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ABSTRACTIntroductionPharmacogenomics (PGx) investigates how genomes control enzyme expression. Developmental pharmacology (DP) describes the temporal sequence of enzymes impacting absorption, distribution, metabolism, and excretion (ADME) of food and drugs.Areas coveredUS and European Union (EU) legislation facilitate and/or enforce pediatric studies for all new drugs, called overall ‘pediatric drug development’ (PDD). DP and PDD look at patients’ chronological age, but oscillate between legal and physiological meanings of the term ‘child.’ Children’s bodies become mature with puberty.Expert opinionDecades after first DP observations in babies, PGx offers a better understanding of the variability of safety and efficacy of drugs, of the process of aging, and of shifting enzyme patterns across aging. We should rethink and revise outdated interpretations of ADME changes in minors. The Declaration of Helsinki forbids pointless studies that some pediatric researchers and regulatory agencies, more so the EMA than the FDA, demand pointless pediatric studies is regrettable. Medicine needs to differentiate between legal and physiological meanings of the term ‘child’ and should use objective measures of maturity.

ABSTRACTIntroductionThe concept that children are therapeutic orphans emerged in the 1960s, triggering eventually worldwide legislation to facilitate pediatric studies, called ‘Pediatric Drug Development (PDD).’ However, PDD’s true aim is not better medicines for children but labels in minors; minors are not another species.Areas coveredAbsorption, distribution, metabolism, and excretion (ADME) differ in preterm newborns, but babies mature. With the exception of neonatology, the justifications for clinical, pharmacokinetic, and safety studies were and are exaggerated.Expert opinionPDD reflects an artificial regulatory challenge, reflecting mankind’s transition into a world of effective new drugs compared to previous millennia when only materials taken from nature were available. Minors need dose assessment and proof of safety; there is a tendency to exaggerate the scope of pharmacokinetic and safety studies before and after the eighteenth birthday, potentially motivated not by industry’s greed, but by researchers’ desire for funding and regulatory authorities’ desire for recognition, specifically as since 2007 the European Medicines Agency (EMA) augmented and expanded PDD: a new type of conflict of interest in medicines’ administration and mainstream medical science.

The mediator (MED) multisubunit-complex modulates the activity of the transcriptional machinery, and genetic defects in different MED subunits (17, 20, 27) have been implicated in neurologic diseases. In this study, we identified a recurrent homozygous variant in MED11(c.325C>T; p.Arg109Ter) in 7 affected individuals from 5 unrelated families.

BackgroundRAC3encodes a Rho family small GTPase that regulates the behaviour and organisation of actin cytoskeleton and intracellular signal transduction. Variants in RAC3can cause a phenotypically heterogeneous neurodevelopmental disorder with structural brain anomalies and dysmorphic facies. The pathomechanism of this recently discovered genetic disorder remains unclear.MethodsWe investigated an early adolescent female with intellectual disability, drug-responsive epilepsy and white matter abnormalities. Through exome sequencing, we identified the novel de novo variant (NM_005052.3): c.83T>C (p.Phe28Ser) in RAC3. We then examined the pathophysiological significance of the p.F28S variant in comparison with the recently reported disease-causing p.Q61L variant, which results in a constitutively activated version of RAC3.ResultsIn vitro analyses revealed that the p.F28S variant was spontaneously activated by substantially increased intrinsic GTP/GDP-exchange activity and bound to downstream effectors tested, such as PAK1 and MLK2. The variant suppressed the differentiation of primary cultured hippocampal neurons and caused cell rounding with lamellipodia. In vivo analyses using in utero electroporation showed that acute expression of the p.F28S variant caused migration defects of excitatory neurons and axon growth delay during corticogenesis. Notably, defective migration was rescued by a dominant negative version of PAK1 but not MLK2.ConclusionOur results indicate that RAC3 is critical for brain development and the p.F28S variant causes morphological and functional defects in cortical neurons, likely due to the hyperactivation of PAK1.

BRAT1biallelic variants are associated with rigidity and multifocal seizure syndrome, lethal neonatal (RMFSL), and neurodevelopmental disorder associating cerebellar atrophy with or without seizures syndrome (NEDCAS). To date, forty individuals have been reported in the literature. We collected clinical and molecular data from 57 additional cases allowing us to study a large cohort of 97 individuals and draw phenotype-genotype correlations. Fifty-nine individuals presented with BRAT1-related RMFSL phenotype. Most of them had no psychomotor acquisition (100%), epilepsy (100%), microcephaly (91%), limb rigidity (93%), and died prematurely (93%). Thirty-eight individuals presented a non-lethal phenotype of BRAT1-related NEDCAS phenotype. Seventy-six percent of the patients in this group were able to walk and 68% were able to say at least a few words. Most of them had cerebellar ataxia (82%), axial hypotonia (79%) and cerebellar atrophy (100%). Genotype-phenotype correlations in our cohort revealed that biallelic nonsense, frameshift or inframe deletion/insertion variants result in the severe BRAT1-related RMFSL phenotype (46/46; 100%). In contrast, genotypes with at least one missense were more likely associated with NEDCAS (28/34; 82%). The phenotype of patients carrying splice variants was variable: 41% presented with RMFSL (7/17) and 59% with NEDCAS (10/17).

Protein arginine methyltransferase 7 (PRMT7) is a member of a family of enzymes that catalyzes the methylation of arginine residues on several protein substrates. Biallelic pathogenic PRMT7variants have previously been associated with a syndromic neurodevelopmental disorder characterized by short stature, brachydactyly, intellectual developmental disability, and seizures. To our knowledge, no comprehensive study describes the detailed clinical characteristics of this syndrome. Thus, we aim to delineate the phenotypic spectrum of PRMT7-related disorder.

ABSTRACTIntroductionDravet Syndrome (DS) is a developmental and epileptic encephalopathy carrying high-level psychobehavioral burdens. Although the disease has been known for almost 4 decades, and despite significant progress in the understanding of its physiopathology and natural course, the pharmacological treatment leaves patients and caregivers with significant unmet needs. This review provides a summary of the current and promising therapeutic options for DSAreas coveredPubMed and ClinicalTrials.gov were screened using ‘Dravet Syndrome’ OR ‘DS,’ AND ‘pharmacotherapy,’ AND ‘treatments.’ Randomized clinical trials, structured reviews, and meta-analyses were selected for in-human application of well-known anti-seizure medications; while in-vivoexperiments on models of DS were selected to evaluate the potential of new therapeutic strategies.Expert opinionThe search for new pharmacological treatment options is led by the need for care and defeat of the natural course of the disease, an aspect still largely neglected by the available therapeutic strategies. Yet, the last 6 years have led to a climate of increased interest and availability of clinical trials. Particularly, gene therapy could hopefully prevent DS evolution by directly relieving the specific genetic defect, although the possibility of off-target editing, and the uneasy administration route have still largely prevented its use.

ABSTRACTIntroductionLevetiracetam (LEV) is one of the most widely used anti-seizure medications (ASMs) in clinical practice. This is due both to a different mechanism of action when compared to other ASMs and its easy handling. Indeed, because of its interesting pharmacokinetic properties, it is often used outside of the labeled indications, notably in the neurocritical setting as prophylaxis of epileptic seizures.Areas coveredA literature search was conducted and the most relevant studies on the pharmacokinetic properties of LEV were selected by two independent investigators. Current evidence on the use of ASM prophylaxis in the neurocritical setting was also reviewed, highlighting and discussing the strengths and limits of LEV as drug of choice for anti-epileptic prophylaxis in this scenario.Expert opinionLEV has a ‘near-ideal’ pharmacokinetic profile, which makes it an attractive drug for ASM prophylaxis in neurocritical care. However, current recommendations restrict ASMs prophylaxis to very selected circumstances and the role of LEV is marginal. Moreover, studies are generally designed to compare LEV versus phenytoin, whereas studies comparing LEV versus placebo are lacking. Further, randomized trials will be needed to better elucidate LEV utility and its neuroprotective role in the neurocritical setting.

Pathogenic variants in GABRB3have been associated with a spectrum of phenotypes from severe developmental disorders and epileptic encephalopathies to milder epilepsy syndromes and mild intellectual disability (ID). In this study, we analyzed a large cohort of individuals with GABRB3variants to deepen the phenotypic understanding and investigate genotype–phenotype correlations.

Reflex seizures are consistently evoked by a specific afferent stimulus or by patient activity. Patients experiencing reflex seizures when playing a game on a mobile phone are rarely reported. We describe a boy with reflex seizures after prolonged exposure to the game, Cut the rope,on his mobile phone. The video‐EEG documented electroclinical events characterized by distal myoclonic jerks of the upper limbs, in combination with irregular, diffuse spike‐and‐wave and polyspike‐and‐wave discharges on EEG, followed by a tonic‐clonic seizure. Playing video games on mobile phones may potentially induce reflex seizures, similar to other commonly used platforms such as docking stations connected to video screens.

BackgroundPathogenic KCNQ2variants are a frequent cause of developmental and epileptic encephalopathy.MethodsWe recruited 13 adults (between 18 years and 45 years of age) with KCNQ2encephalopathy and reviewed their clinical, EEG, neuroimaging and treatment history.ResultsWhile most patients had daily seizures at seizure onset, seizure frequency declined or remitted during childhood and adulthood. The most common seizure type was tonic seizures (early) infancy, and tonic-clonic and focal impaired awareness seizures later in life. Ten individuals (77%) were seizure-free at last follow-up. In 38% of the individuals, earlier periods of seizure freedom lasting a minimum of 2 years followed by seizure recurrence had occurred. Of the 10 seizure-free patients, 4 were receiving a single antiseizure medication (ASM, carbamazepine, lamotrigine or levetiracetam), and 2 had stopped taking ASM. Intellectual disability (ID) ranged from mild to profound, with the majority (54%) of individuals in the severe category. At last contact, six individuals (46%) remained unable to walk independently, six (46%) had limb spasticity and four (31%) tetraparesis/tetraplegia. Six (46%) remained non-verbal, 10 (77%) had autistic features/autism, 4 (31%) exhibited aggressive behaviour and 4 (31%) destructive behaviour with self-injury. Four patients had visual problems, thought to be related to prematurity in one. Sleep problems were seen in six (46%) individuals.ConclusionSeizure frequency declines over the years and most patients are seizure-free in adulthood. Longer seizure-free periods followed by seizure recurrence are common during childhood and adolescence. Most adult patients have severe ID. Motor, language and behavioural problems are an issue of continuous concern.

Objective. Coffin‐Siris syndrome (CSS) is a rare congenital malformation syndrome, caused by mutations in the ARID1Bgene in over half of the cases. While the clinical characteristics of the syndrome have been increasingly described, a detailed evaluation of the epileptic phenotype in patients with ARID1Balterations and CSS has not been approached yet. We report seven patients with ARID1B‐related CSS, focusing on epilepsy and its electroclinical features. Methods. The evolution of epilepsy and EEG findings of children with CSS are described and compared with patients previously reported in the literature. Results. The patients described here reveal common features, consistent with those of patients previously described in the literature. Significance. The epilepsy phenotype of CSS due to ARID1Bpathogenic variants may be described as focal epilepsy with seizures, variable in frequency, arising from motor areas, with onset in the first years of life and susceptibility to fever, and interictal perisylvian (centrotemporal) epileptiform abnormalities that are enhanced during sleep with possible evolution to an EEG pattern of continuous spike and wave during sleep (without documented developmental regression). Additional information emerging from other patients is needed to confirm this definition.

Sunflower epilepsy is a rare photosensitive and commonly pharmacoresistant reflex epilepsy characterized by stereotyped seizures involving turning of the head towards light, similar to a sunflower turning towards the sun, and waving of the hands in front of the eyes, sometimes followed by absence seizures, myoclonic jerks, and tonic‐clonic seizures. In the original description, seizures in sunflower epilepsy have been perceived as self‐induced, but contemporary case series suggest that hand waving corresponds to an ictal phenomenon and not to a precipitating factor. We describe a nine‐year‐old girl featuring absence seizures with eye rolling or fluttering associated with hand waving movements. The chronological sequence of events based on a video‐EEG‐documented episode of our patient adds to the controversy surrounding the hypothesis of “self‐induced” epileptic seizures in sunflower epilepsy. Shortly after epilepsy diagnosis, our patient presented with an EEG pattern of continuous spike waves in slow‐wave sleep, an EEG feature that has not been described before and may relate to the cognitive deficit observed in some patients with sunflower epilepsy. Continuous spike waves in slow‐wave sleep resolved, and lasting seizure freedom was achieved by a combination of ethosuximide and lamotrigine, which may be a possible alternative to valproic acid, particularly in girls and women of childbearing age. However, an attempt to taper anti‐seizure drugs two years later led to seizure recurrence. We suggest performing sleep EEG recordings for sunflower epilepsy, particularly in patients with developmental stagnation or regression, to timely diagnose and treat continuous spike waves in slow‐wave sleep syndrome.

ABSTRACTIntroduction: Brivaracetam (BRV) is an antiseizure medication (ASM), which has been approved as an adjunctive treatment in adults and pediatric patients aged four years and older with focal onset seizures. It is a second-generation levetiracetam (LEV) derivative, sharing the same mechanism of action, binding synaptic vesicles 2A (SV2A). BRV shows higher binding affinity and selectivity and higher brain permeability than LEV.Areas covered: This article reviews randomized controlled trials, retrospective and prospective studies published up to December 2020, searched in electronic databases MEDLINE, EMBASE and the Clinical Trial Database and provide an overview of efficacy, safety and tolerability of BRV in pediatric patients with partial epilepsy. Furthermore, the authors provide their expert opinion on the drug and give their future perspectives.Expert opinion: The analysis of the literature data has demonstrated the safety and efficacy of BRV in pediatric patients, with more evidence in children aged 4 to 16 years with an onset of focal seizures. However, a positive response was also achieved in patients affected by some encephalopathic epilepsies. Comparative efficacy studies between BRV and other ASMs, in addition to well-designed RCTs that include larger pediatric populations are needed to better define the role and potentiality of this ASM.

Most families with genetic epilepsy with febrile seizures plus show a mutation in the sodium channel alpha 1 subunit gene, however, but there is much phenotypic heterogeneity and focal epilepsy remains relatively rare. Here, we report a family with electroclinical features indicative of temporal‐parietal‐occipital carrefour epilepsy with common occurrence of post‐ictal migraine. We studied a four‐generation family including nine affected subjects by means of EEG and MRI. Genetic testing was performed by targeted re‐sequencing (gene panel). In most patients, seizure semiology included cognitive, autonomic, and emotional symptoms, eventually evolving towards sensory visual phenomena. Focal sensory vestibular seizures and changes in body perception were also reported in some cases. Post‐ictal migraine was common, occurring in five out of the six (83%) epilepsy patients. A missense mutation (c.1130 G>A; p.R377Q) affecting the S5‐S6 segment (pore region) of the sodium channel alpha 1 subunit was identified in all affected and four unaffected subjects. Temporal‐parietal‐occipital carrefour epilepsy is part of the genetic epilepsy with febrile seizures plus spectrum. The electroclinical features in this family support the involvement of a genetically impaired neural network. High prevalence of post‐ictal migraine suggests the role of posterior brain areas in the clinical expression of this gene defect.

ABSTRACTIntroductionStatus epilepticus (SE) is a common neurological and medical emergency. It has high mortality and morbidity rates, which typically correlate with seizure semiology and duration; therefore, prompt and proper pharmacological intervention is paramount. In a pre-hospital setting, establishing venous access can be difficult, so other routes of drug administration should be considered.Areas coveredThe paper summarizes the data from the literature and provides an evaluation of the efficacy and safety of intramuscular midazolam (IM MDZ) as it pertains to the management of acute seizures and SE.Expert opinionThe cascade of events involved in the genesis and sustenance of seizures, if not promptly stopped, lead to the perpetuation of the condition and may contribute to the refractoriness of pharmacological treatment. Hence, non-venous routes for drug administration were developed to allow untrained personnel to rapidly stop seizures. Among benzodiazepines (BDZs), IM MDZ is at least as effective and safe as other intravenously administered BDZs. Moreover, thanks to IM MDZ’s favorable pharmacodynamic and pharmacokinetic profile, it is a promising alternative to other non-venous drugs such as intranasal-MDZ, buccal-MDZ, and rectal-diazepam in the pre-hospital management of SE cases with motor features.

ObjectiveThe term ‘precision medicine’ describes a rational treatment strategy tailored to one person that reverses or modifies the disease pathophysiology. In epilepsy, single case and small cohort reports document nascent precision medicine strategies in specific genetic epilepsies. The aim of this multicentre observational study was to investigate the deeper complexity of precision medicine in epilepsy.MethodsA systematic survey of patients with epilepsy with a molecular genetic diagnosis was conducted in six tertiary epilepsy centres including children and adults. A standardised questionnaire was used for data collection, including genetic findings and impact on clinical and therapeutic management.ResultsWe included 293 patients with genetic epilepsies, 137 children and 156 adults, 162 females and 131 males. Treatment changes were undertaken because of the genetic findings in 94 patients (32%), including rational precision medicine treatment and/or a treatment change prompted by the genetic diagnosis, but not directly related to known pathophysiological mechanisms. There was a rational precision medicine treatment for 56 patients (19%), and this was tried in 33/56 (59%) and was successful (ie, >50% seizure reduction) in 10/33 (30%) patients. In 73/293 (25%) patients there was a treatment change prompted by the genetic diagnosis, but not directly related to known pathophysiological mechanisms, and this was successful in 24/73 (33%).SignificanceOur survey of clinical practice in specialised epilepsy centres shows high variability of clinical outcomes following the identification of a genetic cause for an epilepsy. Meaningful change in the treatment paradigm after genetic testing is not yet possible for many people with epilepsy. This systematic survey provides an overview of the current application of precision medicine in the epilepsies, and suggests the adoption of a more considered approach.

Major Facilitator Superfamily Domain containing 2a (MFSD2A) is an essential endothelial lipid transporter at the blood-brain barrier. Biallelic variants affecting function in MFSD2Acause autosomal recessive primary microcephaly 15 (MCPH15, OMIM# 616486). We sought to expand our knowledge of the phenotypic spectrum of MCPH15 and demonstrate the underlying mechanism of inactivation of the MFSD2A transporter. We carried out detailed analysis of the clinical and neuroradiological features of a series of 27 MCPH15 cases, including eight new individuals from seven unrelated families. Genetic investigation was performed through exome sequencing (ES). Structural insights on the human Mfsd2a model and in-vitro biochemical assays were used to investigate the functional impact of the identified variants. All patients had primary microcephaly and severe developmental delay. Brain MRI showed variable degrees of white matter reduction, ventricular enlargement, callosal hypodysgenesis, and pontine and vermian hypoplasia. ES led to the identification of six novel biallelic MFSD2Avariants (NG_053084.1, NM_032793.5: c.556+1G>A, c.748G>T; p.(Val250Phe), c.750_753del; p.(Cys251SerfsTer3), c.977G>A; p.(Arg326His), c.1386_1435del; p.(Gln462HisfsTer17), and c.1478C>T; p.(Pro493Leu)) and two recurrent variants (NM_032793.5: c.593C>T; p.(Thr198Met) and c.476C>T; p.(Thr159Met)). All these variants and the previously reported NM_032793.5: c.490C>A; p.(Pro164Thr) resulted in either reduced MFSD2A expression and/or transport activity. Our study further delineates the phenotypic spectrum of MCPH15, refining its clinical and neuroradiological characterization and supporting that MFSD2Adeficiency causes early prenatal brain developmental disruption. We also show that poor MFSD2A expression despite normal transporter activity is a relevant pathomechanism in MCPH15.

Aim:Pharmacoresistance is a major burden in epilepsy treatment. We aimed to identify genetic biomarkers in response to specific antiepileptic drugs (AEDs) in genetic generalized epilepsies (GGE). Materials & methods:We conducted a genome-wide association study (GWAS) of 3.3 million autosomal SNPs in 893 European subjects with GGE – responsive or nonresponsive to lamotrigine, levetiracetam and valproic acid. Results:Our GWAS of AED response revealed suggestive evidence for association at 29 genomic loci (p <10-5) but no significant association reflecting its limited power. The suggestive associations highlight candidate genes that are implicated in epileptogenesis and neurodevelopment. Conclusion:This first GWAS of AED response in GGE provides a comprehensive reference of SNP associations for hypothesis-driven candidate gene analyses in upcoming pharmacogenetic studies.

We established the genetic etiology of a syndromic neurodevelopmental condition characterized by variable cognitive impairment, recognizable facial dysmorphism, and a constellation of extra-neurological manifestations.

ABSTRACTIntroduction: Atypical absences are generalized epileptic seizures typically affecting children with severe epilepsies and learning difficulties along with other seizure types. Video-EEG is essential for their diagnosis. Recently, atypical absence seizures have been reported as a hallmark of some developmental and epileptic encephalopathies.Areas covered: This is a narrative review of the literature which describes the electroclinical features of atypical seizures, the characteristics of developmental epileptic encephalopathies in which this seizure type can occur, and the evidence supporting the use of individual antiseizure drugs for the treatment of atypical absences.Expert opinion: Treatment of absence seizures typically relies on ethosuximide (ineffective against tonic-clonic seizures), valproate (associated with larger proportion of adverse events), or lamotrigine (less effective than the other two). However, unlike typical absences, atypical absences are usually intractable, persist lifetime, and their prognosis depends on the underlying etiology or associated epilepsy syndrome. Besides efficacy, other relevant factors, such as drug formulation, ease of titration and dosing, and drug interactions, should be considered. Drugs that may worsen epilepsy, cognition and behavior should be avoided. In the vast majority of patients, a polytherapy is required, although usually with limited efficacy. Finally, epilepsy syndromes featuring atypical absences require a multidisciplinary approach.

ABSTRACTIntroduction: Sodium valproate is a widely used anti-epileptic drug with a broad spectrum of activity and mechanism of action. It has consequently been the first-line drug for most seizure types in children for the past fifty years. A wide range of side effects come along with these exceptional properties, including teratogenicity and neuro-cognitive impairments in offspring. Therefore, epilepsy treatment in children and adolescents should be reassessed in light of newer antiepileptic drugs as well as a more targeted-approach with older drugs.Areas covered: The authors review the main concerns of valproate use in terms of adverse effects on different systems and drug interactions. The current alternatives to valproate in absence, myoclonic, tonic-clonic and focal onset seizures in children/adolescents are also reviewed.Expert opinion: There are several issues that research should address in antiepileptic therapy and in clinical studies with children, given the peculiarity of this population. Future perspectives in epilepsy therapy should now lead towards an individualized treatment.

Aims. To further characterise CDKL5‐related disorder, previously classified as an early‐onset seizure variant of Rett syndrome, which is currently considered a specific and independent early‐infantile epileptic encephalopathy. Methods. We describe the epileptic phenotype and neurocognitive development in three girls with CDKL5mutations showing severe neurodevelopmental impairment, with different epileptic phenotypes and severity. Results. The patients differed regarding age at epilepsy onset, seizure frequency, duration of “honeymoon periods”, as well as EEG features. The “honeymoon period”, defined as a seizure‐free period longer than two months, represented, in our case series, a good indicator of the epilepsy outcome, but not of the severity of developmental impairment. However, even during the “honeymoon period”, the interictal EEG showed epileptiform abnormalities, slowing, or a disappearance of physiological pattern. The natural history of CDKL5disorder was compared between the three girls, focusing on the relationship between electroclinical features and neurological development. Conclusion. Our findings suggest that CDKL5mutations likely play a direct role in psychomotor development, whereas epilepsy is one of the clinical features associated with this complex disorder.

This study aims to comprehensively delineate the phenotypic spectrum of ACTL6B-related disorders, previously associated with both autosomal recessive and autosomal dominant neurodevelopmental disorders. Molecularly, the role of the nucleolar protein ACTL6B in contributing to the disease has remained unclear.

ABSTRACTIntroduction: Dravet syndrome (DS) is an early-onset genetic developmental epileptic encephalopathy characterized by multiple seizure types which are refractory to antiseizure medication. There is an unmet need for effective and tolerable drugs to control different seizure types in DS types, with the aim of improving quality of life and preventing neurological impairment.Areas covered: Narrative review of efficacy and tolerability of fenfluramine, cannabidiol (CBD), verapamil, and modulators of serotonin signaling pathways (lorcaserin or trazodone) in the treatment of DS.Expert opinion/commentary: A recent large randomized controlled trial has shown that CBD is effective in the treatment of DS; preliminary data from the placebo-controlled trial on fenfluramine are also promising. Further studies are definitely required to evaluate the role of verapamil and modulators of serotonin signaling in DS. At present, drugs used to treat seizures in DS treat the symptoms of epilepsy rather than its cause(s). Future research should focus on elucidating the natural history of DS and whether appropriate treatment can have a beneficial impact on its disease course. A multidisciplinary, individualized approach to care of DS patients is required.

Epilepsy is a frequent feature of neurodevelopmental disorders (NDDs), but little is known about genetic differences between NDDs with and without epilepsy. We analyzed de novo variants (DNVs) in 6,753 parent–offspring trios ascertained to have different NDDs. In the subset of 1,942 individuals with NDDs with epilepsy, we identified 33 genes with a significant excess of DNVs, of which SNAP25and GABRB2had previously only limited evidence of disease association. Joint analysis of all individuals with NDDs also implicated CACNA1Eas a novel disease-associated gene. Comparing NDDs with and without epilepsy, we found missense DNVs, DNVs in specific genes, age of recruitment, and severity of intellectual disability to be associated with epilepsy. We further demonstrate the extent to which our results affect current genetic testing as well as treatment, emphasizing the benefit of accurate genetic diagnosis in NDDs with epilepsy. Analysis of individuals with neurodevelopmental disorders (NDDs) with epilepsy identifies 33 genes with a significant excess of de novo variants. Comparison of rates of de novo variants between NDDs with or without epilepsy highlights differences between these phenotypic groups.

ABSTRACTIntroduction: Recently, an intravenous formulation of carbamazepine (CBZ) (sulphobutylether-7-beta-cyclodextrine carbamazepine, SBECD CBZ) has been developed and approved by the U.S. Food and Drug Administration. It is indicated as a short-term replacement therapy for oral CBZ formulations, when oral administration is temporarily not feasible and in adults with focal seizures with complex symptomatology as well as generalized tonic-clonic seizures and mixed seizure patterns.Areas covered: This review focuses on the drug development, pharmacokinetics and pharmacodynamics of intravenous CBZ and provides a comprehensive overview of the studies assessing its clinical efficacy, tolerability and safety in adults with epilepsy.Expert opinion: Intravenous CBZ has favorable pharmacokinetics and is well tolerated and safe when used as a short-term substitution for oral CBZ. Seizure control was unchanged after switching from oral to IV formulations. Overall, this new formulation represents a useful option to enhance continuity of care in adults with focal or generalized tonic-clonic seizures when oral CBZ administration is temporarily unfeasible. Further studies are needed to assess the efficacy and tolerability of IV CBZ used at larger doses (above 1600 mg/day), for a period longer than 7 days or for other indications not approved by FDA, such as prolonged convulsive seizures and status epilepticus.

ABSTRACTIntroduction: Although novel antiepileptic drugs (AEDs) have been recently released, the issue of drug resistance in epileptic patients remains unsolved and largely unpredictable.Areas covered: We aim to assess the clinical impact of genetic variations that may influence the efficacy of medical treatment in epilepsy patients. Indeed, many genes, including genes encoding drug transporters (ABCB1), drug targets (SCN1A), drug-metabolizing enzymes (CYP2C9, CYP2C19), and human leucocyte antigen (HLA) proteins, may regulate the mechanisms of drug resistance in epilepsy. This review specifically focuses on the ABC genes, which encode multidrug resistance-associated proteins (MRPs) and may reduce the blood–brain barrier penetration of anticonvulsant AEDs.Expert opinion: Drug resistance remains a crucial problem in epilepsy patients. Pharmacogenomic studies may improve our understanding of drug responses and drug resistance by exploring the impact of gene variants and predicting drug responses and tolerability.

Rufinamide was granted orphan drug status in 2004 for the adjunctive treatment of seizures associated with Lennox‐Gastaut syndrome in patients aged ≥4 years, and was subsequently approved for this indication in several countries, including Europe and the United States. Structurally unrelated to other antiepileptic drugs, rufinamide is thought to act primarily by prolonging the inactivation phase of voltage‐gated sodium channels. Rufinamide was approved on the basis of an international, randomised, placebo‐controlled Phase III trial, conducted in 138 patients with Lennox‐Gastaut syndrome, which demonstrated its favourable tolerability profile and efficacy in significantly reducing the frequency of drop attacks and total seizures, compared with placebo. The effectiveness and safety/tolerability of rufinamide in treating seizures associated with Lennox‐Gastaut syndrome have subsequently been confirmed in several other clinical trials and long‐term extension studies. These findings are supported by ‘real‐world’ data from a series of clinical practice studies conducted in Europe, the United States, and Korea. Rufinamide has been shown to be effective and generally well tolerated in children as young as one year and in adults. It is particularly effective as treatment for drop attacks and generalised tonic‐clonic seizures, and it has been suggested that it might be preferred over other antiepileptic drugs as a second‐line treatment for Lennox‐Gastaut syndrome when drop attacks are frequent. The most common side effects of rufinamide treatment include somnolence, headache, dizziness, nausea, vomiting, and fatigue. No new or unexpected safety signals have emerged following long‐term treatment with rufinamide, either in clinical trials or in clinical practice.

A 5-month-old boy came to the emergency department because of a monocular nystagmus with head-nodding and torticollis (Video 1). Fundoscopic examination excluded macular/optic nerve hypoplasia and retinal abnormalities. Brain MRI was unremarkable (Figure). A diagnosis of spasmus nutans (SN) was made.

ABSTRACTIntroduction:Seizures or chronic epilepsy are a relatively common occurrence in a neurosurgical setting. However, seizure treatment after neurosurgery has received less attention compared with other causes and only few data are availaible in the literature on management in neurosurgical patients.Areas covered:This paper reviews the availaible data on the risk of seizures in patients undergoing neurosurgery and discusses the role of antiseizure therapy in the management of the postoperative period. Finally, some controversial issues on this topic are addressed.Expert opinion:Despite the studies so far published on this topic, there are still no guidelines for the clinical practice. International recommendations do not generally support the use of antiseizure drugs in postsurgical patients. Nevertheless, their use still remains wide in the routine practice. Initiation of a treatment should be considered when the risk for prolonged seizures or chronic epilepsy is high and the risk of toxicity is acceptable. First generation antiseizures drugs seem to be quite effective although new drugs are associated with lower adverse effects risk and better tolerability.

Background: Spike-wave discharges, underlying absence seizures, are generated within a cortico-thalamo-cortical network that involves the somatosensory cortex, the reticular thalamic nucleus, and the ventrobasal thalamic nuclei. Activation of T-type voltage-sensitive calcium channels (VSCCs) contributes to the pathological oscillatory activity of this network, and some of the first-line drugs used in the treatment of absence epilepsy inhibit T-type calcium channels. The α2δ subunit is a component of high voltage-activated VSCCs (i.e., L-, N-, P/Q-, and R channels) and studies carried out in heterologous expression systems suggest that it may also associate with T channels. The α2δ subunit is also targeted by thrombospondins, which regulate synaptogenesis in the central nervous system. Objective: To discuss the potential role for the thrombospondin/α2δ axis in the pathophysiology of absence epilepsy. Methods: We searched PubMed articles for the terms “absence epilepsy”, “T-type voltage-sensitive calcium channels”, “α2δ subunit”, “ducky mice”, “pregabalin”, “gabapentin”, “thrombospondins”, and included papers focusing this Review's scope. Results: We moved from the evidence that mice lacking the α2δ-2 subunit show absence seizures and α 2δ ligands (gabapentin and pregabalin) are detrimental in the treatment of absence epilepsy. This suggests that α2δ may be protective against absence epilepsy via a mechanism that does not involve T channels. We discuss the interaction between thrombospondins and α2δ and its potential relevance in the regulation of excitatory synaptic formation in the cortico-thalamo-cortical network. Conclusion: We speculate on the possibility that the thrombospondin/α2 δ axis is critical for the correct functioning of the cortico-thalamo-cortical network, and that abnormalities in this axis may play a role in the pathophysiology of absence epilepsy.

ABSTRACTIntroduction: Status Epilepticus (SE) is the most common neurological emergency of childhood. It requires prompt administration of appropriately selected anti-seizure medications.Areas covered: Following a distinction between estabilished and emergent drugs, we present pharmacological treatment options and their clinical utility in children, with a short mention on alternatives to drug treatment. We also propose an algorithm for the management of pediatric SE. For this review a Pubmed, Medline and Embase search was performed.Expert opinion: In early SE in children, in the prehospital setting, rectal diazepam or buccal midazolam are efficacious drugs; whereas in the hospital setting, intravenous lorazepam or diazepam are indicated. As regard estabilished stage of SE, in addition to the ‘classic’ compounds, such as phenytoin and phenobarbital, other drugs such as valproic acid, levetiracetam and lacosamide have been demonstrated efficacious. Treatment recommendations of refractory SE depend on retrospective case series and uncontrolled studies. We reported experiences about the use of midazolam, propofol, ketamine and lidocaine. They could be a valid option, but further prospective studies are necessary. Over the last few decades, important advances in basic mechanisms underlying refractory SE have been achieved, but few data are available regarding management of these stages.

ABSTRACTShapiro Syndrome is a rare entity defined by the triad of recurrent spontaneous hypothermia, hyperhidrosis, and agenesis of the corpus callosum. Fewer than 100 cases have been reported so far and there are only few cases without a complete agenesis of corpus callosum (“Shapiro Syndrome Variant”). In this article, we report the clinical, electroencephalographic, and neuroimaging data of a patient with early-onset Shapiro Syndrome Variant. The case study describes a 4-year-old patient with episodes characterized by generalized hyperhidrosis, hypotonia, impaired consciousness, and hypothermia with onset before the first year of age. We captured an event during which the EEG showed rhythmic low- to medium-voltage theta waves without clear epileptiform activity. Brain MRI was normal and Shapiro Syndrome Variant was hypothesized. We started treatment with pizotifen, and after 2 years, the patient showed a reduction in frequency and duration of episodes. Shapiro Syndrome, although rare, should be considered in the differential diagnosis in patients with neurovegetative symptoms which suggest epileptic attacks at first. Our case is of particular interest to specialists because Shapiro SyndromeVariant is a rare syndrome and our patient had a very early onset of symptoms.In addition, we report our experience with pizotifen therapy, which produced a good response.

ABSTRACTIntroduction: Myoclonic seizures are brief, involuntary muscular jerks arising from the central nervous system that can occur in different epilepsy syndromes, including idiopathic generalized epilepsies or the most severe group of epileptic encephalopathies. Valproate is commonly the first choice alone or in combination with some benzodiazepines or levetiracetam. However, more treatment options exist today as there is emerging evidence to support the efficacy of some newer antiepileptic drugs. In addition, of major importance remains avoidance of medications (e.g., carbamazepine, phenytoin) that may aggravate myoclonic seizures. This is an updated review on the available therapeutic options for treatment of myoclonic seizures.Areas covered: Key efficacy, tolerability and efficacy data are showed for different antiepileptic drugs with antimyoclonic effect, alone and/or in combination.Expert opinion: Pharmacological treatment of myoclonic seizures is based on clinical experience with little evidence from randomized clinical trials. Valproate, levetiracetam, and some benzodiazepines, are widely used. There is still insufficient evidence for the use of other antiseizure drugs, such as topiramate or zonisamide as monotherapy. Better understanding of pathophysiologic mechanisms of myoclonic epilepsies could yield great improvement in the treatment and quality of life of patients.

Vitamin-B6-dependent epilepsies are a heterogenous group of treatable disorders due to mutations in several genes (ALDH7A1, PNPO, ALPLor ALDH4A1). In neonatal seizures, defects in ALDH7A1 and PNPOexplain a major fraction of cases. Very recently biallelic mutations in PROSCwere shown to be a novel cause in five families. We identified four further unrelated patients harbouring a total of six different mutations, including four novel disease mutations. Vitamin B6plasma profiles on pyridoxine did not enable the differentiation of patients with PROSCmutations. All four patients were normocephalic and had normal cranial imaging. Pyridoxine monotherapy allowed complete seizure control in one, while two patients had occasional febrile or afebrile seizures and one needed additional valproate therapy for photosensitive seizures. Two patients underwent a controlled pyridoxine withdrawal with signs of encephalopathy within a couple of days. Three had favourable outcome with normal intellectual properties at age 12.5, 15.5 and 30 years, respectively, while one child had marked developmental delay at age 27 months. The clinical and electroencephalographic phenotype in patients with PROSCmutations was indistinguishable from ALDH7A1and PNPOdeficiency. We therefore confirm PROSCas a novel gene for vitamin-B6-dependent epilepsy and delineate a non-specific plasma vitamin B6profile under pyridoxine treatment.