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While ataxia is a relatively common presenting feature in pediatric patients, it represents only one possible cause of uncoordinated movements. Other possible causes of uncoordinated movements include ingestion of toxic substances, musculoskeletal diseases, psychogenic disorders, extrapyramidal movement disorders, peripheral neuropathies, spasticity from any cause, and epilepsy. Therefore, primary health care providers must recognize and exclude other etiologies of uncoordinated movements before attaching the label “ataxia” to any patient presenting with poor coordination. Once the presence of ataxia is confirmed, the cause should be investigated. As ataxia may be vestibular, sensory, or cerebellar in origin, medical practitioners must evaluate the diverse symptoms and signs to effectively differentiate the various types of ataxia. Three case studies are presented to illustrate the complexity associated with the assessment of ataxia. Each case will discuss a pediatric patient who displays cerebellar ataxia as a concurrent feature of a gene-specific developmental and epileptic encephalopathy. These cases will provide an example of how ataxia may be differentiated from other causes of uncoordinated movements related to epilepsy and anti-seizure medications, namely: nonconvulsive seizures, postictal state, and medication side effects or toxicity. The assessment of poor balance can be challenging at times; however, with knowledge of the differential diagnosis of poor balance, medical practitioners will be able to confidently determine the presence of true ataxia from various ataxia mimickers, thereby allowing for timely and accurate diagnosis, and appropriate management.

Epilepsy is a common, often severe, feature of LAMA2-related muscular dystrophy (LAMA2-RD) and could represent its onset and main manifestation, even in the absence of overt muscle involvement. To date, there is no systematic characterization of epilepsy in LAMA2-RD, and its impact on neurodevelopment and on the clinical course remains poorly established. In view of this knowledge gap, we conducted a systematic review of the literature and, as an illustrative example, reported the clinical case of a boy with late-onset LAMA2-related limb-girdle muscular dystrophy presenting with severe epilepsy. Our analyses of the literature data revealed a mean age at first seizure of 8 years, with significant differences between early- versus late-onset disease (5.78 ± 4.11 and 9.00 ± 2.65 years, respectively; p = 0.0007), and complete versus partial merosin deficiency (5.33 ± 3.70 and 10.36 ± 5.49 years, respectively; p = 0.0176). A generalized onset was the most common seizure presentation, regardless of merosin expression levels or the timing of muscular distrophy onset. Cortical malformations were not significantly associated with an earlier epilepsy onset, and were found to be quasi-significantly associated with a greater incidence of focal, or focal and generalized, onset seizures. No clear conclusions could be reached on the electrophysiological and neurodevelopmental features of the disorder, or on the relative efficacy of anti-epileptic treatments; further research on these aspects is needed. This systematic review helps to show that epilepsy in LAMA2-RD may be more than an ancillary manifestation of the disease, but rather one of its core features. A targeted and prompt electroencephalographic and epilepsy assessment, in addition to the specific neuromuscular workup, is therefore mandatory in early clinical management to pursue the best possible outcome for affected children.

Mesial temporal lobe epilepsy (MTLE) is one of the most common types of focal epilepsy in the adult population. MTLE is frequently associated with a specific histopathological lesion in the medial temporal structures, namely hippocampal sclerosis (HS). A significant proportion of patients with MTLE+HS have severe epilepsy, which is often resistant to clinical treatment. For these patients, surgical resection of the epileptogenic lesion can be performed. Our understanding of the underlying mechanisms leading to MTLE+HS has improved significantly over the past few decades. In this review, we aim to present and discuss the most recent findings regarding the genetic determinants of MTLE+HS. Furthermore, we will address studies about transcriptomics, proteomics, metabolomics, and epigenomic signatures of the tissue that is surgically removed from patients with refractory MTLE+HS and animal models of the disorder. We expect to provide an overview and a critical discussion of the findings, limitations, new approaches, and future directions for multi-omics studies in MTLE+HS.

Objectives To describe and quantify the nature and severity of sleep disruptions in young people with Dravet syndrome (DS) based upon parent report. Methods Qualitative review of available pediatric sleep instruments with parent members of the Dravet syndrome Foundation led to the design of a series of questions customized to DS and other severe epilepsies. The questionnaire was administered as part of an on-line survey that reflected specific sleep-related concerns of parents of children with severe epilepsy. Results 76 parent-respondents completed the survey for their children-participants. Children’s median age was 7.5 years (IQR 4.7–15.3); 41 (54 %) were female. The majority of parents (70/76, 93 %) used some method to monitor children while sleeping; co-sleeping was the most common method (45/76, 59 %). Seizures disrupted sleep in 40/76 (53 %); 19(48 %) reported nocturnal seizures 3 or more nights per week. In addition, 58/76 (76 %) also reported non-seizure-related nocturnal awakenings with 30 reporting awakenings 3 or more nights affected per week. Significance Young people with Dravet syndrome have frequently disrupted sleep secondary to seizures and other factors. Co-sleeping practices, medication effects, enuresis during seizures and other factors are not considered on standard sleep questionnaires. Current findings highlight the frequency of epilepsy-specific concerns and lay groundwork for sleep measures more appropriate for this population.

Background Literature regarding congenital subependymal giant cell astrocytomas (SEGA) is limited, and suggests they are at risk of rapid growth and complications. We sought to characterise the growth patterns of congenital SEGA. The second part of the study was an exploratory analysis of congenital SEGA as a possible biomarker for poor neurological outcome. Methods This single-centre case series describes ten patients with TSC who had SEGA diagnosed before 12 months. SEGA diameter and volumetric growth were analysed using serial MRIs. Neurological outcomes were compared to a genotype-matched group. Results All children with congenital SEGA had a TSC2 mutation. Patients were followed for 1-8.7 years, during which median SEGA growth rate was 1.1 mm/yr in diameter or 150 mm3/yr volumetrically. SEGA with volume > 500 mm3 had a significantly higher growth rate compared with smaller SEGA (462 mm3/yr vs. 42 mm3/yr, p = 0.0095). Children with congenital SEGA had a high prevalence of severe epilepsy, developmental disability and autism spectrum disorder. Conclusion Congenital SEGA can follow a relatively benign course with a lower growth rate compared with published literature. Frequent neuroimaging surveillance is recommended for congenital SEGA with volumes exceeding 500 mm3. Impact Congenital SEGA occur in 9.2% of paediatric patients with tuberous sclerosis complex.There are few published cases of congenital SEGA to date. This case series of ten patients adds our experience seen in a tertiary referral hospital over 10 years.Congenital SEGA can follow a relatively benign course with a lower growth rate compared with published literature.Congenital SEGA with volume exceeding 500 mm3 had a significantly higher growth rate compared with smaller SEGA and should have more frequent neuroimaging surveillance.

dCas9-Based Scn1a Gene Activation Restores Inhibitory Interneuron Excitability and Attenuates Seizures in Dravet Syndrome MiceColasante G, Lignani G, Brusco S, et al. Mol Ther. 2020;28(1):235-253. doi:10.1016/j.ymthe.2019.08.018Dravet syndrome (DS) is a severe epileptic encephalopathy caused mainly by heterozygous loss-of-function mutations of the SCN1A gene, indicating haploinsufficiency as the pathogenic mechanism. Here, we tested whether catalytically dead Cas9 (dCas9)-mediated Scn1a gene activation can rescue Scn1a haploinsufficiency in a mouse DS model and restore physiological levels of its gene product, the Nav1.1 voltage-gated sodium channel. We screened single guide RNAs (sgRNAs) for their ability to stimulate Scn1a transcription in association with the dCas9 activation system. We identified a specific sgRNA that increases Scn1a gene expression levels in cell lines and primary neurons with high specificity. Nav1.1 protein levels were augmented, as was the ability of wild-type immature GABAergic interneurons to fire action potentials. A similar enhancement of Scn1a transcription was achieved in mature DS interneurons, rescuing their ability to fire. To test the therapeutic potential of this approach, we delivered the Scn1a-dCas9 activation system to DS pups using adeno-associated viruses. Parvalbumin interneurons recovered their firing ability, and febrile seizures were significantly attenuated. Our results pave the way for exploiting dCas9-based gene activation as an effective and targeted approach to DS and other disorders resulting from altered gene dosage.Scn8a Antisense Oligonucleotide Is Protective in Mouse Models of SCN8A Encephalopathy and Dravet syndromeLenk GM, Jafar Nejad P, Hill SF, et al. Ann Neurol. 2020;87(3):339-346. doi:10.1002/ana.25676SCN8A encephalopathy is a developmental and epileptic encephalopathy caused by de novo gain-of-function mutations of sodium channel Nav 1.6 that result in neuronal hyperactivity. Affected individuals exhibit early-onset drug-resistant seizures, developmental delay, and cognitive impairment. This study was carried out to determine whether reducing the abundance of the Scn8a transcript with an antisense oligonucleotide (ASO) would delay seizure onset and prolong survival in a mouse model of SCN8A encephalopathy. Antisense oligonucleotide treatment was tested in a conditional mouse model with Cre-dependent expression of the pathogenic patient SCN8A mutation p.Arg1872Trp (R1872 W). This model exhibits early onset of seizures, rapid progression, and 100% penetrance. An Scn1a+/− haploinsufficient mouse model of Dravet syndrome was also treated. Antisense oligonucleotide was administered by intracerebroventricular injection at postnatal day 2, followed in some cases by stereotactic injection at postnatal day 30. We observed a dose-dependent increase in length of survival from 15 to 65 days in the Scn8a-R1872W/+ mice treated with ASO. Electroencephalographic recordings were normal prior to seizure onset. Weight gain and activity in an open field were unaffected, but treated mice were less active in a wheel running assay. A single treatment with Scn8a ASO extended survival of Dravet syndrome mice from 3 weeks to >5 months. Reduction of Scn8a transcript by 25% to 50% delayed seizure onset and lethality in mouse models of SCN8A encephalopathy and Dravet syndrome. Reduction of SCN8A transcript is a promising approach to treatment of intractable childhood epilepsies.

The purpose of this study was to compare HMGB-1, TLR4, IL-1β, IL-1R1, and TNF-α levels in patients with mild and severe epilepsy with those in a healthy control group. Children aged 4-17 years, diagnosed with epilepsy for at least three years and with no progressive neurological disease, metabolic disease or infection, were selected for the study. The severe epilepsy group consisted of 28 children with at least one episode a week despite receiving three or more antiepileptic drugs. The mild epilepsy group consisted of 29 children with no seizures in the previous year, receiving only one antiepileptic drug, while 27 healthy children were selected as the control group. HMGB-1, TLR4, IL-1R1, TNF-α and IL-1β levels were investigated in these three groups. The MRI findings and clinical characteristics of the patients in the epilepsy group were also compared with these markers. HMGB-1, TLR4, TNF-α, and IL-1β levels in the severe epilepsy group were higher than in the control group and the mild epilepsy group (p

Introduction: The large number of different syndromes and seizure types, together with an inter-individual variable response to antiepileptic drugs (AEDs), makes the treatment of epilepsy c...

Objectives To assess symptoms of post-traumatic stress disorder (PTSD) in children with severe epilepsy and the associations of trauma symptoms across age, comorbid symptoms, epilepsy-specific factors, parental resources, and psychopathology. Methods Fifty children with severe epilepsy across three different age groups (0–5 yrs., 6–12 yrs., 13–18 yrs.) were assessed with developmental-sensitive and standardized PTSD assessment tools when hospitalized at the tertiary epilepsy center Filadelfia, Denmark. The Diagnostic Infant and Preschool Assessment (DIPA), the Darryl test, and the ITQ questionnaire were used to assess the three age groups, respectively. Results Twenty-two percent of the overall sample met the criteria for PTSD, with a prevalence of symptoms increasing with age (6%, 28%, and 40%). Comorbid psychiatric symptoms in preschoolers were present in 81% of the children witnessing a high level of distress in this group. Behavioral difficulties were elevated across all three age groups, and 40% of the children with trauma symptoms had a parent with concurrent psychopathology. Conclusion To the authors’ knowledge, this study is the first to assess trauma symptoms with standardized tests in children with more complicated epilepsies. Trauma symptoms in the group are high; however, there is a need for larger scale studies and research into trauma symptoms in children with more severe epilepsy than those assessable with the included assessment tools. The trauma perspective in severe childhood epilepsy might further clarify the complex associations of biological and contextual variables that affect the children’s life quality and enable better preventative treatment options for this group.

Cannabidiol (CBD) oils are low tetrahydrocannabinol products derived from Cannabis sativa that have become very popular over the past few years. Patients report relief for a variety of conditions, particularly pain, without the intoxicating adverse effects of medical marijuana. In June 2018, the first CBD-based drug, Epidiolex, was approved by the US Food and Drug Administration for treatment of rare, severe epilepsy, further putting the spotlight on CBD and hemp oils. There is a growing body of preclinical and clinical evidence to support use of CBD oils for many conditions, suggesting its potential role as another option for treating challenging chronic pain or opioid addiction. Care must be taken when directing patients toward CBD products because there is little regulation, and studies have found inaccurate labeling of CBD and tetrahydrocannabinol quantities. This article provides an overview of the scientific work on cannabinoids, CBD, and hemp oil and the distinction between marijuana, hemp, and the different components of CBD and hemp oil products. We summarize the current legal status of CBD and hemp oils in the United States and provide a guide to identifying higher-quality products so that clinicians can advise their patients on the safest and most evidence-based formulations. This review is based on a PubMed search using the terms CBD, cannabidiol, hemp oil, and medical marijuana. Articles were screened for relevance, and those with the most up-to-date information were selected for inclusion.

Objective: In recent years, the use of cannabidiol in the treatment of refractory epilepsy has been increasingly investigated and has been gaining public support as a novel way to treat these disorders. Marijuana has been used for medical purposes for thousands of years, and a lot of research has been conducted over the last several decades into the chemistry and pharmacology of marijuana and its many compounds, including cannabidiol. Methods: Using PubMed, we performed a review of the literature regarding the history of cannabinoid use in treating epilepsy. Results and conclusions: There are historical and recent scientific developments that support the use of cannabidiol in rare severe epilepsy syndromes.

Objective: The present study aims to understand perceptions of deep brain stimulation (DBS) for severe obsessive-compulsive disorder (OCD) in adolescents among two groups: parents of children with a history of OCD and adults with a history of OCD. Methods: Two hundred sixty participants completed a questionnaire exploring their treatment history, relevant symptom severity, DBS knowledge, and DBS attitudes using an acceptability scale and a series of statements indicating levels of willingness or reluctance to consider DBS for adolescents with severe OCD or severe epilepsy. Results: Overall, participants found DBS to be fairly acceptable for adolescents with severe OCD, with 63% reporting at least 7/10 on a 0-10 acceptability Likert scale. Respondents were more willing to consider DBS for epilepsy than for OCD. Several factors were associated with greater willingness to consider DBS for OCD, including familiarity with DBS, the presence of suicidal thoughts, assurances of daily functioning improvements, and assurances of substantial symptom reduction. Concerns about safety, personality changes, and long-term effects on the body were associated with greatest reluctance to consider DBS for OCD. Conclusions: Our findings support the importance of increasing parents' familiarity with DBS, monitoring factors participants identified as most important to their DBS perceptions in future DBS research, and communicating benefits and risks clearly. We also highlight the need for further research on perceptions of DBS for severe and refractory OCD in adolescents.

West syndrome is a severe epilepsy syndrome characterised by the appearance of drug-resistant epileptic disorders associated with hypsarrhythmia and intellectual disability. Among non-pharmacological treatments, the ketogenic diet, which consists of low carbohydrate intake and a rich lipid intake, stands out. This treatment induces a state of ketosis, which has been related to a decrease in the number of seizures. It is essential to control the carbohydrate intake within drug treatment for these patients since many pharmaceutical forms, specifically liquid oral medication, may contain carbohydrates in the form of mono/polysaccharides or polyols. We describe the case report of an infant with drug-resistant West syndrome, treated with a ketogenic diet, whose antiseizure liquid medication impeded a proper response to the diet. After the substitution of these medications, the patient showed a remarkable decrease in the number of seizures.

Hemispheric surgery is an effective and cost-effective option for hemispheric epilepsy. Data specifically focusing on very early infancy are scant. In our study, we report the results of hemispheric surgery in children under three years of age, along with clinical, neuroradiological and EEG features, from two Italian epilepsy surgery centres. After reviewing our epilepsy surgery databases (2008-2018), we identified 14 patients (seven males) submitted to hemispheric surgery, under three years (range: 2-29 months), with a follow-up of at least 12 months. No deaths occurred, and surgical complications were observed in 3/17 procedures. At final follow-up visit (mean: 30.8 months; range: 12-90), 10/14 patients (71.4%) achieved Engel Class I (eight Class 1A, one Class 1B, and one Class 1C). Antiepileptic drugs were completely discontinued in three and reduced in eight, thus a significant decrease in drug regimen after surgery was achieved in 11/14 patients (78.6%). Before surgery, severe developmental delay was present in 10 patients, moderate in two and mild in two. At the last follow-up visit, the degree of developmental delay changed from severe to moderate in five patients, remained unchanged in six cases (four severe and two moderate), and changed from mild to moderate in two following surgery. In many cases, hemispheric surgery in children under three years is effective in achieving seizure freedom or reducing seizure frequency, with the possibility of simplifying complex drug regimens. Moreover, it appears to be a safe and well tolerated procedure, leading to improvement in cognition and posture.

Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) are two serious epileptic syndromes with paediatric onset which are refractory to therapy and are associated with an important increase in mortality rates and comorbidities compared to the general population. These pathologies have a strong impact on the lives of patients and their families, because they undergo multiple pharmacological therapies (many of them without specific indication), with frequent changes due to poor efficacy and associated adverse effects. The specialists who care for these patients highlight unmet needs and the lack of specific, safe and effective treatments for better management of the syndrome.

Although the classic phenotype of episodic ataxia type 1 (EA1) caused by variants in KCNA1 includes episodic ataxia and myokymia, further genotype-phenotype correlations are difficult to establish due to highly heterogeneous clinical presentations associated with KCNA1 pathogenic variants. De novo variants in the paralogous Pro-Val-Pro motif (PVP) of KCNA2, an essential region for channel gating, have been reported to be associated with severe epilepsy phenotypes, including developmental and epileptic encephalopathies (DEE). Here, we describe the first patient with a DEE who developed an encephalopathy related to status epilepticus during sleep (ESES) and cerebellar signs, harbouring a variant in the Kv-specific PVP motif of the KCNA1 gene. Interestingly, he showed a remarkable long-term electroclinical response to IM ACTH therapy. This report extends the range of phenotypes associated with KCNA1 variants to include that of ESES, and suggests that ACTH therapy is likely to have a positive effect in patients with these variants.

Objective: We aimed to delineate the phenotypic spectrum and long-term outcome of individuals with KCNB1 encephalopathy. Methods: We collected genetic, clinical, electroencephalographic, and imaging data of individuals with KCNB1 pathogenic variants recruited through an international collaboration, with the support of the family association “KCNB1 France.” Patients were classified as having developmental and epileptic encephalopathy (DEE) or developmental encephalopathy (DE). In addition, we reviewed published cases and provided the longterm outcome in patients older than 12 years from our series and from literature. Results: Our series included 36 patients (21 males, median age = 10 years, range = 1.6 months-34 years). Twenty patients (56%) had DEE with infantile onset seizures (seizure onset = 10 months, range = 10 days-3.5 years), whereas 16 (33%) had DE with late onset epilepsy in 10 (seizure onset = 5 years, range = 18 months-25 years) and without epilepsy in six. Cognitive impairment was more severe in individuals with DEE compared to those with DE. Analysis of 73 individuals with KCNB1 pathogenic variants (36 from our series and 37 published individuals in nine reports) showed developmental delay in all with severe to profound intellectual disability in 67% (n = 41/61) and autistic features in 56% (n = 32/57). Long-term outcome in 22 individuals older than 12 years (14 in our series and eight published individuals) showed poor cognitive, psychiatric, and behavioral outcome. Epilepsy course was variable. Missense variants were associated with more frequent and more severe epilepsy compared to truncating variants. Significance: Our study describes the phenotypic spectrum of KCNB1 encephalopathy, which varies from severe DEE to DE with or without epilepsy. Although cognitive impairment is worse in patients with DEE, long-term outcome is poor for most and missense variants are associated with more severe epilepsy outcome. Further understanding of disease mechanisms should facilitate the development of targeted therapies, much needed to improve the neurodevelopmental prognosis.

From the pathological biographical event is born the reflective work of those who experience it as a helper, then the skill to transform this painful experience into learning. But, in a context where the acquisition of a reflective experience becomes essential for survival, in the particular case of severe epilepsies - rare diseases and disabilities - caregivers must also act with complete uncertainty. Faced with the unpredictable chronicity of crises, what then are the characteristics of the care provided by caregivers, and to what extent do their knowledge contribute to a global balance (personal and family) that goes well beyond care in itself?In the first place, knowledge about the rare disease is akin to action that is developed according to the circumstances. This action relates to the field of uses "in the process of being made" and the knowledge that results from it essentially depends on adaptation, at the interface of learning and constant questioning. This form of care that families call "taking charge of the moment" is gradually becoming more unique and it involves going through daily trials that will make the person who experiences them a unique actant.Second, adapting to the unforeseeable amounts to developing a hybrid form of knowledge, at the interface of experiential knowledge, social interactions and the personal journey of caregivers. This form of knowledge acts on the identity of those involved in care. It particularizes a given situation because it is collectively the result of interrelationships arising from the context of the affection and its management. In addition, the individual identity dimension it contains is based on tactics and life choices which, in large part, are linked to the appropriation of the disease as it evolves. It is about situational awareness, in situ., De l'événement biographique pathologique naît le travail réflexif de celui qui le vit comme aidant, puis la compétence à transformer cette expérience douloureuse en apprentissage. Mais, dans un contexte où l'acquisition d'une expérience réflexive devient indispensable à la survie, dans le cas particulier des épilepsies sévères-maladies et handicaps rares-les aidants doivent en outre agir en toute incertitude. Face à la chronicité imprévisible des crises, quelles sont alors les caractéristiques de la prise en charge par les aidants, et dans quelle mesure leurs connaissances participent-elles d'un et à un équilibre global (personnel et familial) qui va bien au-delà du soin en lui-même ? En premier lieu, les connaissances liées à la maladie rare s'apparentent à un agir qui est élaboré au gré des circonstances. Cet agir rejoint le domaine des usages « en train de se faire » et la connaissance qui en découle relève essentiellement de l'adaptation, à l'interface de l'apprentissage et de la remise en question constante. En premier lieu, les connaissances liées à la maladie rare s’apparentent à un agir quiest élaboré au gré des circonstances. Cet agir rejoint le domaine des usages « en train de sefaire » et la connaissance qui en découle relève essentiellement de l’adaptation, à l’interfacede l’apprentissage et de la remise en question constante. Cette forme de soin que les famillesnomment « une prise en charge de l’instant » se singularise peu à peu et elle suppose la traversée d’épreuves quotidiennes qui feront de celui ou de celle qui les vit un actantsingulier.En second lieu, s’adapter à l’imprévisible revient à élaborer une forme deconnaissance hybride, à l’interface de la connaissance expérientielle, des interactions socialeset du cheminement personnel des aidants. Cette forme de connaissance agit sur l’identité desacteurs du soin. Elle particularise une situation donnée car elle est collectivement le fruit desinterrelations issues du contexte de l’affection et de sa prise en charge. En outre, la dimensionidentitaire individuelle qu’elle recèle est basée sur les tactiques et les choix de vie qui, engrande partie, sont liés à l’appropriation de la maladie au fur et à mesure de son évolution. Ils’agit d’une connaissance de situation, en situation.

The parasitic helminth infection neurocysticercosis (NCC) is the most common cause of adult-acquired epilepsy in the world. Despite the serious consequences of epilepsy due to this infection, an in-depth review of the distinct characteristics of epilepsy due to neurocysticercosis has never been conducted. In this review, we evaluate the relationship between NCC and epilepsy and the unique characteristics of epilepsy caused by NCC. We also discuss recent advances in our understanding of NCC-related epilepsy, including the importance of anti-inflammatory therapies, the association between NCC and temporal lobe epilepsy, and the recent discovery of biomarkers of severe epilepsy development in individuals with NCC and seizures.

The passage of the 2018 United States Agriculture Improvement Act removed industrial hemp, defined as Cannabis sativa L. containing less than 0.3% THC content by dry weight, from Schedule I of the Controlled Substances Act and made it an agricultural commodity. Following these changes, the popularity of hemp-derived cannabidiol (CBD) dietary supplements by consumers has greatly exceeded the scientific understanding of purported benefits, safety and composition of these botanical extracts. Further complicating CBD hemp supplement regulation, Food and Drug Administration (FDA) considers CBD to be an approved drug (Epidiolex) in the treatment of severe epilepsy disorders, Dravet and Lennox-Gastaut syndromes. At the same time, hemp-derived CBD supplements can contain a complex phytochemical matrix from the hemp plant, distinguishing the composition of these products from isolated CBD preparations. This work aims to provide clarity on differentiating botanical full-spectrum hemp extracts containing CBD from isolates, from a phytochemical, toxicological and regulatory perspective.

Objective Lacosamide (LCM) is an antiepileptic drug (AED) with insufficient clinical experience in patients with intellectual disability (ID). They often have more severe epilepsy with comorbidities. The objective was to evaluate the efficacy and tolerability of lacosamide (LCM) in patients with refractory epilepsy with and without ID in a real‐life setting, taking drug monitoring (TDM) data into account therapeutic. Methods Retrospectively, we identified 344 patients using LCM from the TDM service covering the majority of the country, at the National Center for Epilepsy in Norway (2013‐2018). Clinical and TDM data were available for 132 patients. Results Forty‐four of the 132 patients (33%) had ID. The retention rate was significantly higher in the ID vs the non‐ID group after 1 year (84% vs 68%, P < .05). By combining clinical and TDM data, we demonstrated that 37/38 responding patients had serum concentrations above the lower limit of the reference range (>10 µmol/L), and 16/17 with lower concentrations were non‐responders. Mean serum concentration/dose ratios were similar in both groups, 0.06 and 0.07 µmol/L/mg. There were no significant differences regarding efficacy and tolerability. The risk of LCM withdrawal was significantly higher when LCM was added to sodium channel blockers, even if the latter was discontinued. Significance Lacosamide was generally well tolerated in patients with drug‐resistant epilepsy, where one third had ID, and in these patients the retention rate was higher. The combination of clinical and TDM data could possibly facilitate LCM therapy in these vulnerable patients. This article will not be available due to copyright restrictions. (c) 2019 by Wiley.

Integrative palliative care involves a team of professionals working together to improve the quality of a child’s life. In children with refractory epilepsy, the primary focus is to treat the seizures. This manuscript reviews common epileptic encephalopathies which can serve as prototypes for devastating refractory seizure disorders and demonstrate the need for involvement of pediatric palliative care in patients with severe epilepsy. It provides an update on etiology, prognosis, and overall treatment, delivering insightful information for the palliative care team as they work to improve the quality of life. A number of pharmacologic and non-pharmacologic treatments are important in the management of refractory epilepsy. This article reviews the various treatment options for patients with refractory epilepsy and highlights the importance of palliative care. A child neurologist should participate as an integral part of the palliative care team in patients with refractory epilepsy to help guide the discussion about etiology, prognosis, and actively manages seizures as they work with other members of pediatric palliative care team towards improving the quality of life for the patient, caregiver, and family members.

Mutations in GNAO1 (guanine nucleotide-binding protein, alpha-activating activity polypeptide O) were recently identified as being causative for early epileptic encephalopathy. Since then approximately 27 patients with severe developmental delay and different neurological phenotypes for epilepsy and involuntary movement disorder have been reported. We report four additional patients with mutations in GNAO1 including a report of siblings of different sex harboring the same de novo mutation (c.736G > A, p.Glu246Lys) but showing differences in phenotype with pronounced dystonia in the boy and epilepsy in his sister. Another de novo mutation in GNAO1 (c.607G > A, p.Gly203Arg) was identified in two unrelated girls with severe epilepsy. Both girls later also developed severe dystonia with severe nonepileptic spasms. An extensive review of published cases revealed that epilepsy was reported in only one male patient so far. Thus it appears possible that epilepsy is a sex-dependent phenotypic feature of GNAO1-related diseases.

The Thirteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIII) took place in Madrid, Spain, on June 26-29, 2016, and was attended by >200 delegates from 31 countries. The present Progress Report provides an update on experimental and clinical results for drugs presented at the Conference. Compounds for which summary data are presented include an AED approved in 2016 (brivaracetam), 12 drugs in phase I-III clinical development (adenosine, allopregnanolone, bumetanide, cannabidiol, cannabidivarin, 2-deoxy-d-glucose, everolimus, fenfluramine, huperzine A, minocycline, SAGE-217, and valnoctamide) and 6 compounds or classes of compounds for which only preclinical data are available (bumetanide derivatives, sec-butylpropylacetamide, FV-082, 1OP-2198, NAX 810-2, and SAGE-689). Overall, the results presented at the Conference show that considerable efforts are ongoing into discovery and development of AEDs with potentially improved therapeutic profiles compared with existing agents. Many of the drugs discussed in this report show innovative mechanisms of action and many have shown promising results in patients with pharmacoresistant epilepsies, including previously neglected rare and severe epilepsy syndromes.

There are two popular strategies for current drug treatment of epilepsy; starting early may be better and polytherapy conveys advantages over monotherapy. This review briefly examines if the historical record is much of a guide to determine the clinical value of these two strategies. Great clinical scientists of the 19th and early 20th century, such as Sir William Gowers, and William Aldren Turner, offered vivid single case studies and showed early results of seizure remission in groups of subjects. The historical record offered, however, no evidence of clear clinical benefits for early treatment and polytherapy. Combination treatment was thought to be useful in only some cases. In agreement, current evidence shows no clear clinical benefit of starting treatment early, except perhaps in severe epilepsy. Polytherapy is clinically useful in a subgroup of subjects, but despite being a standard treatment strategy for over one hundred years, it has been poorly studied. In fact, there is no compelling experimental or clinical evidence for a difference in seizure outcome between monotherapy and polytherapy. This surprising finding should prompt a re-appraisal regarding the need to test both strategies separately for the licensing of new antiepileptic drugs.

Mitochondria generate 90% of the energy required to sustain life. As a result, loss of mitochondrial function compromises almost every facet of human physiology. Accordingly, most mitochondrial diseases tend to present themselves as complex, multi-systemic disorders that can be difficult to diagnose. Depending on the severity of the mitochondrial dysfunction, the pathology can range from mild discomfort to severe epilepsy, blindness and paralysis. To develop therapies to these diseases, it will be important to optimize experimental techniques that can reliably quantify mitochondrial function, particularly in live cells or intact organisms. Here, we describe how a Seahorse XF24 Analyzer can be used to measure both basal and maximal respiration in the nematode Caenorhabditis elegans, and how this data can be interpreted to evaluate mitochondrial function.

8q22.2q22.3 microdeletion syndrome has been described in only seven patients. We present a new case from Colombia. The characteristics of this condition are developmental delay, microcephaly, seizures, and typical facial dysmorphism. We discuss the clinical phenotype of the patient presenting relevant findings like hearing loss and severe epilepsy and the possible relations between the phenotype and the genes involved in the microdeletion. We describe a female with developmental delay, microcephaly, epilepsy, severe short stature, impaired speech, facial dysmorphism, and congenital deafness. A minimal/maximal deletion of 5.238 Mb and 5.374Mb, respectively, at 8q22.2q22.3 was diagnosed using a genome-wide array. The clinical phenotype is similar to the others seven patients previously reported; however, the severity of epilepsy and the concomitant hearing loss is remarkable, characteristics previously observed independently in only two patients. The KCNS2 gene is located in the deleted regions (8q22.2). Therefore it is a possible candidate for explaining the complex neurologic phenotype.

The majority of neonatal seizures are related to common diagnoses, including hypoxic-ischemic encephalopathy and intraventricular hemorrhage. While relatively uncommon, neonatal epileptic encephalopathies represent an important group of neonatal seizure disorders that require immediate diagnosis and intervention. In this review, we provide a summary of the benign and severe neonatal epilepsy syndromes. While benign epilepsy syndromes have favorable prognoses, rapid and accurate diagnosis may prevent an unnecessarily long course of antiseizure medications. The severe epilepsy syndromes may be related to a number of underlying genetic disorders and often carry a poor prognosis. Herein we review diagnostic and therapeutic strategies, and provide a set or algorithms for said purposes.

Cognitive impairment is common in children and adolescents with epilepsy. Though there is increasing recognition that even children with more benign epilepsy syndromes may show cognitive loss over time, this is particularly true in children with severe epilepsies, termed the epileptic encephalopathies. The current article discusses general cognition in children with epilepsy, focusing on risk factors for cognitive decline over time in severe epilepsies. The “epileptic encephalopathies” are briefly introduced and methods for assessing cognitive loss over time are discussed with an emphasis on the use of reliable change indices. The strengths and the limitations of this approach are noted as they pertain to children. The article concludes with an illustrative case example of a young child with a severe epilepsy syndrome and apparent cognitive loss. The utility and limitations of reliable change indices are discussed within the context of this case.

Aim . Evaluate of the efficacy and safety of microsurgical callosotomy in the early postoperative period, taking into account the features of the vascularization of the corpus callosum in the surgical treatment of severe symptomatic epilepsy. Material and methods. In study were enrolled 13 children with drug-resistant epilepsy aged from 2 t 16 years (mean 7.3 ± 2.8 years) who underwent callosotomy. At the time of the surgery frequency of seizures was 20.3 ± 9.8 per day, 11 from 13 (84.6%) had repeated status epilepticus. Six (46.2%) had one-stage total callosotomy and 7 (53.8%) underwent anterior callosotomy. Postoperative follow-up was from 8 to 30 moths (mean - 16.7 ± 3.6 months). Results . After surgery 4 (30.8%) were seizure-free (Engel scale – 1), 5 (38.5%) had rare short auras (Engel scale – 2), in 3 (23.0%) cases the seizure frequency significantly reduced – over 80%. In 1 (7.7) child who had Rasmussen encephalitis secondary generalised seizures were stopped but partial motor fits persist (Engel scale – 4). Conclusion . Callosotomy is effective and safe methods of treatment severe epilepsy. Positive outcome is caused by establishing the correct indications for surgery and application of modern microsurgical equipment, taking into account topographic and anatomic features of the blood supply of the corpus callosum.

The article describes the phenomenon of dual pathology – a combination of structural changes in the brain and benign epileptiform discharge of childhood on electroencephalogram. The uniqueness lies in the observation that the child, since birth suffering from spastic form of cerebral palsy and severe epilepsy, demonstrated the development of Stevens–Johnson syndrome due to intolerance of one of the antiepileptic drugs. Therapeutic approaches to overcome a whole range of violations are discussed in the article.

RFT1-congenital disorder of glycosylation (CDG) syndrome, a recessive N-glycosylation disorder caused by mutation in the RFT1 gene, is a very rare subtype of CDG syndrome associated with deafness, developmental delay, and non-specific epilepsy. The aim of this report is to describe the electroclinical presentation of epilepsy associated with this condition. [Published with video sequences online].

Incontinentia pigmenti (IP) is an uncommon neurocutaneous syndrome characterized by skin lesions, ocular abnormalities, and central nervous system (CNS) involvement. Mutations in IKBKG gene were discovered as a cause of IP. The most frequent neurologic manifestations are seizures, usually observed in the first week, and sometimes in the first year of life or in childhood. The most frequent types of presenting seizures are partial clonic or generalized seizures. Epilepsy usually showed a good prognosis in most patients with a good response to treatment. However, in some patients a more severe epilepsy related to various degree of CNS involvement can occur. Clinicians should pay special attention to cutaneous signs of IP in infants presenting with neonatal seizures.

Objective Pediatric epilepsy is associated with a wide range of neurodevelopmental challenges. Few studies have established children’s cognitive function prior to seizure onset making study of the direct impact of seizures challenging. This is especially true in cases with preexisting neurological disorders. The present case provides insight into the impact that new onset of seizures (including status epilepticus) have on cognitive development and illustrates how documented cognitive change informs clinical decision-making. Method The patient is a 10-year-old boy with a history of cerebral palsy who initially completed neuropsychological testing in the fall of 2018. New onset of drug-resistant seizures presented in January 2019, including episodes of status epilepticus leading to repeat neuropsychological evaluation in the fall of 2019. EEG studies in infancy showed poorly regulated background rhythm and MRI showed dysplastic corpus callosum and bilateral occipital heterotopias. Following the onset of seizures EEG showed independent seizure foci over temporal regions bilaterally. MRI showed extensive bilateral temporal and occipital subependymal gray matter heteropi, and dysgenesis of the corpus callosum, cerebral vermis, and anterior commissure. Results Repeated neuropsychological assessment documented significant declines in intellectual function, visual and verbal memory (visual worse than verbal), and executive function, with limited academic progression. Persistent epileptic symptoms throughout testing complicated interpretation. Conclusions Findings were highly concerning for cognitive deterioration and the neurosurgical team deemed him as high risk for sudden unexpected death in epilepsy. He underwent right anterior temporal lobectomy and left stereoelectroencephalography placement in January 2020. Scheduled repeat neuropsychological evaluation will further monitor neurocognitive functioning post neurosurgical intervention.

Introduction Children with epilepsy report lower health-related quality of life (QOL) compared with healthy children and those with other chronic disorders. This study piloted the recently published Pediatric Quality of Life Inventory (PedsQL) Epilepsy Module (PedsQL-EM) in an ambulatory setting and studied epilepsy-related factors contributing to QOL in children with epilepsy. Methods Children with epilepsy aged 8–18 years who were ambulant and verbal were recruited from pediatric neurology clinics. Children and their caregivers completed age-appropriate versions of the PedsQL-EM (8–12 or 13–18 years) in the clinic waiting area. Treating neurologists completed medical questionnaires about their patients' epilepsy. Results We collected 151 parent-report and 127 self-report PedsQL-EMs. Administration time was 5–10 min with some children receiving assistance from the researcher. Mean age of children was 12.9+/-3.0, with 77 females (51%). Parents reported lower mean QOL scores across all subdomains compared with their children. Parents reported significantly lower QOL for children with earlier age at epilepsy onset, longer epilepsy duration, presence of seizures during the last month, more severe epilepsy, increased number of antiepileptic drugs (AEDs), and cognitive comorbidity. The same factors impacted on child self-reporting, but with more variability across subdomains. Conclusions The PedsQL-EM is an epilepsy-specific measure of QOL that is quick and easy to administer and is sensitive to the clinical factors reported to impact on QOL in pediatric epilepsy.

Neuroserpin (NS) is predominantly expressed in brain and inhibits tissue-type plasminogen activator (tPA) with implications in brain development and memory. Nature of conformational change in pathological variants in strand 6B and helix B of NS that cause a relatively mild to severe epilepsy (and/or dementia) remains largely elusive. MD simulation with wild type (WT) NS, strand 6B and helix B variants indicated that substitution in this region affects the conformation of the strands 5B, 5A and reactive centre loop. Therefore, we designed variants of NS in strand 6B (I46D and F48S) and helix B (A54F, L55A and L55P) to investigate their role in tPA inhibition mechanism and propensity to aggregate. An interaction analysis showed disturbance of a hydrophobic patch centered at strands 5B, 6B and helix B in I46D and F48S but not in A54F, L55A, L55P and WT NS. Purified I46D, F48S and L55P variants showed decrease in fluorescence emission intensity but have similar α-helical content, however results of A54F and L55A were comparable to WT NS. Analysis of tPA inhibition showed marginal effect on A54F and L55A variant with tPA-NS complex formation. In contrast, I46D, F48S and L55P variants showed massive decrease in tPA inhibition, with no tPA-NS complex formation. Analysis of native PAGE under under polymerization condition showed prompt conversion of I46D, F48S and L55P to latent conformation but not A54F and L55A variants. Identification of these novel conformational changes will aid in the understanding of variable clinical phenotype of shutter region NS variants and other serpins.

Background Scientific and anecdotal evidence suggest that whole plant cannabis extracts are effective in reducing seizure frequency in individuals with a range of epileptic etiologies. We report a case series of 10 individuals using CBMPs in the UK to treat their conditions. Methods In this retrospective study, we report on patients (aged 2-48) with severe, intractable, childhood onset epilepsies using combined cannabinoid therapy. Carers of patients provided details through the charity ‘End our Pain’ and these data were subsequently analysed. Our primary objective was to assess changes in monthly seizure frequency pre and post initiation of CBMPs. We also report on previous and current AED, CBD:THC daily dose, quality of life and financial costs associated with CBMP private prescription. Change in monthly seizure frequency were assessed using a Wilcoxon Signed-ranks test. Results Of the 10 patients enrolled in the study there was an 97% mean reduction in monthly seizure frequency post initiation of CBMPs which was statistically significant (Z = 0, p Interpretation Our findings suggest a combination of CBD and THC based products are effective in reducing seizure frequency in a range of epileptic conditions. We highlight the inefficacy of the healthcare system in supporting these patients who bare great personal and financial burdens. We encourage specialist physicians and relevant bodies to permit greater ease of access of these medications to those patients where efficacy has been shown.

Recent surveys suggest that many parents are using illicit cannabis extracts in the hope of managing seizures in their children with epilepsy. In the current Australian study we conducted semi-structured interviews with families of children with diverse forms of epilepsy to explore their attitudes towards and experiences with using cannabis extracts. This included current or previous users of cannabis extracts to treat their child’s seizures (n = 41 families), and families who had never used (n = 24 families). For those using cannabis, extracts were analysed for cannabinoid content, with specific comparison of samples rated by families as “effective” versus those rated “ineffective”. Results showed that children given cannabis extracts tended to have more severe epilepsy historically and had trialled more anticonvulsants than those who had never received cannabis extracts. There was high variability in the cannabinoid content and profile of cannabis extracts rated as “effective”, with no clear differences between extracts perceived as “effective” and “ineffective”. Contrary to family’s expectations, most samples contained low concentrations of cannabidiol, while Δ9-tetrahydrocannabinol was present in nearly every sample. These findings highlight profound variation in the illicit cannabis extracts being currently used in Australia and warrant further investigations into the therapeutic value of cannabinoids in epilepsy.

Implantable, closed-loop devices for automated early detection and stimulation of epileptic seizures are promising treatment options for patients with severe epilepsy that cannot be treated with traditional means. Most approaches for early seizure detection in the literature are, however, not optimized for implementation on ultra-low power microcontrollers required for long-term implantation. In this paper we present a convolutional neural network for the early detection of seizures from intracranial EEG signals, designed specifically for this purpose. In addition, we investigate approximations to comply with hardware limits while preserving accuracy. We compare our approach to three previously proposed convolutional neural networks and a feature-based SVM classifier with respect to detection accuracy, latency and computational needs. Evaluation is based on a comprehensive database with long-term EEG recordings. The proposed method outperforms the other detectors with a median sensitivity of 0.96, false detection rate of 10.1 per hour and median detection delay of 3.7 seconds, while being the only approach suited to be realized on a low power microcontroller due to its parsimonious use of computational and memory resources., Comment: Accepted at IJCNN 2018

Cognitive problems ranging from mild specific learning problems to profound intellectual disability (ID) are very common in children with epilepsy. For most affected patients there is good evidence that the cognitive problems are present at the onset of seizures and do not deteriorate over time. There is no evidence that a few seizures lead to cognitive deterioration. An exception may occur in children with epileptic encephalopathies, although this contention is not always easy to prove. ID is a strong predictor of intractable epilepsy, and the greater the degree of the ID the greater the risk of medication resistant epilepsy. It is not known if specific learning disorders are associated with more severe epilepsy. Rolandic epilepsy is unusual because possibly one-third of patients have transient cognitive and behavioral difficulties during the active phase but later have normal adult social outcome. More longitudinal studies with baseline and repeated cognitive assessments are needed to fully understand the relationship of cognitive problems to childhood onset epilepsy.

The chromosome 2q24.3 region appears to be important in childhood epilepsy and contains three genes encoding a sodium channel, which are involved in the disorder (SCN1A, SCN2A, and SCN3A). There have been several reports indicating an association between epilepsy and 2q24.3 deletion or duplication. Epilepsy phenotypes markedly differ between patients with 2q24.3 deletion and those with duplication. The majority of patients with 2q24.3 deletion are characterized by severe epilepsy phenotypes such as Dravet syndrome or Dravet syndrome–like intractable epilepsy, which onsets during infancy. This is particularly applicable to patients with SCN1A deletion. In addition, facial dysmorphism (and other dysmorphic features) is observed in all patients with 2q24.3 deletion–associated epilepsy. SCN1A contributes to epileptogenicity; several other genes involved in the deleted region may also play a role in dysmorphism. In all reported cases, patients with 2q24.3 duplication had neonatal- or infantile-onset epilepsy. Although these patients typically experienced multiple daily seizures, seizures were controlled by the appropriate antiepileptic treatment in the majority of cases. SCN2A and SCN3A were duplicated in all patients and are presumed to contribute to epileptogenicity. Facial or other dysmorphic features were infrequent in patients with 2q24.3 duplication. Array comparative genomic hybridization should be considered in patients with neonatal- or infantile-onset epilepsy, because information obtained using this method is likely to be instructive in diagnosis, prognostication, and treatment regimen decisions.

The incidence of seizures is greatest during the neonatal period, with an estimated rate of 2–4 per 1,000 live births. Although the majority of seizures in the newborn are due to acquired brain disorders, a substantial proportion are due to metabolic and genetic disorders causing neonatal- and infantile-onset epilepsies. For decades, genetics has played a critical role in identification and treatment of seizures in the newborn and infantile period.1,2 With newborn screening, disorders such as phenylketonuria and biotinidase deficiency can be identified before patients develop seizures. Early identification and treatment prevents the development of often severe epilepsy syndromes and associated comorbidities. Detection and early treatment will continue to improve as newborn screening methods advance, whether based in genetics or clinical observation: the first channelopathy that causes epilepsy was identified in families with benign familial neonatal convulsions in the 1990s, before completion of the human genome project and modern genomics.3