated with an AED other than VPA, VPA therapy should be considered if not trialed previously. Thereafter, the approach for a de novo patient should be followed. Where possible, no more than two AEDs should be used concomitantly. Patients with established LGS should undergo review by a neurologist specialized in epilepsy on at least an annual basis, including a thorough reassessment of their diagnosis and treatment plan. Clinicians should always be vigilant to the possibility of treatable etiologies and alert to the possibility that a patient’s diagnosis may change, since the seizure types and electroencephalographic features that characterize LGS evolve over time. To date, available treatments are unlikely to lead to seizure remission in the majority of patients and therefore the primary focus of treatment should always be optimization of learning, behavioral management, and overall quality of life.

In many experimental systems, proinflammatory stimuli exhibit proconvulsant properties. There are also accumulating data suggesting that inflammation may contribute to epileptogenesis in experimental models as well as in humans. Using two different models (Lithium-pilocarpine induced-status epilepticus (SE) and rapid kindling), we address this issue in the developing brain. Using P14 Wistar rat pups, we showed that inflammation induced by LPS results, after SE, into a more severe disease in adulthood. The main histological feature was an active gliosis that was observed only when inflammation and SE was combined. The use of a kindling model at P14, a model where seizure progress without any neurodegeneration, permits to show that systemic inflammation is responsible of an enhancement of epileptogenesis. The role of inflammation should be further explored in immature brain to identify therapeutic targets that may be relevant to clinical practice where the association of inflammation and epileptic events is common.

Jean-Christophe Cuvellier1, Frédéric Couttenier2, Stéphane Auvin1, Louis Vallée11Department of Child Neurology, Pediatric Clinic, University Hospital, Lille, France; 2Division of Gastroenterology, Hepatology and Nutrition, Pediatric Clinic, University Hospital, Lille, FranceAbstract: Few data are available on the applicability of both the criteria proposed by Silberstein and Lipton (S-L) and the International Classification of Headache Disorders-II (ICHD-II) in the classification of children and adolescents with chronic daily headache (CDH). The International Headache Society recently added revised criteria (ICHD-IIR) for chronic migraine to its Appendix. We retrospectively reviewed all charts of 34 children and adolescents (

Stéphane AuvinDepartment of Pediatric Neurology, Lille University Hospital, Lille, France; Pharmacology Laboratory, Lille Medical School, Lille, FranceAbstract: Drug treatment of Juvenile myoclonic epilepsy (JME) is mainly based on clinical experience and prospective and retrospective studies, with little evidence from randomized clinical trials. There are no head-to-head comparisons between old and new antiepileptic drugs (AEDs) and no drugs licensed specifically for JME. Valproate is unquestionably the drug of the first choice in men with JME. In women, lamotrigine should be preferred regarding teratogenicity and side effects of valproate. In addition, levetiracetam and topiramate are effective and can be use in combination or as second line treatment. Some AEDs can aggravate JME. In addition of AEDs, non-pharmacological treatments are important in JME. JME usually require lifelong treatment because seizures nearly always return after withdrawal of therapy.Keywords: myoclonic seizure, myoclonic epilepsy, antiepileptic drugs