Next Generation Sequencing and Electromyography Reveal the Involvement of the P2RX6 Gene in Myopathy.

Ion channelopathies result from impaired ion channel protein function, due to mutations affecting ion transport across cell membranes. Over 40 diseases, including neuropathy, pain, migraine, epilepsy, and ataxia, are associated with ion channelopathies, impacting electrically excitable tissues and significantly affecting skeletal muscle. Gene mutations affecting transmembrane ionic flow are strongly linked to skeletal muscle disorders, particularly myopathies, disrupting muscle excitability and contraction. Electromyography (EMG) analysis performed on a patient who complained of weakness and fatigue revealed the presence of primary muscular damage, suggesting an early-stage myopathy. Whole exome sequencing (WES) did not detect potentially causative variants in known myopathy-associated genes but revealed a novel homozygous deletion of the P2RX6 gene likely disrupting protein function. The P2RX6 gene, predominantly expressed in skeletal muscle, is an ATP-gated ion channel receptor belonging to the purinergic receptors (P2RX) family. In addition, STRING pathways suggested a correlation with more proteins having a plausible role in myopathy. No previous studies have reported the implication of this gene in myopathy. Further studies are needed on patients with a defective ion channel pathway, and the use of in vitro functional assays in suppressing P2RX6 gene expression will be required to validate its functional role.

Whole Exome Sequencing as a First-Line Molecular Genetic Test in Developmental and Epileptic Encephalopathies.

Developmental and epileptic encephalopathies (DEE) are severe neurodevelopmental disorders characterized by recurrent, usually early-onset, epileptic seizures accompanied by developmental impairment often related to both underlying genetic etiology and abnormal epileptiform activity. Today, next-generation sequencing technologies (NGS) allow us to sequence large portions of DNA quickly and with low costs. The aim of this study is to evaluate the use of whole-exome sequencing (WES) as a first-line molecular genetic test in a sample of subjects with DEEs characterized by early-onset drug-resistant epilepsies, associated with global developmental delay and/or intellectual disability (ID). We performed 82 WESs, identifying 35 pathogenic variants with a detection rate of 43%. The identified variants were highlighted on 29 different genes including, 3 new candidate genes (KCNC2, STXBP6, DHRS9) for DEEs never identified before. In total, 23 out of 35 (66%) de novo variants were identified. The most frequently identified type of inheritance was autosomal dominant de novo (60%) followed by autosomal recessive in homozygosity (17%) and heterozygosity (11%), autosomal dominant inherited from parental mosaicism (6%) and X-linked dominant de novo (6%). The most frequent mutations identified were missense (75%) followed by frameshift deletions (16%), frameshift duplications (5%), and splicing mutations (3%). Considering the results obtained in the present study we support the use of WES as a form of first-line molecular genetic testing in DEEs.

Treatment of seizures in the neonate: Guidelines and consensus-based recommendations-Special report from the ILAE Task Force on Neonatal Seizures.

Seizures are common in neonates, but there is substantial management variability. The Neonatal Task Force of the International League Against Epilepsy (ILAE) developed evidence-based recommendations about antiseizure medication (ASM) management in neonates in accordance with ILAE standards. Six priority questions were formulated, a systematic literature review and meta-analysis were performed, and results were reported following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 standards. Bias was evaluated using the Cochrane tool and risk of Bias in non-randomised studies - of interventions (ROBINS-I), and quality of evidence was evaluated using grading of recommendations, assessment, development and evaluation (GRADE). If insufficient evidence was available, then expert opinion was sought using Delphi consensus methodology. The strength of recommendations was defined according to the ILAE Clinical Practice Guidelines development tool. There were six main recommendations. First, phenobarbital should be the first-line ASM (evidence-based recommendation) regardless of etiology (expert agreement), unless channelopathy is likely the cause for seizures (e.g., due to family history), in which case phenytoin or carbamazepine should be used. Second, among neonates with seizures not responding to first-line ASM, phenytoin, levetiracetam, midazolam, or lidocaine may be used as a second-line ASM (expert agreement). In neonates with cardiac disorders, levetiracetam may be the preferred second-line ASM (expert agreement). Third, following cessation of acute provoked seizures without evidence for neonatal-onset epilepsy, ASMs should be discontinued before discharge home, regardless of magnetic resonance imaging or electroencephalographic findings (expert agreement). Fourth, therapeutic hypothermia may reduce seizure burden in neonates with hypoxic-ischemic encephalopathy (evidence-based recommendation). Fifth, treating neonatal seizures (including electrographic-only seizures) to achieve a lower seizure burden may be associated with improved outcome (expert agreement). Sixth, a trial of pyridoxine may be attempted in neonates presenting with clinical features of vitamin B6-dependent epilepsy and seizures unresponsive to second-line ASM (expert agreement). Additional considerations include a standardized pathway for the management of neonatal seizures in each neonatal unit and informing parents/guardians about the diagnosis of seizures and initial treatment options.

The Role of Supplements and Over-the-Counter Products to Improve Sleep in Children: A Systematic Review.

The sleep-wake cycle is a complex multifactorial process involving several neurotransmitters, including acetylcholine, norepinephrine, serotonin, histamine, dopamine, orexin and GABA, that can be, in turn, regulated by different nutrients involved in their metabolic pathways. Although good sleep quality in children has been proven to be a key factor for optimal cognitive, physical and psychological development, a significant and ever-increasing percentage of the pediatric population suffers from sleep disorders. In children, behavioral interventions along with supplements are recommended as the first line treatment. This systematic review was conducted, according to the PRISMA guidelines, with the purpose of assessing the principal nutrients involved in the pathways of sleep-regulating neurotransmitters in children and adolescents. Our focus was the utilization of over the counter (OTC) products, specifically iron, hydroxytryptophan, theanine and antihistamines in the management of different pediatric sleep disorders with the intention of providing a practical guide for the clinician.

STXBP6 Gene Mutation: A New Form of SNAREopathy Leads to Developmental Epileptic Encephalopathy.

Syntaxin-binding protein 6 (STXBP6), also known as amysin, is an essential component of the SNAP receptor (SNARE) complex and plays a crucial role in neuronal vesicle trafficking. Mutations in genes encoding SNARE proteins are often associated with a broad spectrum of neurological conditions defined as "SNAREopathies", including epilepsy, intellectual disability, and neurodevelopmental disorders such as autism spectrum disorders. The present whole exome sequencing (WES) study describes, for the first time, the occurrence of developmental epileptic encephalopathy and autism spectrum disorders as a result of a de novo deletion within the STXBP6 gene. The truncated protein in the STXBP6 gene leading to a premature stop codon could negatively modulate the synaptic vesicles' exocytosis. Our research aimed to elucidate a plausible, robust correlation between STXBP6 gene deletion and the manifestation of developmental epileptic encephalopathy.

Eating and Sensory Features of Children With Autism Spectrum Disorder and Their Typically Developing Peers.

IMPORTANCE: Impaired sensory processing is associated with eating problems. There seem to be no previous studies that compare those who have autism spectrum disorder (ASD) with eating problems (ASD-W) and those with ASD without eating problems (ASD-WO) with typically developing (TD) groups. Comparisons are expected to provide further knowledge to guide the intervention programs. OBJECTIVE: To investigate differences among ASD-W, ASD-WO, and TD groups in eating and sensory features; to detect associations between sensory and eating behaviors and any most involved sensory dimensions; and to search for age-related differences in sensory and eating features in ASD. DESIGN: Nonrandomized comparison study. SETTING: Questionnaires administered as parent interviews. PARTICIPANTS: A total of 165 children were recruited: 117 with ASD and 48 TD children. OUTCOMES AND MEASURES: Standardized questionnaires: the Brief Autism Mealtime Behaviors Inventory for eating problems; the Short Sensory Profile and the Sensory Experience Questionnaire for sensory problems. RESULTS: The ASD-W group showed generalized, impaired eating behaviors and turned out to be the most impaired with regard to sensory responsiveness. No differences in feeding behaviors were found between the ASD-WO and TD groups. All children with ASD showed sensory hyper- or hyporesponsiveness. Four main sensory dimensions were found to be associated with eating behaviors in ASD. No age differences were found in the eating and sensory behaviors of children with ASD. CONCLUSIONS AND RELEVANCE: Differing eating and sensory profiles were found between the ASD and TD groups, especially in children with ASD-W. Early eating interventions using sensory stimulations are strongly recommended. What This Article Adds: This study reports novel information derived from the comparisons of children with ASD with eating problems and those with ASD without eating problems with typically developing groups of children.

Heterozygous Deletion of Long Noncoding RNA AK127244 Is a Susceptibility Factor for Neurodevelopmental Delay.

Neurodevelopmental syndromes due to copy number variation are well-known clinical entities. While the numerical variation of gene-harboring regions has been widely investigated at both molecular and clinical levels, much less is understood about unbalanced expression of long noncoding RNAs. Few studies have been performed on the clinical consequences of such unbalanced expression. Heterozygous deletions of NRXN1 have been well described to cause neuropsychological features. Heterozygous deletion of adjacent long noncoding RNA AK127244, either isolated or combined with partial NRXN1 deletion, was recently reported in association with neurodevelopmental delay. In our retrospective study, we analyze a bicentric cohort of 4 individuals, comprising 2 siblings, which bear an isolated heterozygous deletion in long noncoding RNA AK127244 and present with nonsyndromic neurodevelopmental delay.

Epilepsy, electroclinical features, and long-term outcomes in Pitt-Hopkins syndrome due to pathogenic variants in the TCF4 gene.

BACKGROUND AND PURPOSE: Pitt-Hopkins syndrome (PTHS) is a rare neurodevelopmental disorder caused by deletions/variants in the TCF4 gene. Seizures may be present in up to half of the patients, leading to a more severe disease burden. This study aims to analyse the electroclinical phenotype, treatment options, and long-term outcomes of epilepsy in PTHS. METHODS: A multicentre observational cohort study was performed, and the electroclinical data of PTHS individuals affected by epileptic seizures were retrospectively reviewed and analysed. RESULTS: The series includes 21 patients (11 female) with a median age at seizure onset of 2 years (range = 0.5-8). The median time of follow-up was 7.9 years (range = 2-27). Both generalized and focal epilepsies were present at the same prevalence (42.8%), whereas a minority of patients presented developmental and epileptic encephalopathies (14.4%). At the long-term follow-up, 42.8% achieved seizure freedom, whereas 42.8% developed drug-resistant epilepsy (DRE). The age at seizure onset was found to be an independent predictor for seizure outcome; in this regard, patients having seizure onset after the age of 2 years were more prone to achieve seizure freedom (odds ratio = 0.04, 95% confidence interval = 0.003-0.53; p = 0.01). During evolution, seizures tended to settle down, and even in patients with DRE, seizures tended to persist at a lower frequency and appeared to be more easily manageable over time. CONCLUSIONS: This study provides new insight into the natural history of epilepsy in PTHS. Better characterization of epileptic phenotype and prompt tailored treatment improve overall management and quality of life.

Determination of Perampanel in Dried Plasma Spots: Applicability to Therapeutic Drug Monitoring.

BACKGROUND: Although therapeutic drug monitoring of antiepileptic drugs is typically based on the analysis of plasma samples, alternative matrices, such as dried plasma spots (DPSs), may offer specific advantages. The aims of this work were to (1) develop and validate a bioanalytical method for the quantitative determination of the second-generation antiepileptic drug perampanel in DPSs; (2) assess short- and long-term stability of perampanel in DPSs; and (3) test the clinical applicability of the developed method. METHODS: Two hundred microliters of plasma were dispensed on a glass paper filter and dried. Glass paper filter discs were then inserted into clean tubes. After addition of the internal standard (ie, promethazine), the analytes were extracted with 5-mL methanol, dried at room temperature (23 ± 2°C), and reconstituted. Separation and quantification were achieved on 2 serial reverse-phase monolithic columns connected to an UV detector (λ = 320 nm). RESULTS: Calibration curves were linear in the validated concentration range (25-1000 ng/mL). Intraday and interday accuracy were in the range of 99.2%-111.4%, whereas intraday and interday precision (coefficient of variation) ranged from 2.8% to 8.6%. The lowest limit of quantitation was 25 ng/mL. The stability of the analyte in DPSs was assessed and confirmed under different storage conditions. Perampanel concentrations estimated in DPS samples from patients receiving therapeutic doses were equivalent to those measured in plasma samples. CONCLUSIONS: This simple method enables the quantitation of perampanel in DPSs with adequate accuracy, precision, specificity, and sensitivity. The short- and long-term stabilities of perampanel in DPSs are highly beneficial for sample shipment or storage at ambient temperature. Moreover, DPSs decreases the costs associated with storage and transportation compared with conventional wet samples.

Cognitive, adaptive, and behavioral effects of adjunctive rufinamide in Lennox-Gastaut syndrome: A prospective observational clinical study.

INTRODUCTION: Lennox-Gastaut syndrome (LGS) is a severe pediatric epilepsy syndrome characterized by multiple drug-resistant seizure types. Children with LGS usually experience cognitive regression, and LGS is almost always associated with moderate to severe cognitive impairment. Rufinamide (RFM) was approved by the European Medicines Agency in 2007 for the adjunctive treatment of seizures associated with LGS in patients ≥4 years of age. The primary objective of our study was to assess cognitive, adaptive, and behavior functioning of patients with LGS after 12 months of RFM therapy. METHODS: This was an observational, multicenter, prospective study involving 16 patients diagnosed with LGS aged between 7 and 58 years (mean = 22 ±â€¯16.3). Fourteen of 16 patients were already on therapy with 3 antiseizure drugs and 2/16 with 4 antiseizure drugs; RFM has been added with 100 mg/week increments up to a dose of 300-2400 mg/day. The participants and their parents underwent a neuropsychological evaluation for the assessment of intellectual, adaptive, and emotional/behavioral functioning (Leiter International Performance Scale-Revised (LEITER-R), Vineland, and Child Behavior CheckList (CBCL), respectively) before the RFM introduction (baseline) and 12 months after the RFM therapy (T2). Physical and neurological examination, electroencephalography (EEG) recording, seizure type and frequency, and adverse reactions were also considered. RESULTS: After 12 months, the total intelligence quotient (IQ) assessed by LEITER-R did not show statistical significant changes, such as there were no statistically significant changes in adaptive functions, assessed by Vineland. Furthermore, there were no statistically significant changes in internalizing and externalizing problems assessed by CBCL. CONCLUSION: Adjunctive treatment with RFM did not negatively affect cognitive, adaptive function, and emotional profile in patients with LGS after 1 year of follow-up.

Perampanel tolerability in children and adolescents with focal epilepsy: Effects on behavior and executive functions.

OBJECTIVES: Perampanel (PER) is a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonist recently approved for focal and generalized epilepsies as an add-on therapy. It is well tolerated and effective as treatment of various pediatric epilepsy syndromes; PER does not seem to negatively affect the cognitive profile of children and adolescents, but its influence on executive functions is still to be assessed. METHODS: Our sample included 37 children aged 12-18 years, with focal pharmacoresistant epilepsy already in therapy with 2 or 3 antiepileptic drug (AED); PER was added with 1 mg/week increments up to a dose of 2-4 mg/day. Changes in executive functions were assessed by the EpiTrack Junior test. Emotional and behavioral aspects were evaluated through the interview for parents Child Behavior Checklist (CBCL). Both tests were performed before taking PER and after 6 and 12 months of treatment. RESULTS: After 12 months of PER in 22/30 patients, global score of the EpiTrack Junior test remained almost unchanged; in 7/30 patients, this score improved. The CBCL did not show significant changes in emotional or behavioral problems. CONCLUSIONS: Adjunctive treatment with PER did not negatively affect executive functions that could also be improved. No emotional/behavioral negative effects have been reported, and this suggests a good tolerability in the middle/long term.

Are Mutations in the DHRS9 Gene Causally Linked to Epilepsy? A Case Report.

The DHRS9 gene is involved in several pathways including the synthesis of allopregnanolone from progesterone. Allopregnanolone is a positive modulator of gamma aminobutyric acid (GABA) action and plays a role in the control of neuronal excitability and seizures. Whole-exome sequencing performed on a girl with an early onset epilepsy revealed that she was a compound heterozygote for two novel missense mutations of the DHRS9 gene likely to disrupt protein function. No previous studies have reported the implication of this gene in epilepsy. We discuss a new potential pathogenic mechanism underlying epilepsy in a child, due to a defective progesterone pathway.

Mutations in ACTL6B, coding for a subunit of the neuron-specific chromatin remodeling complex nBAF, cause early onset severe developmental and epileptic encephalopathy with brain hypomyelination and cerebellar atrophy.

Developmental and epileptic encephalopathies (DEEs) are genetically heterogenous conditions, often characterized by early onset, EEG interictal epileptiform abnormalities, polymorphous and drug-resistant seizures, and neurodevelopmental impairments. In this study, we investigated the genetic defects in two siblings who presented with severe DEE, microcephaly, spastic tetraplegia, diffuse brain hypomyelination, cerebellar atrophy, short stature, and kyphoscoliosis. Whole exome next-generation sequencing (WES) identified in both siblings a homozygous non-sense variant in the ACTL6B gene (NM_016188:c.820C>T;p.Gln274*) coding for a subunit of the neuron-specific chromatin remodeling complex nBAF. To further support these findings, a targeted ACTL6B sequencing assay was performed on a cohort of 85 unrelated DEE individuals, leading to the identification of a homozygous missense variant (NM_016188:c.1045G>A;p.Gly349Ser) in a patient. This variant did not segregate in the unaffected siblings in this family and was classified as deleterious by several prediction softwares. Interestingly, in both families, homozygous patients shared a rather homogeneous phenotype. Very few patients with ACTL6B gene variants have been sporadically reported in WES cohort studies of patients with neurodevelopmental disorders and/or congenital brain malformations. However, the limited number of patients with incomplete clinical information yet reported in the literature did not allow to establish a strong gene-disease association. Here, we provide additional genetic and clinical data on three new cases that support the pathogenic role of ACTL6B gene mutation in a syndromic form of DEE.

Eyelid myoclonia with absences: Electroclinical features and prognostic factors.

OBJECTIVE: Eyelid myoclonia with absences (EMA) is a syndrome characterized by eyelid myoclonia with or without absences, eye closure-induced generalized electroencephalographic (EEG) paroxysms and photosensitivity. Few data are available about the prognostic factors of this syndrome. The main objectives of our study were to describe the clinical and EEG features of a group of patients with EMA and to evaluate the presence of prognostic factors. METHODS: We retrospectively selected a cohort of patients with diagnosis of EMA evaluated in the epilepsy service of the Neurological Clinic of Catania, in the Neurology and Clinical Neurophysiopathology Unit of Oasi Research Institute, Troina and in the Regional Epilepsy Centre of Bianchi-Melacrino-Morelli Hospital of Reggio Calabria. We considered the features of the patients during the first year of disease, and at the last follow-up visit. We stratified the patients into two groups: "seizure-free", defined as the absence of seizures for at least 2 years, and "not seizure-free" and we evaluated the evolution of their characteristics and the presence of factors associated with outcome. RESULTS: We enrolled 51 patients (40 women (78%); mean age: 30.8 years ± 15.5 [range 10-79]). The mean follow-up time was 8.7 ± 5.8 years. Eleven patients (21.6%) achieved the condition of seizure-free. Family history of epilepsy was associated with the condition of seizure-free (P = 0.05). At the last follow-up visit, EEG photosensitivity and eye closure sensitivity were significantly associated with the condition of "not seizure-free". SIGNIFICANCE: The results of our study revealed that a positive family history of epilepsy might be associated with a better outcome in EMA. Furthermore, the persistence of photosensitivity and eye closure sensitivity might indicate persistence of seizures, offering an aid in therapeutic management.

Do neurologists agree in diagnosing drug resistance in adults with focal epilepsy?

OBJECTIVE: To evaluate interrater agreement in categorizing treatment outcomes and drug responsiveness status according to the International League Against Epilepsy (ILAE) definition of drug-resistant epilepsy. METHODS: A total of 1053 adults with focal epilepsy considered by the investigators to meet ILAE criteria for drug resistance were enrolled consecutively at 43 centers and followed up prospectively for 18-34 months. Treatment outcomes for all antiepileptic drugs (AEDs) used up to enrollment (retrospective assessment), and on an AED newly introduced at enrollment, were categorized by individual investigators and by 2 rotating members of a 16-member expert panel (EP) that reviewed the patient records independently. Interrater agreement was tested by Cohen's kappa (k) statistics and rated according to Landis and Koch's criteria. RESULTS: Agreement between EP members in categorizing outcomes on the newly introduced AED was almost perfect (90.1%, k = 0.84, 95% confidence interval [CI] 0.80-0.87), whereas agreement between the EP and individual investigators was moderate (70.4%, k = 0.57, 95% CI 0.53-0.61). Similarly, categorization of outcomes on previously used AEDs was almost perfect between EP members (91.7%, k = 0.83, 95% CI 0.81-0.84) and moderate between the EP and investigators (68.2%, k = 0.50, 95% CI 0.48-0.52). Disagreement was related predominantly to outcomes considered to be treatment failures by the investigators but categorized as undetermined by the EP. Overall, 19% of patients classified as having drug-resistant epilepsy by the investigators were considered by the EP to have "undefined responsiveness." SIGNIFICANCE: Interrater agreement in categorizing treatment outcomes according to ILAE criteria ranges from moderate to almost perfect. Nearly 1 in 5 patients considered by enrolling neurologists to be "drug-resistant" were classified by the EP as having "undefined responsiveness."

Electroclinical features of epilepsy monosomy 1p36 syndrome and their implications.

OBJECTIVIES: Monosomy 1p36 syndrome is a recognized syndrome with multiple congenital anomalies; medical problems of this syndrome include developmental delay, facial dysmorphisms, hearing loss, short stature, brain anomalies, congenital heart defects. Epilepsy can be another feature but there are few data about the types of seizures and long term prognosis. The aim of this work was to analyse the electroclinical phenotype and the long-term outcome in patients with monosomy 1p36 syndrome and epilepsy. MATERIALS AND METHODS: Data of 22 patients with monosomy 1p36 syndrome and epilepsy were reconstructed by reviewing medical records. For each patient we analysed age at time of diagnosis, first signs of the syndrome, age at seizure onset, seizure type and its frequency, EEG and neuroimaging findings, the response to antiepileptic drugs treatment and clinical outcome up to the last follow-up assessment. RESULTS: Infantile Spasm (IS) represents the most frequent type at epilepsy onset, which occurs in 36.4% of children, and a half of these were associated with hypsarrhythmic electroencephalogram. All patients with IS had persistence of seizures, unlike other patients with different seizures onset. Children with abnormal brain neuroimaging have a greater chance to develop pharmacoresistant epilepsy. CONCLUSION: This syndrome represents a significant cause of IS: these patients, who develop IS, can suffer from pharmacoresistent epilepsy, that is more frequent in children with brain abnormalities.

Epilepsy and sleep disorders improve in adolescents and adults with Angelman syndrome: A multicenter study on 46 patients.

OBJECTIVE: Actual knowledge on evolution of Angelman syndrome (AS) relies on questionnaire-based cohort studies, phone interviews, or small retrospective cohort studies focused on specific clinical-genetic features. These reports provide conflicting results. The aim of this study was to assess the long-term outcome of epilepsy, sleep disorders, and EEG in a vast series of AS subjects. METHODS: We collected patients with genetically confirmed AS, aged ≥14years, followed in three tertiary epilepsy Centers or attending the meetings of the Italian Organization for AS (OrSA). Retrospective clinical and EEG data were retrieved from hospital archives or family documents. At index evaluation (IE) (last visit at tertiary Centers or single visit during OrSA meetings), caregivers were interviewed about anamnestic data and filled questionnaires on sleep disorders and daily-living skills. Patients underwent general and neurologic evaluation, and video-EEG recordings. All available EEGs were analyzed to compare evolution of spike-wave index (SWI) over the years. RESULTS: Forty-six subjects aged 14-45years were included: 24 from tertiary Centers, 22 from OrSA meetings. During childhood, 42/46 (91.3%) had seizures, which improved over the years in all subjects. Among patients with epilepsy, 27(64%) became seizure-free at a median age of 10years and 4 remained seizure-free even after antiepileptic withdrawal. During childhood, 39/46 (84.8%) had sleep disorders, which improved in 27/39 (69%) over the years. At IE, daily-living skills corresponded to age≤1.6years in 29/46 (63%). Electroencephalogram showed typical AS patterns in 35/46 (76.1%). In EEGs recorded from 10 patients, SWI was not significantly different between infancy/childhood and adolescence/adulthood. CONCLUSION: Improvement of epilepsy or sleep disorders should not disregard the clinical suspicion of AS in adolescent or adult patients with suggestive features. Drug withdrawal might be considered in the management of epilepsy despite the persistence of epileptiform abnormalities.

Autism, epilepsy, and synaptopathies: a not rare association.

Autism spectrum disorders (ASD) are neurodevelopmental disorders typically diagnosed in childhood, characterized by core social dysfunction, rigid and repetitive behaviors, restricted interests, and abnormal sensorial sensitivity. ASD belong to multifactorial diseases: both genetic and environmental factors have been considered as potential risk factors for their onset. ASD are often associated with neurological conditions: the co-occurrence of epilepsy is well documented and there is also evidence of a higher prevalence of EEG abnormalities with 4-86% of individuals with ASD presenting epileptiform or not epileptiform EEG abnormalities. The presence of epilepsy in people with ASD may be determined by several structural alterations, genetic conditions, or metabolic dysfunctions, known to play a role in the emergence of both epilepsy and autism. The purpose of this article is to discuss precisely such latter cause of the autism-epilepsy association, focusing specifically on those "synaptic genes," whose mutation predisposes to both the diseases.

Risk factors for unprovoked epileptic seizures in multiple sclerosis: a systematic review and meta-analysis.

The role of different factors in influencing the risk of seizures during multiple sclerosis (MS) is not known. To perform a systematic review and meta-analysis of risk factors for epilepsy during MS. Pubmed, Google scholar, and Scopus databases were searched. Articles published in English (1986-2016) were included. Nine studies were included (3 retrospective cohort and 6 case-control) enrolling 2845 MS patients (217 with epilepsy; 7.6%). MS patients with epilepsy had a younger age at onset compared to MS patients without seizures (difference in means = -5.42 years, 95% CI -7.19 to -3.66, p < 0.001). Mean EDSS value at inclusion tended to be higher in patients with epilepsy, without reaching statistical significance (difference in means = 0.45, 95% CI -0.01 to 0.91, p = 0.054). No differences were observed in sex distribution (OR = 0.94, 95% CI 0.51-1.72, p = 0.83) and clinical form (OR = 1.03, 95% CI 0.33-3.21, p = 0.96). Two studies evaluated presence and number of cortical lesions as a risk factor for epilepsy in MS using different MRI techniques: in one study, cortical lesions were more frequently observed in patients with epilepsy (OR = 7.06, 95% CI 2.39-20.8; p < 0.001). In the other, cortico-juxtacortical lesions were more frequently observed in patients with epilepsy (OR = 2.6, 95% CI 1.0-6.5; p = 0.047). Studies about risk factors for epilepsy during MS are heterogeneous. Compared to MS patients without seizures, patients with epilepsy have an earlier MS onset and a higher EDSS score after similar disease duration. Clinical form of MS and sex do not predict the appearance of seizures.

Epilepsy in the setting of full trisomy 18: A multicenter study on 18 affected children with and without structural brain abnormalities.

This paper reports on the clinical aspects, electroencephalographic (EEG) features, and neuroimaging findings in children with full trisomy 18 and associated epilepsy, and compares the evolution and outcome of their neurological phenotype. We retrospectively studied 18 patients (10 males and 8 females; aged 14 months to 9 years) with full trisomy 18 and epilepsy. All patients underwent comprehensive assessment including neuroimaging studies of the brain. We divided patients into two groups according to neuroimaging findings: (Group 1) 10 patients harboring structural brain malformations, and (Group 2) 8 patients with normal brain images. Group 1 had a significantly earlier age at seizure onset (2 months) compared to Group 2 (21 months). The seizure semiology was more severe in Group 1, who presented multiple seizure types, need for polytherapy (80% of patients), multifocal EEG abnormalities and poorer outcome (drug resistant epilepsy in 90% of patients) than Group 2 who presented a single seizure type, generalized or focal, and non-specific EEG pattern; these patients were successfully treated with monotherapy with good outcome. Imaging revealed a wide and complex spectrum of structural brain abnormalities including anomalies of the commissures, cerebellar malformations, cortical abnormalities, and various degrees of cortical atrophy. Epilepsy in full trisomy 18 may develop during the first months of life and can be associated with structural brain malformations. Patients with brain malformations can show multiple seizure types and can frequently be resistant to therapy with antiepileptic drugs. © 2016 Wiley Periodicals, Inc.