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Objective: The mechanisms by which antiepileptic drugs (AEDs) cause birth defects (BDs) are unknown. Data suggest that AED-induced BDs may result from a genome-wide increase of de novo variants in the embryo, a mechanism that we investigated.Methods: Whole exome sequencing data from child-parent trios were interrogated for de novo single-nucleotide variants/indels (dnSNVs/indels) and de novo copy number variants (dnCNVs). Generalized linear models were applied to assess de novo variant burdens in children exposed prenatally to AEDs (AED-exposed children) versus children without BDs not exposed prenatally to AEDs (AED-unexposed unaffected children), and AED-exposed children with BDs versus those without BDs, adjusting for confounders. Fisher exact test was used to compare categorical data.Results: Sixty-seven child-parent trios were included: 10 with AED-exposed children with BDs, 46 with AED-exposed unaffected children, and 11 with AED-unexposed unaffected children. The dnSNV/indel burden did not differ between AED-exposed children and AED-unexposed unaffected children (median dnSNV/indel number/child [range] = 3 [0-7] vs 3 [1-5], p = 0.50). Among AED-exposed children, there were no significant differences between those with BDs and those unaffected. Likely deleterious dnSNVs/indels were detected in 9 of 67 (13%) children, none of whom had BDs. The proportion of cases harboring likely deleterious dnSNVs/indels did not differ significantly between AED-unexposed and AED-exposed children. The dnCNV burden was not associated with AED exposure or birth outcome.Interpretation: Our study indicates that prenatal AED exposure does not increase the burden of de novo variants, and that this mechanism is not a major contributor to AED-induced BDs. These results can be incorporated in routine patient counseling. ANN NEUROL 2020;87:897-906. [ABSTRACT FROM AUTHOR]

The epilepsy-linked gene SV2A, has a number of potential roles in the synaptic vesicle (SV) life cycle. However, how loss of SV2A function translates into presynaptic dysfunction and ultimately seizure activity is still undetermined. In this study, we examined whether the first SV2A mutation identified in human disease (R383Q) could provide information regarding which SV2A-dependent events are critical in the translation to epilepsy. We utilized a molecular replacement strategy in which exogenous SV2A was expressed in mouse neuronal cultures of either sex, which had been depleted of endogenous SV2A to mimic the homozygous human condition. We found that the R383Q mutation resulted in a mislocalization of SV2A from SVs to the plasma membrane, but had no effect on its activity-dependent trafficking. This SV2A mutant displayed reduced mobility when stranded on the plasma membrane and reduced binding to its interaction partner synaptotagmin-1 (Sytl). Furthermore, the R383Q mutant failed to rescue reduced expression and dysfunctional activity-dependent trafficking of Sytl in the absence of endogenous SV2A. This suggests that the inability to control Sytl expression and trafficking at the presynapse may be key in the transition from loss of SV2A function to seizure activity. [ABSTRACT FROM AUTHOR]

Objective: Genetic testing has become a routine part of the diagnostic workup in children with early onset epilepsies. In the present study, we sought to investigate a cohort of adult patients with epilepsy, to determinate the diagnostic yield and explore the gain of personalized treatment approaches in adult patients. Methods: Two hundred patients (age span = 18‐80 years) referred for diagnostic gene panel testing at the Danish Epilepsy Center were included. The vast majority (91%) suffered from comorbid intellectual disability. The medical records of genetically diagnosed patients were mined for data on epilepsy syndrome, cognition, treatment changes, and seizure outcome following the genetic diagnosis. Results: We found a genetic diagnosis in 46 of 200 (23%) patients. SCN1A, KCNT1, and STXBP1 accounted for the greatest number of positive findings (48%). More rare genetic findings included SLC2A1, ATP6A1V, HNRNPU, MEF2C, and IRF2BPL. Gene‐specific treatment changes were initiated in 11 of 46 (17%) patients (one with SLC2A1, 10 with SCN1A) following the genetic diagnosis. Ten patients improved, with seizure reduction and/or increased alertness and general well‐being. Significance: With this study, we show that routine diagnostic testing is highly relevant in adults with epilepsy. The diagnostic yield is similar to previously reported pediatric cohorts, and the genetic findings can be useful for therapeutic decision‐making, which may lead to better seizure control, ultimately improving quality of life. [ABSTRACT FROM AUTHOR]

Objective: Sodium valproate (VPA), the most effective antiepileptic drug for patients with genetic generalized epilepsy (GGE), is a potent human teratogen that increases the risk of a range of congenital malformations, including spina bifida. The mechanisms underlying this teratogenicity are not known, but may involve genetic risk factors. This study aimed to develop an animal model of VPA‐induced birth defects. Methods: We used three different rat strains: inbred Genetic Absence Epilepsy Rats From Strasbourg (GAERS), a model of GGE with absence seizures; inbred Non‐Epileptic Controls (NEC); and outbred nonepileptic Wistars. Female rats were fed standard chow or VPA (20 g/kg food) mixed in standard chow for 2 weeks prior to conception, and then mated with same‐strain males. Treatment continued throughout pregnancy. Fetuses were extracted via C‐section on gestational day 21 and examined for birth defects, including external assessment and spinal measurements. Results: VPA‐exposed pups showed significant reductions in weight, length, and whole‐body development compared with controls of all three strains (P <.0001). Gestational VPA treatment altered intravertebral distances, and resulted in underdeveloped vertebral arches between thoracic region T11 and caudal region C2 in most pups (GAERS, 100%; NEC, 95%; Wistar, 80%), more frequently than in controls (9%, 13%, 19%). Significance: Gestational VPA treatment results in similar developmental and morphological abnormalities in three rat strains, including one with GGE, indicating that the genetic underpinnings of epilepsy do not contribute markedly to VPA‐induced birth defects. This model may be used in future studies to investigate mechanisms involved in the pathogenesis of antiepileptic drug–induced birth defects. [ABSTRACT FROM AUTHOR]

P2X7 receptors (P2X7Rs) are ATP sensitive cation channels and have been shown to be effective in various epilepsy models. Absence epilepsy is a type of idiopathic, generalized, non-convulsive epilepsy. Limited data exist on the role of P2X7Rs and no data has been reported regarding the interaction between P2X7Rs and glutamate receptor NMDA in absence epilepsy. Thus, this study was designed to investigate the role of P2X7 and NMDA receptors and their possible interaction in WAG/Rij rats with absence epilepsy. Permanent cannula and electrodes were placed on the skulls of the animals. After the healing period of the electrode and cannula implantation, ECoG recordings were obtained during 180 min before and after drug injections. P2X7R agonist BzATP, at doses of 50 μg and 100 μg (intracerebroventricular; i.c.v.) and antagonist A-438079, at doses of 20 μg and 40 μg (i.c.v.) were administered alone or prior to memantine (5 mg/kg, intraperitoneal; i.p.) injection. The total number (in every 20 min), the mean duration, and the amplitude of spike-wave discharges (SWDs) were calculated and compared. Rats were decapitated and the right and left hemisphere, cerebellum, and brainstem were separated for the measurements of the advanced oxidation protein product (AOPP), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), catalase (CAT), glutathione peroxide (GPx), and glutathione reductase (GR). BzATP and A-438079 did not alter measured SWDs parameters, whereas memantine reduced them, which is considered anticonvulsant. BzATP did not alter the anticonvulsant effect of memantine, while A-438079 decreased the effect of memantine. Administration of BzATP increased the levels of SOD and GR in cerebrum hemispheres. A-438079 did not alter any of the biochemical parameters. Memantine reduced the levels of MDA, GSH, and GR while increased the level of CAT in the cerebrum. Administration of BzATP before memantine abolished the effect of memantine on MDA levels. The evidence from this study suggests that P2X7Rs does not directly play a role in the formation of absence seizures. P2X7Rs agonist, reduced the antioxidant activity of memantine whereas agonist of P2X7Rs reduced the anticonvulsant action of memantine, suggesting a partial interaction between P2X7 and NMDA receptors in absence epilepsy model. [ABSTRACT FROM AUTHOR]

Drug hypersensitivity reactions (DHRs) are associated with high global morbidity and mortality. Cutaneous T cell–mediated reactions classically occur more than 6 hours after drug administration and include life‐threatening conditions such as toxic epidermal necrolysis, Stevens‐Johnson syndrome, and hypersensitivity syndrome. Over the last 20 years, significant advances have been made in our understanding of the pathogenesis of DHRs with the identification of human leukocyte antigens as predisposing factors. This has led to the development of pharmacogenetic screening tests, such as HLA‐B*57:01 in abacavir therapy, which has successfully reduced the incidence of abacavir hypersensitivity reactions. We have completed a PRISMA‐compliant systematic review to identify genetic associations that have been reported in DHRs. In total, 105 studies (5554 cases and 123 548 controls) have been included in the review reporting genetic associations with carbamazepine (n = 31), other aromatic antiepileptic drugs (n = 24), abacavir (n = 11), nevirapine (n = 14), trimethoprim‐sulfamethoxazole (n = 11), dapsone (n = 4), allopurinol (n = 10), and other drugs (n = 5). The most commonly reported genetic variants associated with DHRs are located in human leukocyte antigen genes and genes involved in drug metabolism pathways. Increasing our understanding of genetic variants that contribute to DHRs will allow us to improve diagnosis, develop new treatments, and predict and prevent DHRs in the future. [ABSTRACT FROM AUTHOR]

Many aspects of epilepsy in mitochondrial disorders (MDs) need to be further clarified. To this aim, we explored retrospectively a cohort of individuals with MDs querying the "Nationwide Italian Collaborative Network of Mitochondrial Diseases" (NICNMD) database (1467 patients included since 2010 to December 2016). We collected information on age at epilepsy onset, seizure type and frequency, genetic findings, and antiepileptic drugs (AEDs). At the time of our survey, 147/1467 (10%) patients in the NICNMD database had epilepsy. Complete information was available only for 98 patients, 52 males and 46 females, aged 5–92 years (mean age 40.4 ± 18.4; 14/98 children/teenagers and 84 adults). Epilepsy was the presenting feature of MD in 46/98 (47%) individuals, with onset at a median age of 19 years (range, 0.2–68; < 3 years in 14/97 (14%), 3–19 years in 36/97 (37%), > 19 years in 47/97 (49%)). Moreover, 91/98 patients (93%) displayed multiple seizures, with daily or weekly frequency in 25/91 (28%). Interictal EEG was abnormal in 70/78 (90%) patients, displaying abnormal background (47/70; 67%) and/or interictal paroxysms (53/70; 76%). Eighty of 90 patients (89%) displayed a 50–100% reduction of seizures on AEDs; levetiracetam was the most commonly used. Forty-one patients (42%) carried the m.3243A>G mutation, 16 (16%) the m.8344A>G, and 9 (9%) nuclear DNA (nDNA) mutations. Individuals with early-onset seizures mainly carried nDNA mutations and had a more severe epilepsy phenotype, higher seizure frequency, and disorganized background EEG activity. A better definition of epilepsy in MDs may foster the diagnostic workup, management, and treatment of affected patients, and allow more homogeneous patient stratification. [ABSTRACT FROM AUTHOR]

• Absence epilepsy (AE) is associated with cognitive comorbidities that may persist throughout life. • GAERS, a rat AE model, have elevated anxiety and altered social behaviour, but cognition has not been adequately assessed. • Visual discrimination and reversal learning were tested with touchscreen-equipped operant chambers. • Female GAERS were impaired on pretraining and reversal, whereas males were impaired on discrimination and reversal. • This study demonstrates general and sex-specific impairments in cognition and behavioural flexibility in GAERS. Absence Epilepsy (AE) is associated with recurrent losses of awareness and synchronous bilateral spike-wave discharges (SWDs). While seizures do not generally continue into adulthood, cognitive and behavioral comorbidities persist. One preclinical model used to investigate AE is the Genetic Absence Epilepsy Rats from Strasbourg (GAERS) which consistently have bilateral SWDs and similar behavioral profiles. In this experiment, we characterized discrimination learning and behavioral flexibility in female and male GAERS (n = 7 per sex) and Non-Epileptic Controls (NEC; n = 8 per sex) in a touchscreen-based version of visual discrimination (VD) and reversal learning (RL). We found that, on average, female GAERS required more sessions (12.3) to complete pretraining compared to female and male NEC (8.2 and 7.3, respectively) and male GAERS (9.4). In contrast, there was a sex-specific impairment during VD with male GAERS requiring more sessions on average (12.3) than male and female NEC (both 7.5) and female GAERS (8.3). Additionally, male GAERS completed >30% more selection and correction trials during VD and made >30% more errors. Both female and male GAERS required more sessions on average (9.1 and 10.7, respectively) of RL compared to female and male NEC (6.4 and 6.0 sessions, respectively). Accordingly, GAERS performed ∼30% more selection trials and correction trials compared to NEC, although only male GAERS made significantly more errors (>40%). Deficits in VD and RL were not associated with differences in correct or incorrect response latency, or reward collection latency, suggesting impairments are not due to alterations in locomotor activity or motivation. Together, these data suggest that GAERS have impaired behavioral flexibility and identify some sex-dependent differences. Thus, GAERS may be suitable for assessing the potential benefit of antiepileptic drugs on comorbid behavioral and cognitive deficits. [ABSTRACT FROM AUTHOR]

Genetic generalized epilepsies (GGE), previously called idiopathic generalized epilepsies, constitute about 20% of all epilepsies, and include childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and epilepsy with generalized tonic-clonic seizures alone (CAE, JAE, JME, and GGE-GTCS, respectively). GGE are characterized by high heritability, likely underlain by polygenetic mechanisms, which may relate to atypical neurodevelopmental trajectories. Age of onset ranges from pre-school years, for CAE, to early adulthood for GGE-GTCS. Traditionally, GGE have been considered benign, a belief contrary to evidence from neuropsychology studies conducted over the last two decades. In JME, deficits in executive and social functioning are common findings and relate to impaired frontal lobe function. Studies using neuropsychological measures and cognitive imaging paradigms provide evidence for hyperconnectivity between prefrontal and motor cortices, aberrant fronto-thalamo-cortical connectivity, and reduced fronto-cortical and subcortical gray matter volumes, which are associated with altered cognitive performance. Recent research has also identified associations between abnormal hippocampal morphometry and fronto-temporal activation during episodic memory. Longitudinal studies on individuals with newly diagnosed JME have observed cortical dysmaturation, which is paralleled by delayed cognitive development compared to the patients' peers. Comorbidities and cognitive deficits observed in other GGE subtypes, such as visuo-spatial and language deficits in both CAE and JAE, have also been correlated with atypical neurodevelopment. Although it remains unclear whether cognitive impairment profiles differ amongst GGE subtypes, effects may become more pronounced with disease duration, particularly in absence epilepsies. Finally, there is substantial evidence that patients with JME and their unaffected siblings share patterns of cognitive deficits, which is indicative of an underlying genetic etiology (endophenotype), independent of seizures and anti-epileptic medication. [ABSTRACT FROM AUTHOR]

Aim: To characterize the clinical and genetic characteristics of a large cohort of patients with pyridoxine-dependent epilepsy (PDE).Method: We retrospectively collected clinical and genetic information of 33 (15 males, 18 females; mean [SD] age 4y 11mo [2y 5mo]; 1y 3mo-10y 4mo) patients with PDE from 31 unrelated families at a single centre.Results: There were many types of seizures, with focal seizures in 32 cases. Dravet syndrome was suspected clinically in two patients. Electroencephalogram (EEG) was normal in seven patients at the initial stage and then in 17 patients during pyridoxine maintenance therapy. Genetic studies revealed 26 kinds of variants in ALDH7A1 and four in PLPBP with 18 variants unreported previously, and 48 ALDH7A1 variants were located in exon 11, 12, 14, and 17 or intron 9 and 11. In addition, three patients carried different exons deletion. Among these, seizures could be controlled for several years in one patient by levetiracetam monotherapy. Another patient remained seizure free for up to 7 months without therapy. All patients received oral pyridoxine treatment, with only one case (with exon 8-13 deletion) showing poor control.Interpretation: This study illustrates the range of clinical presentations and genetic causes in PDE, as well as responsiveness to antiepileptic drugs. A relationship between EEG and pyridoxine therapy could be seen in many cases. Seizure control was seen in all with pyridoxine monotherapy except for one patient.What This Paper Adds: There is a parallel relationship between electroencephalogram and pyridoxine therapy in many patients. Patients with pyridoxine-dependent epilepsy may respond well to low-dose pyridoxine. [ABSTRACT FROM AUTHOR]

An ever-increasing number of neurogenetic conditions presenting with both epilepsy and atypical movements are now recognized. These disorders within the 'genetic epilepsy-dyskinesia' spectrum are clinically and genetically heterogeneous. Increased clinical awareness is therefore necessary for a rational diagnostic approach. Furthermore, careful interpretation of genetic results is key to establishing the correct diagnosis and initiating disease-specific management strategies in a timely fashion. In this review we describe the spectrum of movement disorders associated with genetically determined epilepsies. We also propose diagnostic strategies and putative pathogenic mechanisms causing these complex syndromes associated with both seizures and atypical motor control. WHAT THIS PAPER ADDS: Implicated genes encode proteins with very diverse functions. Pathophysiological mechanisms by which epilepsy and movement disorder phenotypes manifest are often not clear. Early diagnosis of treatable disorders is essential and next generation sequencing may be required. [ABSTRACT FROM AUTHOR]

Background and Purpose: Epilepsy is a common chronic neurological disorder. About one third of epilepsy patients will suffer from drug resistance after rational selection of antiepileptic drug treatment. The formation of drug-resistant epilepsy has quite a few causes of which genetic factors are considered to be the most important. Previous studies have suggested that the aquaporin 4(AQP4) and inward rectifier potassium ion channel Kir4.1 (encoded by gene KCNJ10) may act in concert to adjust water homeostasis and concentration of potassium ions in extracellular spaces of the central nervous system. Therefore, these two molecules would play a major role in the regulation of the excitability of neurons. In order to explore the potential mechanism of genetic factors related to AQP4 and Kir4.1, we conducted a study to analyze the effects of the AQP4 and KCNJ10 genes' single nucleotide polymorphisms (SNPs) on epileptic drug resistance and seizure susceptibility in a group of Chinese Han patients with focal epilepsy. Materials and Methods: In total, 510 patients with focal-onset seizures and 206 healthy controls were recruited. Among the patients, 222 were drug resistant and 288 were responsive. The selection of tag SNPs was based on the Hapmap database and Haploview software. Genotyping of three loci of the AQP4 gene (rs1058424, rs3763043 and rs35931) and nine loci of the KCNJ10 gene (rs12122979, rs1186685, rs6690889, rs2486253, rs1186675, rs12402969, rs12729701, rs1890532 and rs3795339) was conducted on the Sequenom MassARRAY iPLEX platform. Results: The distribution of genotype and allele frequencies of selected SNP loci of AQP4 and KCNJ10 genes showed no significant difference between the drug-resistant and drug-responsive groups (p>0.05), and no significant difference between all the idiopathic focal epilepsy patients and healthy controls either. Conclusion: AQP4 and KCNJ10 genetic polymorphisms may not be associated with drug resistance or seizure susceptibility of focal epilepsy in the Chinese Han population. [ABSTRACT FROM AUTHOR]

Status epilepticus is a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms that lead to abnormally prolonged seizures and require urgent administration of antiepileptic drugs. Refractory status epilepticus requires anesthetics drugs and may lead to brain injury with molecular and cellular alterations (eg, inflammation, and neuronal and astroglial injury) that could induce neurologic sequels and further development of epilepsy. Outcome scores based on demographic, clinical, and electroencephalography (EEG) condition are available, allowing prediction of the risk of mortality, but the severity of brain injury in survivors is poorly evaluated. New biomarkers are needed to predict with higher accuracy the outcome of patients admitted with status in an intensive care unit. Here, we summarize the findings of studies from patients and animal models of status epilepticus. Specific protein markers can be detected in the cerebrospinal fluid and the blood. One of the first described markers of neuronal death is the neuron‐specific enolase. Gliosis resulting from inflammatory responses after status can be detected through the increase of S100‐beta, or some cytokines, like the High Mobility Group Box 1. Other proteins, like progranulin may reflect the neuroprotective mechanisms resulting from the brain adaptation to excitotoxicity. These new biomarkers aim to prospectively identify the severity and development of disability, and subsequent epilepsy of patients with status. We discuss the advantages and disadvantages of each biomarker, by evaluating their brain specificity, stability in the fluids, and sensitivity to external interferences, such as hemolysis. Finally, we emphasize the need for further development and validation of such biomarkers in order to better assess patients with severe status epilepticus. [ABSTRACT FROM AUTHOR]

Our understanding of the genetic aetiology of paediatric epilepsies has grown substantially over the last decade. However, in order to translate improved diagnostics to personalised treatments, there is an urgent need to link molecular pathophysiology in epilepsy to whole-brain dynamics in seizures. Zebrafish have emerged as a promising new animal model for epileptic seizure disorders, with particular relevance for genetic and developmental epilepsies. As a novel model organism for epilepsy research they combine key advantages: the small size of larval zebrafish allows high throughput in vivo experiments; the availability of advanced genetic tools allows targeted modification to model specific human genetic disorders (including genetic epilepsies) in a vertebrate system; and optical access to the entire central nervous system has provided the basis for advanced microscopy technologies to image structure and function in the intact larval zebrafish brain. There is a growing body of literature describing and characterising features of epileptic seizures and epilepsy in larval zebrafish. Recently genetically encoded calcium indicators have been used to investigate the neurobiological basis of these seizures with light microscopy. This approach offers a unique window into the multiscale dynamics of epileptic seizures, capturing both whole-brain dynamics and single-cell behaviour concurrently. At the same time, linking observations made using calcium imaging in the larval zebrafish brain back to an understanding of epileptic seizures largely derived from cortical electrophysiological recordings in human patients and mammalian animal models is non-trivial. In this review we briefly illustrate the state of the art of epilepsy research in zebrafish with particular focus on calcium imaging of epileptic seizures in the larval zebrafish. We illustrate the utility of a dynamic systems perspective on the epileptic brain for providing a principled approach to linking observations across species and identifying those features of brain dynamics that are most relevant to epilepsy. In the following section we survey the literature for imaging features associated with epilepsy and epileptic seizures and link these to observations made from humans and other more traditional animal models. We conclude by identifying the key challenges still facing epilepsy research in the larval zebrafish and indicate strategies for future research to address these and integrate more directly with the themes and questions that emerge from investigating epilepsy in other model systems and human patients. [ABSTRACT FROM AUTHOR]

The advent of Next Generation Sequencing (NGS) has led to a redefining of the genetic landscape of the epilepsies. Hundreds of single gene epilepsies have been described. Genes associated with epilepsy involve diverse processes. Now a substantial proportion of individuals with epilepsy can receive a high definition molecular genetic diagnosis. In this review we update the current genetic landscape of the epilepsies and categorise the major functional groupings of epilepsy-associated genes. We describe currently available genetic testing approaches. We perform a literature review of NGS studies and review the factors which determine yield in cohorts undergoing testing. We identify factors associated with positive genetic diagnosis and consider the utility of genetic testing in terms of treatment selection as well as more qualitative aspects of care. Epilepsy-associated genes can be grouped into five broad functional categories: ion transport; cell growth and differentiation; regulation of synaptic processes; transport and metabolism of small molecules within and between cells; and regulation of gene transcription and translation. Early onset of seizures, drug-resistance, and developmental comorbidity are associated with higher diagnostic yield. The most commonly implicated genes in NGS studies to date, in order, are SCN1A, KCNQ2, CDKL5, SCN2A, and STXBP1. In unselected infantile cohorts PRRT2 , a gene associated with self-limited epilepsy, is frequently implicated. Genetic diagnosis provides utility in terms of treatment choice closing the diagnostic odyssey, avoiding unnecessary further testing, and informing future reproductive decisions. Genetic testing has become a first line test in epilepsy. As techniques improve and understanding advances, its utility is set to increase. Genetic diagnosis, particularly in early onset developmental and epileptic encephalopathies, influences treatment choice in a significant proportion of patients. The realistic prospect of gene therapy is a cause for optimism. [ABSTRACT FROM AUTHOR]

Mutations in GABAA-receptor subunit genes are associated with a heterogeneous spectrum of epilepsies. Patients with epilepsy caused by mutations in a specific GABAA-receptor (GABRA3) occasionally present with orofacial dysmorphism (e.g., cleft palates). While cleft palates have been described in Gabrb3 knockout mice and in humans with GABRB3 variants without epilepsy, the specific combination of epilepsy and cleft palate in humans with GABRB3 mutations has not yet been reported. We describe a patient with epileptic encephalopathy (EE) who presented with therapy-refractory neonatal-onset myoclonic seizures and severe developmental delay. Electroencephalogram showed burst suppression pattern at neonatal age and hypsarrhythmia at infantile age. Initial magnetic resonance imaging was unremarkable. As he additionally presented with a cleft palate, we were curious whether cleft palate and EE had the same genetic origin. Whole exome sequencing of the index patient revealed a novel pathogenic heterozygous de novo mutation in GABRB3 (c.899T > C; p.I300T). In consistency with Gabrb3 knockout mice data, this is the first report of cleft palate in a patient with GABRB3 associated EE. We suggest to add cleft palate to the phenotypic GABRB3 spectrum and to screen for mutations in GABAA-receptors in patients with EE and orofacial dysmorphism. [ABSTRACT FROM AUTHOR]

Objective: More than one‐third of patients with temporal lobe epilepsy (TLE) continue to have seizures despite treatment with antiepileptic drugs, and many experience severe drug‐related side effects, illustrating the need for novel therapies. Selective expression of inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) allows cell‐type‐specific reduction of neuronal excitability. In this study, we evaluated the effect of chemogenetic suppression of excitatory pyramidal and granule cell neurons of the sclerotic hippocampus in the intrahippocampal mouse model (IHKA) for temporal lobe epilepsy. Methods: Intrahippocampal IHKA mice were injected with an adeno‐associated viral vector carrying the genes for an inhibitory DREADD hM4Di in the sclerotic hippocampus or control vector. Next, animals were treated systemically with different single doses of clozapine‐N‐oxide (CNO) (1, 3, and 10 mg/kg) and clozapine (0.03 and 0.1 mg/kg) and the effect on spontaneous hippocampal seizures, hippocampal electroencephalography (EEG) power, fast ripples (FRs) and behavior in the open field test was evaluated. Finally, animals received prolonged treatment with clozapine for 3 days and the effect on seizures was monitored. Results: Treatment with both CNO and clozapine resulted in a robust suppression of hippocampal seizures for at least 15 hours only in DREADD‐expressing animals. Moreover, total EEG power and the number of FRs were significantly reduced. CNO and/or clozapine had no effects on interictal hippocampal EEG, seizures, or locomotion/anxiety in the open field test in non‐DREADD epileptic IHKA mice. Repeated clozapine treatment every 8 hours for 3 days resulted in almost complete seizure suppression in DREADD animals. Significance: This study shows the potency of chemogenetics to robustly and sustainably suppress spontaneous epileptic seizures and pave the way for an epilepsy therapy in which a systemically administered exogenous drug selectively modulates specific cell types in a seizure network, leading to a potent seizure suppression devoid of the typical drug‐related side effects. [ABSTRACT FROM AUTHOR]

The mechanistic target of rapamycin (mTOR) pathway has been implicated in a growing number of malformations of cortical development (MCD) associated with intractable epilepsy. Mutations in single genes encoding mTOR pathway regulatory proteins have been linked to MCD such as focal cortical dysplasia (FCD) types IIa and IIb, hemimegalencephaly (HME), and megalencephaly. Recent studies have demonstrated that the GATOR1 protein complex, comprised of DEPDC5, NPRL3, and NPRL2, plays a pivotal role in regulating mTOR signaling in response to cellular amino acid levels and that mutations in DEPDC5, NPRL3, or NPRL2 are linked to FCD, HME, and seizures. Histopathological analysis of FCD and HME tissue specimens resected from individuals harboring DEPDC5, NPRL3, or NPRL2 gene mutations reveals hyperactivation of mTOR pathway signaling. Family pedigrees carrying mutations in either DEPDC5 or NPRL3 share clinical phenotypes of epilepsy and MCD, as well as intellectual and neuropsychiatric disabilities. Interestingly, some individuals with seizures associated with DEPDC5, NPRL3, or NPRL2 variants exhibit normal brain imaging suggesting either occult MCD or a role for these genes in non‐lesional neocortical epilepsy. Mouse models resulting from knockdown or knockout of either Depdc5 or Nprl3 exhibit altered cortical lamination, neuronal dysmorphogenesis, and enhanced neuronal excitability as reported in models resulting from direct mTOR activation through expression of its canonical activator RHEB. The role of the GATOR1 proteins in regulating mTOR signaling suggest plausible options for mTOR inhibition in the treatment of epilepsy associated with mutations in DEPDC5, NPRL3, or NPRL2. [ABSTRACT FROM AUTHOR]

Objective: Studies have found that affected individuals who believe the cause of their disorder is genetic may react in various ways, including optimism for improved treatments and pessimism due to perceived permanence of the condition. This study assessed the psychosocial impact of genetic attribution among people with epilepsy. Methods: Study participants were 165 persons with epilepsy from multiplex epilepsy families who completed a self‐administered survey. Psychosocial impact of epilepsy was assessed with the Impact of Epilepsy Scale, containing items about relationships, employment, overall health, self‐esteem, and standard of living. Genetic attribution was assessed using a scale derived from three items asking about the role of genetics in causing epilepsy in the family, the chance of having an epilepsy‐related mutation, and the influence of genetics in causing the participant's epilepsy. We estimated prevalence ratios (PRs) for impact of epilepsy above the median using Poisson regression with robust standard errors, adjusting for number of lifetime seizures and time since last seizure. Results: Participants' age averaged 51 years; 87% were non‐Hispanic white, 63% were women, and 54% were college graduates. The genetic attribution scale was significantly associated with having a high impact of epilepsy (adjusted PR = 1.4, 95% confidence interval = 1.07‐1.91, P = .02). One of the three genetic attribution questions was also significantly associated with a high impact of epilepsy (belief that genetics had a big role in causing epilepsy in the family, adjusted PR = 1.8). Significance: These findings reflect an association between the psychosocial impact of epilepsy and the belief that epilepsy has a genetic cause, among people with epilepsy in families containing multiple affected individuals. This association could arise either because belief in a genetic cause leads to increased psychosocial impacts, or because a greater psychosocial impact of epilepsy leads some to believe their epilepsy is genetic. [ABSTRACT FROM AUTHOR]

• Liraglutide has antiepileptogenic effects in the post-SE kainate model. • Liraglutide is not antiepileptogenic in the WAG/Rij rat model. • Liraglutide antiepileptogenic effects may be linked to its neuroprotective effects. • Liraglutide prevents cognitive impairment. Liraglutide (LIR) is a novel long-lasting glucagon-like peptide-1 (GLP-1) analogue that facilitates insulin signalling and shows also neuroprotective properties in different brain disease models. In this study, we explored the potential antiepileptogenic effects of LIR in two different animal models; namely, the mouse intrahippocampal kainic acid (KA) model of temporal lobe epilepsy and the WAG/Rij rat model of absence epileptogenesis. Moreover, we evaluated LIR effects on comorbidities in various behavioural tests. Mice with kainate-induced epilepsy were treated with LIR (300 μg/kg/day s.c.) for 4 weeks after status epilepticus and then evaluated for drug effects on seizure development and behavioural alterations, whereas WAG/Rij rats were treated for 17 weeks (starting at 30 days of age, before seizure onset) with LIR (300 μg/kg/day s.c.) in order to investigate whether an early chronic treatment was able to reduce the development of absence seizures and related comorbidities. Our results indicate that LIR was effective in reducing the development of spontaneous seizures in kainate-induced epilepsy; moreover, in this model, it prevented memory impairment and related anxiety-like behaviour in the open field (OF) test while in the forced swimming test (FST), LIR displayed an apparent pro-depressant effect that was instead related to reduced endurance as confirmed by rotarod test. In contrast, LIR was unable to modify the epileptogenic process underlying the development of absence seizures in WAG/Rij rats while being antidepressant in the FST in this strain. Our results indicate that LIR may represent a promising novel treatment to prevent and treat the epileptogenic process and its associated behavioural and cognitive alterations in some models of convulsive epilepsy characterized by neurodegeneration, since LIR effects are likely secondary to its recognised neuroprotective properties. [ABSTRACT FROM AUTHOR]

Epidemiological data and gene association studies suggest a genetic predisposition to developing epilepsy after an acquired brain insult, such as traumatic brain injury. An improved understanding of genetic determinants of vulnerability is imperative for early disease diagnosis and prognosis prediction, with flow‐on benefits for the development of targeted antiepileptogenic treatments as well as optimal clinical trial design. In the laboratory, one approach to investigate why some individuals are more vulnerable to acquired epilepsy than others is to examine unique rodent models exhibiting either vulnerability or resistance to epileptogenesis. This review focuses on the most well‐characterized of these models, the FAST (seizure‐prone) and SLOW (seizure‐resistant) rat strains, which were derived by selective breeding for differential amygdala electrical kindling rates. We describe how these strains differ in their seizure profiles, neuroanatomy, and neurobehavioral phenotypes, both at baseline and after a brain insult, with this knowledge proving fruitful to identify common pathological abnormalities associated with seizure susceptibility and psychiatric comorbidities. It is important to note that accruing data on strain differences in multiple biological processes provides insight into why some individuals may be more vulnerable to epileptogenesis, although future studies are evidently needed to identify the precise molecular and genetic risk factors. Together, the FAST and SLOW rat strains, and other similar experimental models, are invaluable neurobiological tools to investigate the effect of genetic background on acquired epilepsy risk, as well as the poorly understood relationship between epilepsy development and associated comorbidities. [ABSTRACT FROM AUTHOR]

Background: IVS5-91G>A (rs3812718) polymorphism of the sodium voltage-gated channel alpha subunit 1 (SCN1A) gene has been associated with inadequate responsiveness to common antiepileptic drugs which act as sodium channel blockers. This study was performed to investigate the effect of IVS5-91G>A (rs3812718) polymorphism on lamotrigine (LTG) efficacy in a cohort of patients with non-lesional focal epilepsy taking LTG as monotherapy. Methods: A total of 100 of patients with non-lesional focal epilepsy on LTG monotherapy was included in this prospective interventional study. After reaching a stable dose of LTG patients were followed-up for 12 consecutive months. LTG responsiveness was defined as a 75% or more reduction in seizure frequency on a stable dose of LTG. Genotyping was performed at the end of the study using standard procedures and data were correlated with clinical data. Results: There were no significant differences in the prevalence of responsiveness to LTG between carriers of different genotypes. Average maintenance LTG doses in the responder group differed by genotype in the order AA>GA>GG, but these differences did not reach statistical significance. Conclusion: Our data suggest lack of association between SCN1A IVS5-91G>A (rs3812718) polymorphism and response to LTG. [ABSTRACT FROM AUTHOR]

Objective: The relationship between antiepileptic drugs and bone health and also the genetic aspect of this relationship is not clear and has been investigated in recent years. The aim of this study was to determine the effects of different antiepileptic drugs (AEDs) on bone mineral density results in long term follow up and to evaluate the relationship with the vitamin D profile (Bsml mutation) of the patients. Material and Methods: Eighty ambulatory patients (21 male, 59 female; mean age: 9.1±3.85 years) were included in the study. The patients were divided into four groups; Group 1 (levetiracetam), Group 2 (Carbamazepine), Group 3 (Valproic acid) and Group 4 (control). The plasma calcium, phosphorus, parathyroid hormone, alkaline phosphatase, vitamin D levels and bone mineral density values of femur and spine (L1-4) were compared. The patients were divided into two groups according to vitamin D receptor genes as the patients with Bsml mutations and without (wild type) Bsml mutations. Results: The difference between bone mineral density, Z score, phosphorus, parathyroid hormone, alkaline phosphatase and vitamin D levels of the patients in all four groups was not statistically significant. The phosphorus, parathyroid hormone, alkaline phosphatase and vitamin D levels and bone mineral density and Z score results of the patients with and without Bsml mutations were not significantly different. Conclusion: In this cross-sectional analysis, we found that the bone mineral status of the patients receiving different AEDs for a long time (> 2 years) was not significantly different. There was also no loss of bone mineral content in the patient group when compared with age-appropriate controls. According to the results of this study, Bsml polymorphism is not determinant in the progression of bone mineral loss. [ABSTRACT FROM AUTHOR]

Epilepsy is a chronic neurological disease characterized by an enduring propensity for generation of seizures. The pathogenic processes of seizure generation and recurrence are the subject of intensive preclinical and clinical investigations as their identification would enable development of novel treatments that prevent epileptic seizures and reduce seizure burden. Such treatments are particularly needed for pharmacoresistant epilepsies, which affect ~30% of patients. Neuroinflammation is commonly activated in epileptogenic brain regions in humans and is clearly involved in animal models of epilepsy. An increased understanding of neuroinflammatory mechanisms in epilepsy has identified cellular and molecular targets for new mechanistic therapies or existing anti-inflammatory drugs that could overcome the limitations of current medications, which provide only symptomatic control of seizures. Moreover, inflammatory mediators in the blood and molecular imaging of neuroinflammation could provide diagnostic, prognostic and predictive biomarkers for epilepsy, which will be instrumental for patient stratification in future clinical studies. In this Review, we focus on our understanding of the IL-1 receptor-Toll-like receptor 4 axis, the arachidonic acid-prostaglandin cascade, oxidative stress and transforming growth factor-β signalling associated with blood-brain barrier dysfunction, all of which are pathways that are activated in pharmacoresistant epilepsy in humans and that can be modulated in animal models to produce therapeutic effects on seizures, neuronal cell loss and neurological comorbidities. [ABSTRACT FROM AUTHOR]

The objective of this study was to evaluate the current evidence regarding the effect of antiepileptic drugs (AEDs) on epileptiform discharge (ED) burden in genetic generalized epilepsy (GGE). We conducted a comprehensive literature search of PubMed, Embase, PsycINFO, and the Web of Science Core Collection databases using the keywords 'genetic generalized epilepsy', 'antiepileptic drugs' and 'epileptiform discharge'. Primary human studies published in English that reported the effect of AEDs on EDs captured on electroencephalogram (EEG) recordings of at least 24 h in duration in patients with GGE were included. Six studies published between 1984 and 2017, which reported the effect of AEDs on EDs, involving a total of 116 patients with GGE, were analyzed. Our systematic review found a tendency for AEDs to reduce ED density, frequency, cumulative duration, and burst duration in GGE. Furthermore, we found evidence that the AED-mediated reduction in ED burden was associated with improved seizure control and cognitive outcomes. Antiepileptic drugs tend to reduce ED burden in GGE, but the significance of this association remains uncertain. • We reviewed the impact of antiepileptic drug therapy on epileptiform discharge (ED) burden in genetic generalised epilepsy. • Antiepileptic drug therapy tends to reduce ED burden. • Reduced ED burden is associated with improved seizure control and some cognitive outcomes. • The statistical significance of some associations is not clearly described. [ABSTRACT FROM AUTHOR]

Objective: An epilepsy mouse model for Tuberous Sclerosis Complex (TSC) was developed and validated to investigate the mechanisms underlying epileptogenesis. Furthermore, the possible antiepileptogenic properties of commonly used antiepileptic drugs (AEDs) and new compounds were assessed. Methods: Tsc1 deletion was induced in CAMK2A‐expressing neurons of adult mice. The antiepileptogenic properties of commonly used AEDs and inhibitors of the mTOR pathways were assessed by EEG recordings and by molecular read outs. Results: Mice developed epilepsy in a narrow time window (10 ± 2 days) upon Tsc1 gene deletion. Seizure frequency but not duration increased over time. Seizures were lethal within 18 days, were unpredictable, and did not correlate to seizure onset, length or frequency, reminiscent of sudden unexpected death in epilepsy (SUDEP). Tsc1 gene deletion resulted in a strong activation of the mTORC1 pathway, and both epileptogenesis and lethality could be entirely prevented by RHEB1 gene deletion or rapamycin treatment. However, other inhibitors of the mTOR pathway such as AZD8055 and PF4708671 were ineffective. Except for ketogenic diet, none of commonly used AEDs showed an effect on mTORC1 activity. Vigabatrin and ketogenic diet treatment were able to significantly delay seizure onset. In contrast, survival was shortened by lamotrigine. Interpretation: This novel Tsc1 mouse model is highly suitable to assess the efficacy of antiepileptic and ‐epileptogenic drugs to treat mTORC1‐dependent epilepsy. Additionally, it allows us to study the mechanisms underlying mTORC1‐mediated epileptogenesis and SUDEP. We found that early treatment with vigabatrin was not able to prevent epilepsy, but significantly delayed seizure onset. [ABSTRACT FROM AUTHOR]

Abstract Recent studies have suggested an important role of de novo mutations (DNMs) in neuropsychiatric disorders. As DNMs are not subject to elimination due to evolutionary pressure, they are likely to have greater disruptions on biological functions. While a number of sequencing studies have been performed on neuropsychiatric disorders, the implications of DNMs for drug discovery remain to be explored. In this study, we employed a gene-set analysis approach to address this issue. Four neuropsychiatric disorders were studied, including schizophrenia (SCZ), autistic spectrum disorders (ASD), intellectual disability (ID) and epilepsy. We first identified gene-sets associated with different drugs, and analyzed whether the gene-set pertaining to each drug overlaps with DNMs more than expected by chance. We also assessed which medication classes are enriched among the prioritized drugs. We discovered that neuropsychiatric drug classes were indeed significantly enriched for DNMs of all four disorders; in particular, antipsychotics and antiepileptics were the most strongly enriched drug classes for SCZ and epilepsy respectively. Interestingly, we revealed enrichment of several unexpected drug classes, such as lipid-lowering agents for SCZ and anti-neoplastic agents. By inspecting individual hits, we also uncovered other interesting drug candidates or mechanisms (e.g. histone deacetylase inhibition and retinoid signaling) that might warrant further investigations. Taken together, this study provided evidence for the usefulness of DNMs in guiding drug discovery or repositioning. [ABSTRACT FROM AUTHOR]

Background. Epilepsy is one of the common neurological illnesses which affects millions of individuals globally. Although the majority of epileptic patients have a good response for the currently available antiepileptic drugs (AEDs), about 30-40% of epileptic patients are developing resistance. In addition to low safety profiles of most of existing AEDs, there is no AED available for curative or disease-modifying actions for epilepsy so far. Objectives. This systematic review is intended to evaluate the effect of metformin in acute and chronic animal models of an epileptic seizure. Methods. We searched PubMed, SCOPUS, Sciences Direct, and grey literature in order to explore articles published in English from January 2010 to November 2018, using key terms "epilepsy," "seizure," "metformin," "oral hypoglycemic agents," and "oral antidiabetic drugs". The qualities of all the included articles were assessed according to the Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies (CAMARADES). Results. Out of six hundred fifty original articles retrieved, eleven of them fulfilled the inclusion criteria and were included for final qualitative analysis. In these studies, metformin showed to control seizure attacks by attenuating seizure generation, delaying the onset of epilepsy, reducing hippocampal neuronal loss, and averting cognitive impairments in both acute and chronic models of an epileptic seizure. The possible mechanisms for its antiseizure or antiepileptic action might be due to activation of AMPK, antiapoptotic, antineuroinflammatory, and antioxidant properties, which possibly modify disease progression through affecting epileptogenesis. Conclusion. This review revealed the benefits of metformin in alleviating symptoms of epileptic seizure and modifying different cellular and molecular changes that affect the natural history of the disease in addition to its good safety profile. [ABSTRACT FROM AUTHOR]

Objectives: To assess the effectiveness and safety/tolerability of eslicarbazepine acetate (ESL) monotherapy in clinical practice in Europe. Materials and methods: Euro‐Esli was a pooled analysis of 14 European clinical practice studies. Responder rate (≥50% seizure frequency reduction) and seizure freedom rate (seizure freedom at least since prior visit) were assessed after 3, 6 and 12 months of ESL treatment and at last visit. Adverse events (AEs) and AEs leading to ESL discontinuation were assessed throughout follow‐up. A subanalysis was conducted to assess outcomes for patients treated initially with ESL monotherapy and for patients treated at the last visit with ESL monotherapy. Results: ESL was used as monotherapy in 88/2045 (4.3%) patients initially and in 229/1340 (17.1%) patients at the last visit. At 12 months, responder and seizure freedom rates were 94.1% and 88.2%, respectively, in patients treated initially with ESL monotherapy, and 93.2% and 77.4%, respectively, in patients treated at the last visit with ESL monotherapy. Corresponding values for patients treated initially with ESL adjunctive therapy were 74.8% and 39.0%, respectively; and for patients treated at the last visit with ESL adjunctive therapy, corresponding values were 70.4% and 25.9%, respectively. Safety and tolerability were generally comparable in patients treated with ESL as monotherapy or adjunctive therapy. The most commonly reported AEs (≥5% of patients in any group) were dizziness, somnolence, instability/ataxia, and fatigue. Conclusions: These clinical practice data support the use of ESL as monotherapy, as well as adjunctive therapy, for focal‐onset seizures, complementing evidence from clinical trials. [ABSTRACT FROM AUTHOR]

Second and third generation AEDs have been directly compared to controlled‐release carbamazepine (CBZ‐CR) as initial monotherapy for new‐onset focal epilepsy. Conversely, no head‐to‐head trials have been performed. The aim of this study was to estimate the comparative efficacy and tolerability of the antiepileptic monotherapies in adults with newly diagnosed focal epilepsy through a network meta‐analysis (NMA). Randomized, double‐blinded, parallel group, monotherapy studies comparing any AED to CBZ‐CR in adults with newly diagnosed untreated epilepsy with focal‐onset seizures was identified. The outcome measures were the seizure freedom for 6 and 12 months, the occurrence of treatment‐emergent adverse events (TEAEs), and the treatment withdrawal due to TEAEs. Mixed treatment comparisons were conducted by a Bayesian NMA using the Markov chain Monte Carlo methods. Effect sizes were calculated as odds ratios (ORs) with 95% credible intervals (CrIs). Four trials were included involving 2856 participants, 1445 for CBZ‐CR and 1411 for the comparative AEDs. Monotherapy AEDs compared to CBR‐CR were levetiracetam (LEV), zonisamide (ZNS), lacosamide (LCM), and eslicarbazepine acetate (ESL). There were no statistical differences in the 6‐ and 12‐month seizure freedom and TEAEs occurrence between LEV, ZNS, LCM, ESL, and CBZ‐CR In the analysis of drug withdrawal due to TEAEs, LCM treatment was associated with a significantly lower discontinuation rate than CBZ‐CR (OR 0.659, 95% CrI 0.428‐0.950). LEV, ZNS, LCM, and ESL are effective initial monotherapy treatments in adult patients with newly diagnosed focal epilepsy and represent suitable alternatives to CBZ‐CR [ABSTRACT FROM AUTHOR]

Abstract Purpose The study aimed to investigate the level of physicians' awareness regarding the adverse effects of antiepileptic drugs (AEDs) that were reported by their patients and to investigate whether these adverse effects caused by AEDs were documented in patients' files. Principal results One hundred one patients and 21 physicians were recruited; one patient and 2 physicians did not take part in the study. Sixty-two percent of the patients had epileptic seizures for more than 3 years, and 74% of them had generalized seizures. Sodium valproate, carbamazepine, topiramate, vigabatrin, levetiracetam, and lamotrigine were the most frequently used AEDs by patients; whereas, phenytoin, clonazepam, and pregabalin were the least used. Drowsiness came on top on the adverse effects' list, where its occurrence was about twice the weight gain and almost three times as frequent as movement and behavioral adverse effects. Conclusion Majority of the adverse effects were not documented in the patients' files. However, physicians were aware of majority of the adverse effects associated with AEDs. Highlights • To investigate physicians' awareness of patient's side effects of antiepileptic drugs (AEDs) and its documentation • Majority of the side effects were not documented in the patients' files. • Assessing the level of physicians' awareness regarding the side effects of antiepileptic drugs (AEDs). • A prospective cross-sectional study in the medical centers of Saudi Arabia. • Patient's education, age and other demographic factors played a vital role in the reporting of side-effects [ABSTRACT FROM AUTHOR]

Lacosamide, one of the last antiepileptic drugs marketed, can cause extension of PR interval. Precautions are recommended when used in elderly and with other drugs extending PR interval. Cases of severe third-degree atrioventricular block have been reported only in post-marketing case reports when used at high-doses and remain rare. We report the case of an 88-year-old woman treated with bisoprolol, who experienced a complete atrioventricular block after initiation of lacosamide for epilepsy associated with neurodegenerative disease. This dramatic event required a pacemaker implementation. Not being dose-dependent (initiation dosage used), it seemed partially explained by drug-drug interaction with bisoprolol. [ABSTRACT FROM AUTHOR]

Purpose: SCN1A (3184 A>G) and SCN2A (56G>A) gene encodes α subunit of the neuronal voltage-gated sodium channel, which is a target for carbamazepine (CBZ). Recent studies have demonstrated that polymorphism of SCN1A (3184 A>G) and SCN2A (56G>A) was associated with use of CBZ. However, it has not been determined whether the polymorphism affects CBZ or other antiepileptic drug responsiveness. The aim of the study was to establish whether the SCN1A (3184 A>G) and SCN2A (56G>A) polymorphisms of the SCN1A and SCN2A genes affect responsiveness to CBZ.Methods: SCN1A (3184 A>G) and SCN2A (56G>A) gene polymorphisms were genotyped in 93 Khyber Pakhtunkhwa epileptic patients treated with CBZ. The association between CBZ responsiveness and the polymorphism was estimated by adjusting for clinical factors affecting the outcome of therapy. The number of seizure episodes was documented at baseline, and the therapy of each of the 93 patients was followed up. The plasma level of CBZ was determined using reverse-phase high-performance liquid chromatography. SCN1A and SCN2A genes were genotyped using RFLP. Data were analyzed using Graph Pad Prism 6.Results: Mean age of the patients was 18.6±9.3 at the 3rd month and 18.7±9.5 at the 6th month. The baseline dose of CBZ was 468±19.8 mg/d and titrated at the rate of 48±1.4 and 4.0±0.2 mg/d. The difference in plasma level of CBZ was significant (P=0.004) between 3rd and 6th month among different genotypes of SCN1A gene in nonresponder and responder patients. At the 3rd month of the therapy, the poor responders were more likely (P=0.003 and P=0.01) to have variants (3184AG and 3184GG) of SCN1A gene. Similarly, poor responsders were more likely (P=0.0007 and P=0.001) to have variant genotypes (56GA, 56AA) of SCN2A gene at the 3rd month of the therapy.Conclusion: This study demonstrated a significant association between the SCN1A (3184 AG and GG) and SCN2A (56GA and AA) genotype with CBZ-nonresponsive epilepsy. [ABSTRACT FROM AUTHOR]

Highlights • Pregnant women carry increased risk of fetal loss while on antiepileptic drugs. • The increased risk is shared by several drugs. • The risk is least with levetiracetam and highest with topiramate. • Within monotherapy comparison shows no excess risk, except for topiramate. • Multiple pathways, independent from malformation may underlie fetal loss. Abstract Objective To ascertain the risk of spontaneous fetal loss (SPFL) in women with epilepsy (WWE) on antiepileptic drugs (AED), and explore the association between specific AED usage and risk of SPFL. Methods We identified all SPFL (including stillbirths) among pregnancies registered at Kerala Registry for Epilepsy and Pregnancy between 1998 and 2015. Rates of SPFL were compared between the AED exposed and unexposed groups. Results There were 139 SPFL out of 1987 eligible pregnancies. The AED exposed had excess SPFL (7.4%, 134 out of 1809, Odds Ratio [OR] 2.77, 95% Confidence Interval [CI] 1.17–6.39) than AED unexposed (2.8%, 5 out of 178). The adjusted OR (95% CI) for SPFL for monotherapies with levetiracetam, phenobarbitone and clobazam were comparable to unexposed, while it was significantly higher for topiramate (OR 38.86, CI 5.02–301.19), lamotrigine (OR 13.33, CI 1.41–125.78), oxcarbazepine (OR 7.53, CI 1.54–36.89), valproate (OR 6.92, CI 1.70–28.18), phenytoin (OR 5.82, CI 1.43–23.73) and carbamazepine (OR 3.53, CI 1.15–10.90). With reference to levetiracetam, only topiramate had significantly higher SPFL (OR 11.14, CI 1.56–79.55). Conclusion SPFL risk is increased in pregnancies with AED exposure, being least with levetiracetam and highest with topiramate. [ABSTRACT FROM AUTHOR]

Long-Term Chemogenetic Suppression of Spontaneous Seizures in a Mouse Model for Temporal Lobe Epilepsy Desloovere J, Boon P, Larsen LE, et al. Epilepsia. 2019;60(11):2314-2324. doi:10.1111/epi.16368. Objective: More than one-third of patients with temporal lobe epilepsy (TLE) continue to have seizures despite treatment with antiepileptic drugs, and many experience severe drug-related side effects, illustrating the need for novel therapies. Selective expression of inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) allows cell-type-specific reduction of neuronal excitability. In this study, we evaluated the effect of chemogenetic suppression of excitatory pyramidal and granule cell neurons of the sclerotic hippocampus in the intrahippocampal mouse model (IHKA) for TLE. Methods: Intrahippocampal IHKA mice were injected with an adeno-associated viral vector carrying the genes for an inhibitory DREADD hM4Di in the sclerotic hippocampus or control vector. Next, animals were treated systemically with different single doses of clozapine-N-oxide (CNO; 1, 3, and 10 mg/kg) and clozapine (0.03 and 0.1 mg/kg), and the effect on spontaneous hippocampal seizures, hippocampal electroencephalography (EEG) power, fast ripples (FRs), and behavior in the open field test was evaluated. Finally, animals received prolonged treatment with clozapine for 3 days, and the effect on seizures was monitored. Results: Treatment with both CNO and clozapine resulted in a robust suppression of hippocampal seizures for at least 15 hours only in DREADD-expressing animals. Moreover, total EEG power and the number of FRs were significantly reduced. Clozapine-N-oxide and/or clozapine had no effects on interictal hippocampal EEG, seizures, or locomotion/anxiety in the open field test in non-DREADD epileptic IHKA mice. Repeated clozapine treatment every 8 hours for 3 days resulted in almost complete seizure suppression in DREADD animals. Significance: This study shows the potency of chemogenetics to robustly and sustainably suppress spontaneous epileptic seizures and pave the way for an epilepsy therapy in which a systemically administered exogenous drug selectively modulates specific cell types in a seizure network, leading to a potent seizure suppression devoid of the typical drug-related side effects. [ABSTRACT FROM AUTHOR]

Paradoxical Effects of Optogenetic Stimulation in Mesial Temporal Lobe Epilepsy Levesque M, Chen LY, Etter G, et al. Ann Neurol. 2019;86(5):714-728. doi:10.1002/ana.25572. Objective: To establish the effects induced by long-term, unilateral stimulation of parvalbumin (PV)-positive interneurons on seizures, interictal spikes, and high-frequency oscillations (80-500 Hz) occurring after pilocarpine-induced status epilepticus (SE)—a proven model of mesial temporal lobe epilepsy (MTLE)—in transgenic mice expressing or not expressing ChR2. Methods: Both PV-ChR2 (n = 6) and PV-Cre (n = 6) mice were treated with pilocarpine to induce SE. Three hours after SE onset, unilateral optogenetic stimulation (450 nm, 25 mW, 20 ms pulses delivered at 8 Hz for 30 seconds every 2 minutes) of CA3 PV-positive interneurons was implemented for 14 continuous days in both groups. Results: Rates of seizures (P <.01), interictal spikes (P <.001), and interictal spikes with fast ripples (250-500 Hz; P <.001) were lower in PV-ChR2 than in PV-Cre mice. Ripples (80-200 Hz) occurring outside of interictal spikes had higher rates in the PV-ChR2 group (P <.01), whereas isolated fast ripples had lower rates (P <.01). However, seizure probability was higher during optogenetic stimulation in PV-ChR2 compared to PV-Cre animals (P <.05). Interpretation: Our findings show that the unilateral activation of CA3 PV-positive interneurons exerts anti-ictogenic effects associated with decreased rates of interictal spikes and fast ripples in this MTLE model. However, PV-positive interneuron stimulation can paradoxically trigger seizures in epileptic animals, supporting the notion that γ-aminobutyric acid type A signaling can also initiate ictogenesis. [ABSTRACT FROM AUTHOR]

Objectives: To assess the prevalence of antiepileptic drug (AED) exposure in pregnant women and the comparative risk of terminations of pregnancy (TOPs), spontaneous abortions, stillbirths, major birth defects (MBDs), neonatal distress and small for gestational age (SGA) infants following intrauterine AED exposure in the Emilia Romagna region, Italy (4 459 246 inhabitants on 31 December 2011).Methods: We identified all deliveries and hospitalised abortions in Emilia Romagna in the period 2009-2011 from the certificate of delivery assistance registry (Certificato di Assistenza al Parto- CedAP) and the hospital discharge card registry, exposure to AEDs from the reimbursed drug prescription registries, MBDs from the regional registry of congenital malformations, and Apgar scores and cases of SGA from the CedAP. Records from different registries were linked.Results: We identified 145 243 pregnancies: 111 284 deliveries, 16 408 spontaneous abortions and 17 551 TOPs. Six hundred and eleven pregnancies (0.42%; 95% Cl 0.39 to 0.46) were exposed to AEDs. In the AED-exposed group 21% of pregnancies ended in TOPs vs 12% in the non-exposed women (OR: 2.24; 95% CI 1.41 to 3.56). Rates of spontaneous abortions, stillbirths, neonatal distress and SGA were comparable. Three hundred and fifty-three babies (0.31%; 95% CI 0.28 to 0.35) were exposed to AEDs during the first trimester. MBD rates were 2.3% in the exposed vs 2.0% in the non-exposed pregnancies (OR: 1.12, 95% CI 0.55 to 2.55).Conclusion: The Emilia Romagna prevalence of AED exposure in pregnancy was 0.42%, comparable with previous European studies. Rates of spontaneous abortions, stillbirths, neonatal distress, SGA and MBDs following AED exposure were not significantly increased. The rate of TOPs was significantly higher in the AED-exposed women. [ABSTRACT FROM AUTHOR]

Anticonvulsant effects of minocycline have been explored recently. This study was designed to examine the anticonvulsant effect of acute administration of minocycline on pentylenetetrazole-induced seizures in mouse considering the possible role of the nitric oxide/N-methyl-d-aspartate (NMDA) pathway. We induced seizure using intravenous administration of pentylenetetrazole. Our results showed that acute administration of minocycline increased the seizure threshold. Furthermore, co-administration of subeffective doses of the nonselective nitric oxide synthase (NOS) inhibitor NG-l-arginine methyl ester (10 mg/kg) and the neuronal NOS inhibitor 7-nitroindazole (40 mg/kg) enhanced the anticonvulsant effect of subeffective doses of minocycline (40 mg/kg). We found that inducible NOS inhibitor aminoguanidine (100 mg/kg) had no effect on the antiseizure effect of minocycline. Moreover, l-arginine (60 mg/kg), as a NOS substrate, reduced the anticonvulsant effect of minocycline. We also demonstrated that pretreatment with the NMDA receptor antagonists ketamine (0.5 mg/kg) and MK-801 (0.05 mg/kg) increased the anticonvulsant effect of subeffective doses of minocycline. Results showed that minocycline significantly decreased the hippocampal nitrite level. Furthermore, co-administration of a neuronal NOS inhibitor like NMDA receptor antagonists augmented the effect of minocycline on the hippocampal nitrite level. In conclusion, we revealed that anticonvulsant effect of minocycline might be, at least in part, due to a decline in constitutive hippocampal nitric oxide activity as well as inhibition of NMDA receptors. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the association between regular antiepileptic drug (AED) use and incident dementia. Design: Case‐control analysis. Setting: Finnish public health register and German health insurance data. Participants: Individuals with dementia of any type (German data, N=20,325) and Alzheimer's disease (AD; Finnish data, N=70,718) were matched with up to four control persons without dementia. Measurements: We analyzed the association between regular AED use and dementia. To address potential protopathic bias, a lag time of 2 years between AED use and dementia diagnosis was introduced. Odds ratios (ORs) were calculated by applying conditional logistic regression, adjusted for potential confounding factors such as comorbidities and polypharmacy. Results: Regular AED use was more frequent in individuals with dementia than controls. Regular use of AEDs was associated with a significantly greater risk of incident dementia (adjusted OR=1.28, 95% confidence interval (CI)=1.14–1.44) and AD (adjusted OR=1.15, 95% CI=1.09–1.22) than no AED use. We also detected a trend toward greater risk of dementia with higher exposure. When AEDs with and without known cognitive adverse effects (CAEs) were compared, a significantly greater risk of dementia was observed for substances with known CAEs (dementia: OR=1.59, 95% CI=1.36–1.86; AD: OR=1.19, 95% CI=1.11–1.27). Conclusion: AEDs, especially those with known CAEs, may contribute to incident dementia and AD in older persons. [ABSTRACT FROM AUTHOR]

Recent evidence suggests that eslicarbazepine acetate (ESL) might be an appropriate alternative to carbamazepine (CBZ) and oxcarbazepine (OXC) due to its better safety profile. Hyponatremia may be one of the limiting safety problems in CBZ and OXC whereas it has been indicated that ESL is less sensitive for the adverse event. Since our clinical experience is different we investigated the incidence of hyponatremia in 560 consecutive adult inpatients treated at our center in 2015 by reviewing their medical records. Only CBZ, OXC and ESL were associated with hyponatremia. The incidence of hyponatremia induced by ESL was not statistically different from that induced by OXC (43% of patients with OXC and 33% with ESL, p >  0.05). Both were associated with hyponatremia more often than CBZ (16%). OXC-induced hyponatremia was dose-related, ESL-induced hyponatremia was not. Furthermore, both OXC- and ESL-induced hyponatremia occurred particularly often in elderly epilepsy patients. Thus, for elderly patients, both OXC and ESL should be considered with caution. [ABSTRACT FROM AUTHOR]

Psychiatric disorders are more common in patients with epilepsy than in the general population. The aims of the study were to assess the frequency and type of psychotropic drug usage in patients with epilepsy, to assess the risk factors for their use, and to assess their proconvulsive potential and the risk of interactions with antiepileptic drugs. This 20-month prospective study included patients treated at the university hospital outpatient clinic. Psychotropic drugs have been classified according to the Anatomical Therapeutic Chemical Classification System. Of the 621 patients (with a mean age of 35.4 years), 60% were women, and 37.5% were in remission; 54.8% of the patients used antiepileptic drug monotherapy. The most commonly used antiepileptic drugs were valproate, levetiracetam, lamotrigine, and carbamazepine. Eighty-nine (14.3%) patients received psychiatric comedication. Sertraline, perazine, and hydroxyzine were the predominantly used psychotropic drugs. Independent variables associated with psychotropic drug usage in the logistic regression model included age, active epilepsy, combined focal and generalized epilepsy type, use of somatic comedication, and phenobarbital. Over one-third of the patients simultaneously received antiepileptic drugs and psychotropic drugs, between which clinically significant interactions may occur, 10% of patients used psychotropic drugs to lower the seizure threshold. The results of the study indicate the need for closer cooperation between doctors of various specialties when caring for patients with epilepsy. [ABSTRACT FROM AUTHOR]

Background: Side effects of anti‐epileptic drugs (AEDs) have not been adequately documented in trigeminal neuralgia and its variants. The aim of this observational cross‐sectional study was to compare the A‐B Neuropsychological Assessment Schedule (ABNAS), which measures cognitive side effects to the Adverse Events Profile (AEP), which looks at a broader range of side effects, and to investigate drug/dosage relationships with questionnaire scores to help determine a point at which a drug change would be indicated. Methods: One hundred five patients were recruited from a facial pain clinic, over a 10‐month period. Self‐complete questionnaire scores were compared between patients using different AEDs. Results: A‐B Neuropsychological Assessment Schedule score correlated well with AEP indicating that cognitive side effects were a significant burden. Toxic range on the ABNAS was estimated to occur when scores were >43/72 (95% CI: 37.4‐48.6). Polytherapy is weakly associated with the higher scores. Oxcarbazepine dosage was found to linearly correlate with AEP and ABNAS scores, better than carbamazepine dosage. Memory alteration was least common with lamotrigine and oxcarbazepine, and there was less association between fatigues with oxcarbazepine/pregabalin. Conclusion: Anti‐epileptic drugs have significant side effects. The ABNAS questionnaire is a useful tool along with the AEP to recognize and monitor AEDs’ side effects and to help to adjust medications to optimal dosage. [ABSTRACT FROM AUTHOR]

Aim: To assess long-term safety and efficacy of stiripentol as an antiepileptic medication for people with Dravet syndrome.Method: A prospective, observational open-label study (2003-2015) of the efficacy and long-term safety of stiripentol in patients with Dravet syndrome and ongoing seizures. Frequency of generalized tonic-clonic seizures, focal seizures, status epilepticus, and adverse events were recorded.Results: Forty-one patients started stiripentol, with median age at enrolment 5 years 7 months (range 11mo-22y) and median duration of treatment 37 months (range 2-141mo). Twenty out of 41 patients had greater than or equal to 50% long-term reduction in frequency of generalized tonic-clonic seizures. Frequency of focal seizures was decreased by greater than or equal to 50% in 11 out of 23 patients over the long-term. Frequency of status epilepticus was decreased by 50% or more in 11 out of 26 patients. The most common adverse events were anorexia, weight loss, sedation, and behavioural changes. One patient had worsening of absence and myoclonic seizures. Another developed recurrent pancreatitis on concurrent valproate.Interpretation: Stiripentol improves long-term seizure frequency in approximately 50% of patients with Dravet syndrome, when used as part of unrestricted polytherapy. Long-term use appears safe. In more than 40% of patients, episodes of status epilepticus markedly decrease after stiripentol initiation. What this paper adds Frequency of status epilepticus is reduced in 40% of patients with Dravet syndrome after stiripentol initiation. Stiripentol is effective for generalized tonic-clonic and focal seizures. Stiripentol can be safely used with a range of antiepileptic drugs. [ABSTRACT FROM AUTHOR]

Objectives Little is known about off-label use and manipulations to achieve the prescribed dose of antiepileptic drugs (AEDs) in outpatient prescriptions. This study aimed to evaluate this practice in a tertiary center for child epilepsy. Methods We reviewed off-label use and manipulations of AEDs delivered to the outpatient's epilepsy clinic. Multivariate logistic regressions were used to determine the factors associated with off-label and manipulated uses. Results Five hundred eleven consultations generated 897 AED deliveries (1.75/consultation). Off-label use involved 182 (20.3%) of prescribed AEDs. Factors associated with off-label use were polytherapy and new AEDs while increase of age and nondevelopmental and structural–metabolic etiologies have a protective effect. Among the 1725 doses of AEDs prescribed per day, 33.5% generated manipulations (n = 582): 40% inadequate (n = 237) and 60% adequate (203 syrups, 112 scored tablets, 30 drops medicine). Polytherapy (p < 10 − 4 ) and the absence of market authorization significantly favored manipulations whereas the increase in age restricted them. Conclusion Off-label use and manipulations of AEDs remain an important problem in home care of children with epilepsy. This is mainly a concern for the most vulnerable groups, i.e., young patients, patients undergoing polytherapy, and patients with developmental and epileptic encephalopathy (DEE). International initiatives have been launched to improve the availability of labeled and adapted drugs in this population. [ABSTRACT FROM AUTHOR]

Introduction Adverse events (AEs) of antiepileptic drugs (AEDs) affect patient compliance and dropout. No questionnaire measuring AEs of AEDs is available for Italian-speaking people with epilepsy. Moreover, no questionnaire has been shown to predict patient dropout. Objective The aim of this study was to provide a validated Italian version of the Liverpool Adverse Events Profile (iLAEP) and to define iLAEP reliability in AE monitoring and dropout risk prediction. Methods The original LAEP was translated and tested for internal consistency and reliability. Patients with epilepsy who are on stable AED regimen completed the questionnaire as well as a 3-month follow-up to assess dropouts. Results Overall, 204 patients with epilepsy were enrolled (mean age: 47.1 ± 21.5). High internal consistency (Cronbach's α = 0.88) was demonstrated, and very quick completion time was registered (mean = 9 min). A 3-month follow-up was performed to assess treatment discontinuation and potential predictive value of the iLAEP score. Treatment was discontinued in 33.3% of the cohort. Moreover, iLAEP scores (mean = 30.71) significantly differed between patients interrupting (39.15 ± 5.66) and those prosecuting treatment (29.4 ± 6.54, p < .001). A cutoff of 36.5 had an 85% accuracy in predicting treatment discontinuation (85% sensitivity, 79% specificity). Scores > 36.5 were associated with a 20.27-fold increase in dropout relative risk (RR), with a 66% positive predictive value. Conclusions The iLAEP represents a reliable, quick, and inexpensive assessment tool for patient-reported AEs of AEDs. An iLAEP cutoff of 36.5 differentiates patients unlikely to interrupt treatment from those more prone to stop AEDs in the following 3 months. The iLAEP might help clinicians in weighting the risk of dropout and better tailor treatment to patients. [ABSTRACT FROM AUTHOR]

Summary: Objective: Several antiepileptic drugs (AEDs) have been associated with a detrimental effect on bone health through a reduction in serum vitamin D. Subsequently, several studies have investigated the effect of vitamin D supplementation in persons with epilepsy being treated with AEDs. The present systematic review of published literature was conducted to determine the effect of vitamin D intervention on bone health in adults with epilepsy. Methods: The following databases were searched using keywords including but not limited to epilepsy, bone, and vitamin D: PubMed, Medline, Embase, Scopus, Cochrane Clinical Trials, International Pharmaceutical Abstracts, Health Canada Clinical Trials Database, ClinicalTrials.gov, EU Clinical Trials, and Google. Studies were eligible if there was an epilepsy diagnosis, participants were adults (18+ years old), and vitamin D treatment and bone outcome were provided. Articles were screened independently by 2 reviewers. Methodological quality was assessed using the Cochrane Collaboration's tool and a modified Newcastle Ottawa Scale for nonrandomized studies. Results: Nine studies were found to be eligible for this review. After vitamin D treatment, there appeared to be positive changes in bone turnover markers; 3 of 8 studies found the increase in serum calcium to be significant, 6 of 8 studies found the decrease in alkaline phosphatase to be significant, and 2 of 4 studies found the decrease in parathyroid hormone to be significant. All 6 studies that investigated bone mineralization had significant findings; however, due to varying methodologies, the impact of vitamin D on bone mineralization was inconclusive. Significance: Vitamin D does appear to have some benefit to bone health in adults with epilepsy, and therefore supplementation could potentially be a requisite to using some AEDs. To clarify the role of vitamin D supplementation to manage the adverse effect of AEDs on bone health in adults with epilepsy, long‐term trials that use higher doses (>1800 IU) and measure bone mineral density are necessary. [ABSTRACT FROM AUTHOR]

Introduction The aims of the current study were to identify patterns and predictors of adherence in adolescents with epilepsy over one year, as well as its impact on seizures and health-related quality of life (HRQOL). Methods Forty-eight adolescents with epilepsy (M age = 14.8 + 1.5, 69% female, 73% White: NonHispanic) and their caregivers completed questionnaires assessing demographics, epilepsy knowledge, side effects, adherence barriers, family functioning, and HRQOL at quarterly clinic visits over one year. Adherence was monitored electronically via MEMS TrackCaps. Seizures were determined via chart review. Results Baseline adherence was 86.05% and significantly decreased over 12 months (b = − 2.07, p < 0.001). Higher adherence was predicted by higher socioeconomic status (SES) (b = 0.04, p < 0.05), more side effects (b = 0.06, p < 0.01), fewer caregiver-reported adherence barriers (b = 0.18, p < 0.05), and lower family conflict (b = − 0.19, p < 0.05). Change in adherence over 12 months did not significantly predict HRQOL or seizures. Conclusions This is the first longitudinal study of objective adherence in adolescents with epilepsy. Given adolescence is a period of vulnerability during development, including declining adherence, caregivers are encouraged to continue collaborating with their adolescents around epilepsy management. Adherence barriers represent an ideal target for intervention and can be implemented in the clinic by frontline providers. Multidisciplinary care can address low SES (social work, financial advocates) and family conflict (psychologists, therapists) in patients with the ultimate goal of optimizing adherence and health outcomes. [ABSTRACT FROM AUTHOR]

Background Lesional epilepsy is an important long-term sequela of stroke. Data on health-related quality of life (HrQoL) in patients with poststroke epilepsy are limited. We investigated HrQoL in patients with epilepsy after ischemic stroke and identified independent HrQoL-determinants. Methods and patients All patients with acute ischemic stroke, who were permanent residents in the district Marburg-Biedenkopf (Hessia, Germany, reference population 240,000 inhabitants) were recruited within 12 months in the population-based Marburg Stroke Register (MARSTREG). Follow-up visits were performed after 6, 12, and 24 months, and patients who developed poststroke epilepsy were identified. Data on demographics, antiepileptic drugs (AEDs), stroke severity (National Institute of Heath Stroke Scale (NIHSS), Barthel-Index, modified Rankin Scale), depression (Geriatric Depression Scale), and HrQoL (EQ-5D and EQ VAS) were collected. A multiple regression analysis was performed to identify HrQoL-determinants. Results Among the study participants (n = 374), 23 (6.1%) developed poststroke epilepsy. The HrQoL of patients with poststroke epilepsy was reduced in comparison with patients without seizures (24-month follow-up: EuroQol Visual Analogue Scale (EuroQol-VAS): 55.3 ± 10.7 versus 64.2 ± 11.4, p = 0.03). Seizure frequency, depression, and functional impairment (Barthel-Index) were identified as independent determinants of HrQoL. The adjustment of AEDs between 6-month and 24-month follow-ups resulted in decrease of seizure frequency by 40% and reduction of complications (dizziness by 27.8%, nausea by 52.2%, fatigue by 84.2%). Conclusion Lesional epilepsy is associated with decreased HrQoL in patients with stroke. We identified HrQoL-determinants, which would improve the management of patients with poststroke epilepsy. These determinants include proper adjustment of AEDs with reduction of seizure frequency, treatment of depression, and focused rehabilitation programs for poststroke epilepsy. [ABSTRACT FROM AUTHOR]

Background The objective of the ZMILE study was to compare the effectiveness of a multicomponent self-management intervention (MCI) with care as usual (CAU) in adult patients with epilepsy (PWE) over a six-month period. Methods Participants (PWE & relative) were randomized into intervention or CAU groups. Self-report questionnaires were used to measure disease-specific self-efficacy as the primary outcome measure and general self-efficacy, adherence, seizure severity, emotional functioning, quality of life, proactive coping, and side-effects of antiepileptic drugs (AED) as secondary outcome measures. Instruments used at baseline and during a six-month follow-up period were the following: disease-specific self-efficacy (Epilepsy Self-Efficacy Scale [ESES], General Self-Efficacy Scale [GSES]); adherence (Medication Adherence Scale [MARS] and Medication Event Monitoring System [MEMS]); seizure severity (National Hospital Seizure Severity Scale [NHS3]); emotional well-being (Hospital Anxiety and Depression Scale [HADS]); quality of life (Quality of Life in Epilepsy [QOLIE-31P]); proactive coping (Utrecht Proactive Coping Competence [UPCC]); and side-effects of antiepileptic drugs [SIDAED]. Multilevel analyses were performed, and baseline differences were corrected by inclusion of covariates in the analyses. Results In total, 102 PWE were included in the study, 52 of whom were in the intervention group. On the SIDAED and on three of the quality of life subscales QOLIE-31P, a significant difference was found (p < 0.05) in the intervention group. Self-efficacy, however, showed no significant differences between the MCI and the CAU groups. None of the other outcome measures showed any significant difference between the two groups. Significance Although we found no statistically significant difference in the primary outcome measure, disease-specific self-efficacy, this MCI could prove promising, since we found improvement in some domains of quality of life in epilepsy scale and a decrease in AED side-effects in the MCI group compared with the CAU group. [ABSTRACT FROM AUTHOR]

While antiepileptic drugs (AEDs) provide adequate seizure control for most patients with epilepsy, ~30% continue to have seizures despite treatment with two or more AEDs.1 In addition to direct harm from seizures, poor epilepsy control correlates with higher mortality, morbidity, 2, 3 and cost to the healthcare system.4 In the subset of patients with persistent seizures despite medical management, surgical intervention and neuromodulation may be more effective. Primary care physicians and general neurologists should be aware of non-AED treatment options that are standard of care for drugresistant epilepsy (DRE). [ABSTRACT FROM AUTHOR]