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• We reviewed 579 consecutive patients who visited for seizure evaluation. • We examined the head-turning sign during the initial medical interview. • Matched data confirmed a significant association between IGE and head-turning sign. • The sign was also associated with myoclonic seizures and comorbid headaches. • The sign may suggest dependence on others or mild cognitive impairment in IGE. Utilizing interictal manifestations for the diagnosis of epilepsy is challenging. We investigated whether an interictal "head-turning sign," typically indicative of dependence on others observed in Alzheimer's disease, can act as a behavioral marker of idiopathic generalized epilepsy. This multicenter study examined 579 consecutive patients, with a mean age of 36.8 ± 20.4 years, who did not have an intellectual disability and had their first outpatient visit for epilepsy evaluation between 2019 and 2023. Patients were categorized into IGE, non-IGE epilepsy, non-epileptic, and psychiatric conditions based on their ultimate diagnostic outcomes to identify difference of the occurrence of the head-turning sign among them. Additionally, we extracted data from patients under the age of 40, specifically adolescents and young adults (AYA). Then we used propensity score matching to confirm the reproducibility of observed differences and to identify associated factors within the AYA age group. The occurrence of the head-turning sign was significantly more prevalent in the IGE group compared to the non-IGE group (20.4 % vs. 2.2 %; P<0.0001) and non-epileptic group (20.4 % vs. 8.3 %; P=0.033). Following the matching, the head-turning sign was still evident in IGE relative to non-IGE patients (14.6 % vs. 4.5; P=0.004), yielding a 94 % specificity for IGE. IGE diagnosis (P<0.0001), myoclonic seizure (P<0.0001), being visited by a parent (P=0.017), and comorbidity with headache (P=0.021) were significantly associated with the head-turning sign. Multivariate analysis revealed that IGE (odds ratio: OR=2.80, P=0.028), attending with a parent (OR=2.92, P=0.029), and comorbidity with headache (OR=4.06, P=0.016) were independently associated with the head-turning sign. We confirmed a substantial association between the interictal "head-turning sign" and IGE. This unique sign may reflect a tendency towards dependence on others in IGE, and may serve as a promising diagnostic auxiliary marker for identifying IGE in the AYA age group. [ABSTRACT FROM AUTHOR]

Epilepsy is characterized by recurrent, chronic, and unprovoked seizures. Epilepsy has a significant negative impact on a patient's quality of life even if seizures are well controlled. In addition to the distress caused by seizures, patients with epilepsy (PwE) may suffer from cognitive impairment with serious social consequences such as poor interpersonal relationships, loss of employment, and reduced social networks. Pathological changes and functional connectivity abnormalities observed in PwE can disrupt the neural network responsible for the theory of mind. Theory of mind is the ability to attribute mental states to other people (intentions, beliefs, and emotions). It is a complex aspect of social cognition and includes cognitive and affective constructs. In recent years, numerous studies have assessed the relationship between social cognition, including the theory of mind, in PwE, and suggested impairment in this domain. Interventions targeting the theory of mind can be potentially helpful in improving the quality of life of PwE. [ABSTRACT FROM AUTHOR]

• This is the first study to examine the effect of valproic acid and levetiracetam monotherapy on vestibulocular and vestibulocolic reflexes in patients with generalized epilepsy using objective test methods. • Valproic acid and levetiracetam have a negative effect on the high-frequency vestibulo-ocular reflex. • Valproic acid and levetiracetam have a negative effect on otolith functions. • Valproic acid and levetiracetam have a negative effect on the vestibulocholic reflex. • Compared to levetiracetam the effect of valproic acid on balance functions is more pronounced. It is reported that antiepileptic drugs have an effect on balance functions. The aim of the study was to evaluate and compare the effects of valproic acid and levetiracetam monotherapy on balance functions in patients with generalized epilepsy using objective test methods. The study included 43 generalized epilepsy patients aged 18–60 years, including 20 patients receiving valproic acid monotherapy, 23 patients receiving levetiracetam monotherapy, and 25 healthy individuals as controls, in the Neurology Clinic of a university hospital in eastern Turkey. The demographic data form was filled out and the Video Head Impulse Test and Vestibular Evoked Myogenic Potentials test were performed. Statistically significant differences were obtained between the groups in lateral, posterior, and anterior semicircular canal gains and RALP and LARP asymmetry values in the V-HIT test (p < 0.05). Statistically significant differences were obtained between the groups in P1, N1 latency and asymmetry values in the C-VEMP test and in N1, P1 latency, amplitude, and asymmetry values in the o-VEMP test (p < 0.05). Valproic acid and levetiracetam may affect the vestibulocular and vestibulocolic reflex pathways negatively. In this cohort, valproic acid had more pronounced adverse effects on balance functions as compared to levetiracetam. [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]

Abstract Previously, we demonstrated an association between cortical hyperexcitability and mood disturbance in healthy adults. Studies have documented hyperexcitability in patients with idiopathic generalized epilepsies (IGEs; long-interval intracortical inhibition [LICI]) and high prevalence of mood comorbidities. This study aimed to investigate the influences of cortical excitability and seizure control on mood state in patients with IGEs. Single and paired-pulse transcranial magnetic stimulation (TMS) was applied to 30 patients with IGEs (16 controlled IGEs [cIGEs], 14 with treatment-resistant IGEs [trIGEs]), and 22 healthy controls (HCs) to assess cortical excitability with LICI. The Profile of Mood Sates (POMS) questionnaire was used to assess total mood disturbance (TMD), as well as, six mood domains: Depression, Confusion, Anger, Anxiety, Fatigue, and Vigor. To assess the effects of seizure control (HC vs. cIGEs vs. trIGEs) and LICI response (inhibitory vs. excitatory) on TMD, a two-way multivariate analysis of variance (MANOVA) was performed. Analyses revealed a significant main effect of long-interval intracortical inhibition (LICI) response on TMD (F (1, 46) = 4.69, p = 0.04), but not seizure control (F (2, 46) = 0.288, p = 0.75). Excitatory responders endorsed significantly higher TMD scores, indicating greater mood disturbance, than inhibitory responders (MD = − 2.12; T (50) = − 2.47, p = 0.04). Also, excitatory responders endorsed more items than inhibitory responders on the Depression (MD = − 2.12; T (50) = − 2.47, p = 0.04) and Fatigue (MD = − 3.42; T (50) = − 2.96, p = 0.03) subscales of the POMS. These findings provide further evidence of a relationship between hyperexcitability and mood disturbance, and indicate that cortical excitability may have greater influence on mood state than seizure control in patients with IGEs. Results also support theories for the underlying role of gamma-aminobutyric acid (GABA) network dysfunction in the etiology of depression. To better understand the clinical relevance and causal nature of these relationships, further investigation is warranted. Highlights • Cortical excitability significantly influences mood state in patients with IGEs. • Hyperexcitability is associated with greater mood disturbance. • GABA network plays a likely role in depressive symptomatology in patients with IGE. [ABSTRACT FROM AUTHOR]

Abstract We recently found that higher cortical excitability is associated with poorer attention performance in healthy adults. While patients with idiopathic generalized epilepsies (IGEs), previously termed genetic generalized epilepsies, are known to demonstrate increased cortical excitability and cognitive deficits, a relationship between these variables in IGEs has not been investigated. Therefore, we aimed to characterize the effects of cortical excitability and seizure control on cognitive performance in IGEs. We studied 30 patients with IGEs (16 patients with controlled IGEs (cIGEs) and 14 patients with treatment-resistant IGEs (trIGEs)) and 24 healthy controls (HCs). Transcranial magnetic stimulation (TMS) was used to measure cortical excitability, including long-interval intracortical inhibition (LICI). Attention was assessed with the Digit Span Forwards, Digit Span Backwards, Trails A, and Flanker tasks. Executive functioning was assessed using Trails B, Stroop Color and Word, and the Wisconsin Card Sorting Task. Two-way multivariate analyses of variance (MANOVAs) were conducted to assess the influences of seizure control (HCs vs. cIGEs vs. trIGEs) and cortical excitability (inhibitory vs. excitatory) on composite measures of attention and executive functions. Attention performance was significantly affected by cortical excitability and seizure control. Participants with primarily excitatory LICI responses, indicating higher cortical excitability, performed worse than inhibitory responders on composite attention (Wilks' lambda = 0.748, F (4, 44) = 3.72, p = 0.011). While participants with cIGEs and trIGEs did not significantly differ in attention performance, participants with trIGEs performed worse on the Digit Forwards (False Discovery Rate (FDR) p < 0.001), Digit Backwards (FDR p = 0.015), and Flanker (FDR p = 0.0075) tasks compared with HCs. These results provide support for the relationship between cortical excitability and attention dysfunction in IGEs. Further investigation is needed to determine whether there is a causal relationship between these variables and whether intracortical gamma-aminobutyric acid (GABA) B networks may be targeted to improve attention deficits in clinical populations with decreased LICI. Findings also suggest that additional research directly comparing cognition in patients with cIGEs and trIGEs is warranted. Highlights • There is a relationship between cortical excitability and cognitive functioning. • Hyperexcitability is associated with poorer attention in patients with IGEs. • GABA B network dysfunction appears to play a central role in this relationship. • Patients with trIGEs performed worse than HCs on tasks of attention. [ABSTRACT FROM AUTHOR]

Abstract Objective Dysexecutive traits have been described in idiopathic generalized epilepsy (IGE), but studies mainly focused on juvenile myoclonic epilepsy (JME). To better understand the neuropsychology of IGE, more research is needed on syndromes other than JME, controlling potential confounding factors as the cognitive effects of valproate and epileptic discharges (ED). We describe the neuropsychological profile of a group of patients with different syndromes of IGE including simultaneous video electroencephalography (EEG). Methods We performed a comprehensive cognitive and neuropsychiatric evaluation with video-EEG on 61 adults with IGE (JME 19; IGE with generalized tonic–clonic seizures [GTCS] alone [IGE-GTCS] 22; childhood absence epilepsy [CAE] or juvenile absences epilepsy [JAE] persisting in adulthood 20). We compared results between patients (globally and by syndrome) and a control group of 21 individuals (similar age, educational level); p-values were adjusted for multiple testing according to a 0.05 false discovery rate. Results Patients obtained significantly lower results than controls on visuospatial working memory, processing speed, cognitive flexibility and strategy, abstract visuospatial reasoning, arithmetic, and acquired knowledge. While CAE/JAE showed the lowest scores on cognitive assessment and highest anxiety index, IGE-GTCS showed the most favorable scores. Most tests were not influenced by valproate intake, and the dose did not correlate with cognitive performance in the test that yielded differences between patients and controls. Epileptic discharges during assessment were not frequent (10 patients, 1–4 tests). Significance Our findings suggest that patients with IGE have significantly lower abilities in various executive functions and acquired knowledge, compared to population of same age and education. The low frequency of ED on simultaneous video-EEG and absence of correlation of scores with valproate dose reinforce that the obtained results are due to a cognitive phenotype in IGE. This phenotype may be influenced by syndrome, and patients with CAE/JAE persisting in the adult may have a wider neuropsychiatric impairment. Highlights • Patients with IGE showed lower executive abilities and acquired knowledge. • The cognitive phenotype was influenced by clinical syndrome. • CAE/JAE showed lower scores on the cognitive assessment and higher anxiety index. • The IGE-GTCS group showed the most favorable scores in the cognitive assessment. • Results were not significantly influenced by valproate and epileptic discharges. [ABSTRACT FROM AUTHOR]

Abstract Introduction Patients with drug-resistant epilepsy (DRE) account for most of the burden of epilepsy, and they have poor prognosis in seizure control, higher morbidity, and mortality. Objectives The objective of the study was to develop a prognostic model of drug resistance in adult patients with generalized epilepsy from Colombia. Methods In this case–control study of patients with generalized epilepsy, patients were separated into two groups: one group with DRE (cases) according to the new International League Against Epilepsy (ILAE) definition after a complete evaluation performed by an epileptologist and the other group without DRE (control). Variables were analyzed to identify statistical differences between groups and were then selected to construct a prognostic model from a logistic regression. Results One hundred thirty-three patients with generalized epilepsy were studied. Thirty-eight (28.5%) patients had DRE, and 95 (71.5%) did not have DRE. History of status epilepticus, abnormal findings from neurological examination, aura, any degree of cognitive impairment, epileptic seizures at any moment of the day, and any comorbidity were risk factors. The presence of seizures only in the waking state and idiopathic etiology were protective factors. A prognostic model was constructed with previously reported risk factors for DRE and other variables available in the population of this study. In the multivariable analysis, the history of status epilepticus (odds ratio (OR): 5.6, confidence interval (CI): 1.1–20.0, p = 0.031), abnormal findings from neurological examination (OR: 5.7, CI: 2.3–13.9, p = 0.000), and aura (OR: 6.1, CI: 1.8–20.8, p = 0.003) were strongly associated with DRE. Conclusions In adult patients with generalized epilepsy, aura, abnormal findings from neurological examination, and history of status epilepticus were predictive factors for DRE. [ABSTRACT FROM AUTHOR]

Here, we describe in generalized epilepsies the alterations of classical neurotransmitters and neuropeptides acting at specific subreceptors. In order to consider a network context rather than one based on focal substrates and in order to make the interaction between neurotransmitters and neuropeptides and their specific subreceptors comprehensible, neural networks in the hippocampus, thalamus, and cerebral cortex are described. In this disease, a neurotransmitter imbalance between dopaminergic and serotonergic neurons and between presynaptic GABAergic neurons (hypoactivity) and glutaminergic neurons (hyperactivity) occurs. Consequently, combined GABA A agonists and NMDA antagonists could furthermore stabilize the neural networks in a multimodal pharmacotherapy. The antiepileptic effect and the mechanisms of action of conventional and recently developed antiepileptic drugs are reviewed. The GASH:Sal animal model can contribute to examine the efficacy of antiepileptic drugs. The issues of whether the interaction of classical neurotransmitters with other subreceptors (5-HT 7 , metabotropic 5 glutaminergic, A 2A adenosine, and alpha nicotinic 7 cholinergic receptors) or whether the administration of agonists/antagonists of neuropeptides might improve the therapeutic effect of antiepileptic drugs should be addressed. This article is part of a Special Issue entitled “Genetic and Reflex Epilepsies, Audiogenic Seizures and Strains: From Experimental Models to the Clinic”. [ABSTRACT FROM AUTHOR]

Introduction: There are over twenty anti-seizure medications and anti-seizure devices available commercially in the United States. The multitude of treatment options for seizures can present a challenge to clinicians, especially those who are not subspecialists in the epilepsy field. Many clinical questions are not adequately answered in double-blind randomized controlled studies. In the presence of a knowledge gap, many clinicians consult a respected colleague with acknowledged expertise in the field. Our survey was designed to provide expert opinions on the treatment of epilepsy in adults and adolescents. Method: We surveyed a group of 42 physicians across the United States who are considered experts based on publication record in the field of epilepsy, or a leadership role in a National Association of Epilepsy Centers comprehensive epilepsy program. The survey consisted of 43 multiple-part patient scenario questions and was administered online using Redcap software. The experts provided their opinion on 1126 treatment options based on a modified Rand 9-point scale. The patient scenarios focused on genetically-mediated generalized epilepsy and focal epilepsy. The scenarios first focused on overall treatment strategy and then on specific pharmacotherapies. Other questions focused on treatment of specific patient populations (pregnancy, the elderly, patients with brain tumors, and post organ transplant patients), epilepsy patients with comorbidities (renal and hepatic disease, depression), and how to combine medications after failure of monotherapy. Statistical analysis of data used the expert consensus method. Results: Valproate was considered a drug of choice in all genetically-mediated generalized epilepsies, except in the population of women of child-bearing age. Ethosuximide was a drug of choice in patient with absence seizures, and levetiracetam was a drug of choice in patients with genetic generalized tonic-clonic seizures and myoclonic seizures. Lamotrigine, levetiracetam and oxcarbazepine were considered drugs of choice for initial treatment of focal seizures. Lamotrigine and levetiracetam were the drugs of choice for women of child-bearing age with either genetic generalized epilepsy or focal epilepsy. Lamotrigine and levetiracetam were the drugs of choice in the elderly population. Lamotrigine was preferred in patients with co-morbid depression. Levetiracetam was the drug of choice in treating patients with hepatic failure, or who have undergone organ transplantation. Compared to the 2005 and 2001 surveys, there was increased preference for the use of levetiracetam and lamotrigine, and decreased preference for the use of phenytoin, gabapentin, phenobarbital and carbamazepine. Discussion: The study presented here provides a “snapshot” of the clinical practices of experts in the treatment of epilepsy. The experts were very often in agreement, and reached consensus in 81% of the possible responses. However, expert opinion does not replace the medical literature; instead, it acts to supplement existing information. Using the study results is similar to requesting an expert consultation. Our findings suggest options that the clinician should consider to achieve best practice. [ABSTRACT FROM AUTHOR]

Objective We sought to investigate the temporal patterns and sleep–wake cycle-related epileptiform discharges (EDs) in genetic generalized epilepsies (GGEs). Methods We studied 24-hour ambulatory electroencephalography (EEG) recordings of patients with GGE, diagnosed and classified according to the International League against Epilepsy criteria. We manually coded the type of discharge, time of occurrence, duration, and arousal state of each ED. We employed mixed effects Poisson regression modeling to study the temporal distribution of epileptiform discharges. Additionally, we used multinomial regression analysis to explore the significance of the relationship between different states of arousal and types of epileptiform discharges. Results We analyzed 6923 EDs from 105 abnormal 24-hour EEGs. Mixed effects Poisson regression analysis demonstrated significant changes in ED counts across time blocks. This distribution was largely influenced by the state of arousal. Generalized fragments (duration < 2 s) and focal discharges were more frequent during non-REM sleep while paroxysms (duration ≥ 2 s) were more frequent in wakefulness. Overall, 67% of epileptiform discharges occurred in non-REM sleep and only 33% occurred in wakefulness. Twenty-four patients (23%) had ED exclusively in sleep. Epileptiform discharges peaked from 23:00 through 07:00 h. Significance There is a time-of-day dependency of ED with a significant influence exerted by the state of arousal. Our observations suggest that the generation of epileptiform discharges is not a random process but is the result of complex interactions among biological rhythms such as the sleep–wake cycle and the intrinsic circadian pacemaker. High density of ED in sleep suggests that 24-hour EEG recording with the capture of natural sleep may be more useful than routine EEG to diagnose GGE. [ABSTRACT FROM AUTHOR]

Because sites of seizure origin may be unknown or multifocal, identifying targets from which activation can suppress seizures originating in diverse networks is essential. We evaluated the ability of optogenetic activation of the deep/intermediate layers of the superior colliculus (DLSC) to fill this role. Optogenetic activation of DLSC suppressed behavioral and electrographic seizures in the pentylenetetrazole (forebrain + brainstem seizures) and Area Tempestas (forebrain/complex partial seizures) models; this effect was specific to activation of DLSC, and not neighboring structures. DLSC activation likewise attenuated seizures evoked by gamma butyrolactone (thalamocortical/absence seizures), or acoustic stimulation of genetically epilepsy prone rates (brainstem seizures). Anticonvulsant effects were seen with stimulation frequencies as low as 5 Hz. Unlike previous applications of optogenetics for the control of seizures, activation of DLSC exerted broad-spectrum anticonvulsant actions, attenuating seizures originating in diverse and distal brain networks. These data indicate that DLSC is a promising target for optogenetic control of epilepsy. [ABSTRACT FROM AUTHOR]

Objectives Using an adult cohort of patients with generalized epilepsy, we aimed to identify risk factors for development of drug-resistant epilepsy (DRE), which if identifiable would allow patients to receive earlier treatment and more specifically individualized treatment plans. Methods For the case–control study, 118 patients with generalized epilepsy (GE) between the ages of 18 and 75 were included after selection from a database of 800 patients referred from throughout the Saskatchewan Epilepsy Program. Definitions were used in accordance with ILAE criteria. The odds ratio and its confidence interval were calculated. We performed a logistic regression analysis. Results Forty-four (37%) patients fulfilled the definition of DRE (cases), and seizures in 74 (63%) patients were not intractable (controls). Patients with DRE were significantly younger than the controls at the onset of epilepsy (6.6 vs. 18.8 years, p = < 0.001). Significant variables on univariate analysis were the following: epilepsy diagnosed prior to 12 years (OR: 12.1, CI: 4.8–29.9, p < 0.001), previous history of status epilepticus (OR: 15.1, CI: 3.2–70.9, p < 0.001), developmental delay (OR: 12.6, CI: 4.9–32, p < 0.001), and cryptogenic epilepsy (OR: 10.5, CI: 3.9–27.8, p < 0.001). Our study showed some protective factors for DRE such as a good response to first AED, idiopathic etiology, and history of febrile seizures. In the logistic regression analysis, two variables remained statistically significant: developmental delay and more than one seizure type. Conclusion Our study has identified a set of variables that predict DRE in patients with generalized epilepsy. Risk factors identified in our study are similar to those previously identified in pediatric studies, however, our study is specifically tailored to adult patients with generalized epilepsy. [ABSTRACT FROM AUTHOR]

For children with pharmacoresistant epilepsy, the ketogenic diet is an established treatment option worldwide. However, for adults, this treatment is less frequently offered, and its efficacy less well-documented. The aim of this study was to examine efficacy and tolerability of such a diet as an adjuvant therapy to antiepileptic drugs for adult patients with pharmacoresistant generalized epilepsy. Thirteen patients (12 women) aged 16–57 years were included prospectively. They were treated with a modified Atkins diet for 12 weeks. Nine of the 13 participants had juvenile myoclonic epilepsy (JME), two had childhood absence epilepsy, one had Jeavons syndrome, and one had generalized epilepsy of unknown type. Six participants, all with JME, completed the 12-week study period. Among these six, four had > 50% seizure reduction. Their seizure severity, using the revised Liverpool Seizure Severity Scale, was reduced by 1, 5, 57.5, and 70 points, respectively (scale: 1–100 points). In three of these four responders, quality of life, assessed by QOLIE-89, increased more than 20 points (scale: 0–100 points). Mean reduction of body weight after 12 weeks on diet was 6.5 (range: 4.3–8.1) kg. Lack of motivation, poor compliance, and seizure aggravation were the main reasons for premature termination of the diet. Apart from one patient who developed gallstones when ending the treatment after 10 months, no adverse effects were noted. In conclusion, using a modified Atkins diet for 12 weeks led to a clinically relevant reduction of seizure frequency in four of thirteen adult patients with pharmacoresistant generalized epilepsy. All responders were diagnosed with JME. In three of the four, the benefits of diet were so considerable that they chose to continue the treatment. [ABSTRACT FROM AUTHOR]

Chromodomain helicase DNA - binding protein 2 (CHD2) gene mutations have been reported in patients with myoclonic–atonic epilepsy (MAE), as well as in patients with Lennox–Gastaut, Dravet, and Jeavons syndromes and other epileptic encephalopathies featuring generalized epilepsy and intellectual disability. The aim of this study was to assess the impact of CHD2 mutations in a series of patients with MAE. Twenty patients affected by MAE were included in the study. We analyzed antecedents, age at onset, seizure semiology and frequency, EEG, treatment, and neuropsychological outcome. We sequenced the CHD2 gene with Sanger technology. We identified a CHD2 frameshift mutation in one patient (c.4256del19). He was a 17-year-old boy with no familial history for epilepsy and normal development before epilepsy onset. Epilepsy onset was at 3 years and 5 months: he presented with myoclonic–atonic seizures, head drops, myoclonic jerks, and absences. Interictal EEGs revealed slow background activity associated with generalized epileptiform abnormalities and photoparoxysmal response. His seizures were highly responsive to valproic acid, and an attempt to withdraw it led to seizure recurrence. Neuropsychological evaluation revealed moderate intellectual disability. Chromodomain - helicase - DNA - binding protein 2 is not the major gene associated with MAE. Conversely, CHD2 could be responsible for a proper phenotype characterized by infantile-onset generalized epilepsy, intellectual disability, and photosensitivity, which might overlap with MAE, Lennox–Gastaut, Dravet, and Jeavons syndromes. [ABSTRACT FROM AUTHOR]

In the majority of neuropsychiatric conditions, marked gender-based differences have been found in the epidemiology, clinical manifestations, and therapy of disease. One possible reason is that sex differences in cerebral morphology, structural and functional connections, render men and women differentially vulnerable to various disease processes. The present review addresses this issue with respect to the functional and structural correlates to some forms of epilepsy. [ABSTRACT FROM AUTHOR]

Background Despite the increasing interest in sex differences in disease manifestations and responses to treatment, very few data are available on sex differences in seizure types and semiology. The Epilepsy Phenome/Genome Project (EPGP) is a large-scale, multi-institutional, collaborative study that aims to create a comprehensive repository of detailed clinical information and DNA samples from a large cohort of people with epilepsy. We used this well-characterized cohort to explore differences in seizure types as well as focal seizure symptoms between males and females. Methods We reviewed the EPGP database and identified individuals with generalized epilepsy of unknown etiology (GE) (n = 760; female: 446, male: 314), nonacquired focal epilepsy (NAFE) (n = 476; female: 245, male: 231), or both (n = 64; female: 33, male: 31). Demographic data along with characterization of seizure type and focal seizure semiologies were examined. Results In GE, males reported atonic seizures more frequently than females (6.5% vs. 1.7%; p < 0.001). No differences were observed in other generalized seizure types. In NAFE, no sex differences were seen for seizure types with or without alteration of consciousness or progression to secondary generalization. Autonomic (16.4% vs. 26.6%; p = 0.005), psychic (26.7% vs. 40.3%; p = 0.001), and visual (10.3% vs. 19.9%; p = 0.002) symptoms were more frequently reported in females than males. Specifically, of psychic symptoms, more females than males endorsed déjà vu (p = 0.001) but not forced thoughts, derealization/depersonalization, jamais vu, or fear. With corrections for multiple comparisons, there were no significant differences in aphasic, motor, somatosensory, gustatory, olfactory, auditory, vertiginous, or ictal headache symptoms between sexes. Conclusions Significant differences between the sexes were observed in the reporting of atonic seizures, which were more common in males with GE, and for autonomic, visual, and psychic symptoms associated with NAFE, which were more common in females. [ABSTRACT FROM AUTHOR]

In the majority of neuropsychiatric conditions, marked gender-based differences have been found in the epidemiology, clinical manifestations, and therapy of disease. One possible reason is that sex differences in cerebral morphology, structural and functional connections, render men and women differentially vulnerable to various disease processes. The present review addresses this issue with respect to the functional and structural correlates to some forms of epilepsy. [ABSTRACT FROM AUTHOR]

• PNES or insufficient adherence to medication/conduct may define pseudoresistance. • Young age, abuse, and high impulsivity are risk factors for pseudoresistance. • Juvenile myoclonic epilepsy and psychiatric diagnosis are not associated with pseudoresistance. • Pseudoresistance is linked to lower rate of full-time employment. • Pseudoresistance may be associated with a risk of overtreatment. The aim of the study was to determine risk factors associated with pseudoresistance in a large, representative cohort of patients with Idiopathic/Genetic Generalized Epilepsy (IGE) and the impact of pseudoresistance on socioeconomic parameters. We performed a literature review on definitions of pseudoresistance in IGE. In an established cohort of patients with IGE from Funen, patients with current or previous pseudoresistant seizures were retrospectively identified based on a comprehensive evaluation of the patients' medical records and direct patient contact, if required. In addition, clinical characteristics, socioeconomic, and demographic data were assessed. Personal interviews were used to determine the brief version of Barratts (BIS-8) impulsivity score. The literature review provided the following definition of pseudoresistance: Seizures due to (I) lacking adherence to antiseizure medication (ASM), (II) incompliance to general rule of conduct, (III) psychogenic nonepileptic seizures (PNES), (IV) inadequate choice of ASM/dosage, and (V) incorrect classification of epilepsy. Applying criteria I-III to a cohort of patients with IGE (n = 499), 73 patients (14.6%) were currently pseudoresistant and 62 (12.4%) were previously pseudoresistant, but currently seizure free. Current pseudoresistance was associated with younger age, drug/alcohol abuse, lower rate of full-time employment, and higher BIS-8 scores. We found no associations of pseudoresistance with juvenile myoclonic epilepsy, psychiatric disease, specific seizure types, or number of seizure types. Patients with previously pseudoresistant seizures have tried more ASMs and were characterized by male preponderance, higher BIS-8, and higher rates of abuse. Surrogate markers for social outcome did not differ. In IGE, pseudoresistance may be defined as PNES or insufficient adherence to medication/conduct and is associated with younger age, drug/alcohol abuse, and higher scores for impulsivity. If transient, its impact on socioeconomic status remains limited but may be associated with a risk of overtreatment with ASM. [ABSTRACT FROM AUTHOR]

Abstract: Epilepsy is a complex neurological disorder manifested by recurrent episodes of convulsive seizures, loss of consciousness, and sensory disturbances. Pentylenetetrazole (PTZ)-induced kindling primarily represents a model of generalized epilepsy. The present study has been undertaken to evaluate the neuroprotective potential of hesperidin and its interaction with nitric oxide modulators against PTZ-induced kindling and associated cognitive dysfunction in mice. The experimental protocol comprised of eleven groups (n=6), where a subconvulsive dose of PTZ (40mg/kg, i.p.) had been administered every other day for a period of 12days, and seizure episodes were noted after each PTZ injection over a period of 30min. The memory performance tests were carried out on days 13 and 14 followed by the estimation of biochemical and mitochondrial parameters. Chronic administration of a subconvulsive dose of PTZ resulted in an increase in convulsive activity culminating in generalized clonic–tonic seizures, as revealed by a progressive increase in seizure score as well as alteration in antioxidant enzyme levels (lipid peroxidation, nitrite, glutathione, super oxide dismutase, and catalase) and mitochondrial complex (I, II, and IV) activities, whereas chronic treatment with hesperidin (200mg/kg) significantly attenuated these behavioral, biochemical, and mitochondrial alterations. Further, treatment with l-arginine (100mg/kg) or l-NAME (10mg/kg) in combination with hesperidin significantly modulated the protective effect of hesperidin which was significant as compared to their effects per se in PTZ-treated animals. Thus, the present study suggests a possible involvement of the NO–cGMP pathway in the neuroprotective effect of hesperidin in PTZ-kindled mice. [Copyright &y& Elsevier]

Abstract: We aimed to study the effect of a potential default mode network (DMN) dysfunction on language performance in epilepsy. Language dysfunction in focal epilepsy has previously been connected to brain damage in language-associated cortical areas. In this work, we studied generalized epilepsy (GE) without focal brain damage to see if the language function was impaired. We used functional magnetic resonance imaging (fMRI) to investigate if the DMN was involved. Eleven persons with GE and 28 healthy controls were examined with fMRI during a sentence-reading task. We demonstrated impaired language function, reduced suppression of DMN, and, specifically, an inadequate suppression of activation in the left anterior temporal lobe and the posterior cingulate cortex, as well as an aberrant activation in the right hippocampal formation. Our results highlight the presence of language decline in people with epilepsy of not only focal but also generalized origin. [Copyright &y& Elsevier]

Abstract: The GABRG2 nonsense mutation, Q40X, is associated with the severe epilepsy syndrome, Dravet syndrome, and is predicted to generate a premature translation–termination codon (PTC) in the GABAA receptor γ2 subunit mRNA in a position that codes for the first amino acid of the mutant subunit. We determined the effects of the mutation on γ2 subunit mRNA and protein synthesis and degradation, as well as on α1β2γ2 GABAA receptor assembly, trafficking and surface expression in HEK cells. Using bacterial artificial chromosome (BAC) constructs, we found that γ2(Q40X) subunit mRNA was degraded by nonsense mediated mRNA decay (NMD). Undegraded mutant mRNA was translated to a truncated peptide, likely the signal peptide, which was cleaved further. We also found that mutant γ2(Q40X) subunits did not assemble into functional receptors, thus decreasing GABA-evoked current amplitudes. The GABRG2(Q40X) mutation is one of several epilepsy-associated nonsense mutations that have the potential to be rescued by reading through the PTC, thus restoring full-length protein translation. As a first approach, we investigated the use of the aminoglycoside, gentamicin, to rescue translation of intact mutant subunits by inducing mRNA read-through. In the presence of gentamicin, synthesis of full length γ2 subunits was partially restored, and surface biotinylation and whole cell recording experiments suggested that rescued γ2 subunits could corporate into functional, surface GABAA receptors, indicating a possible direction for future therapy. [Copyright &y& Elsevier]

Abstract: The purpose of this study is to determine regions of cerebral cortex activated during the onset and propagation of dense array electroencephalographic (dEEG) epileptiform discharges in patients with juvenile myoclonic epilepsy (JME), through the use of 256 channel, dense array scalp EEG recordings. Ten patients (16–58 years old) with the clinical diagnosis of JME comprised the study group. In all cases the MRI and neurological exams were normal, while standard EEG recordings documented typical “generalized” 4–6 Hz epileptiform patterns. Outpatient dEEG recordings captured epileptiform discharges in each patient. Localization of onset and spread of discharges in relation to a standard MRI model was accomplished by applying dipole fits and a distributed linear inverse method of cortically constrained source analysis. All patients showed epileptiform discharges that localized to sources that included orbitofrontal/medial frontopolar cortex, while basal–medial temporal lobe sources were observed in 5/10 subjects. In many ways similar to discharges of typical absence, epileptiform patterns in JME are usually irregular and frequently include temporal lobe structures as the dominant contributors to the discharges. We find that epileptiform discharges in patients with JME are not “generalized” in the sense of bilaterally synchronous diffuse onset. Rather, discharges have both localized onsets and a restricted cortical network during propagation that includes regions of frontal and temporal cortex. [Copyright &y& Elsevier]

• Failure to achieve seizure control commoner in focal epilepsy. • More focal seizures were uncontrolled for a year or more before conception. • Younger age, generalized epilepsy showed lesser risk of seizures. • Risk of convulsive seizures commoner in generalized epilepsy. • Changing valproate before conception does not lead to seizure worsening. To examine factors contributing to failure to achieve full seizure control during pregnancy in women with anti-seizure medication (ASM) treated generalized epilepsy compared with focal epilepsy. Full seizure control was not attained in 51.4% of 1223 pregnancies of women with focal epilepsies in the Australian Pregnancy Register, and in 38.7% of 1026 pregnancies in women with generalized epilepsy (P < 0.05). For convulsive seizures only, the corresponding figures of 20.8% and 22.9% were reasonably similar. Where seizures had occurred in the pre-pregnancy year, 82.5% of the focal epilepsy pregnancies were seizure affected, and 70.1% of the generalized epilepsy ones (P < 0.05). Where the pre-pregnancy year was seizure free, the corresponding figures were 22.6% and 16.4% (P < 0.05), a roughly four-fold lower rate. Maternal age, epilepsy onset age, and epilepsy duration also differed between the focal and generalized epilepsy pregnancies. Multivariate regression analysis showed that generalized epilepsy and younger maternal age were associated with statistically significant decreased risks of seizure-affected pregnancy, and having seizure-affected pre-pregnancy years with an increased risk. However, for convulsive seizures only, the risk of seizure-affected pregnancy appeared increased in generalized epilepsy. The risk of seizure-affected pregnancy appears lower in women with generalized epilepsy, independently of pre-pregnancy seizure control, itself a major determinant of the risk. The risk of having only convulsive seizures in pregnancy was not lower in generalized epilepsy than in focal epilepsy. ASM therapy seemed less effective in controlling focal than generalized epileptic seizures during pregnancy. [ABSTRACT FROM AUTHOR]

Abstract: The influence of sex on face recognition memory was studied in 49 patients with temporal lobe epilepsy, 20 patients with generalized epilepsy, and 32 healthy controls. After learning 20 faces, serially presented for 5 seconds each, subjects had to recognize the 20 among 40 faces (including 20 new faces) immediately and 24 hours later. Women had better face recognition than men, with no significant differences between groups. Women’s advantage was due mainly to superior delayed recognition. Taken together, the results suggest that sex has a similar impact on face recognition in patients with epilepsy and healthy controls, and that testing delayed face recognition raises sensitivity for sex differences. The influence of sex on face recognition in patients with epilepsy should be acknowledged when evaluating individuals or comparing groups. [Copyright &y& Elsevier]

Abstract: Proactive interference (PI) decreases short- and long-term memory in healthy subjects. Neurological patients exhibit a heightened PI effect on short-term memory. It is, however, not known if PI affects long-term memory in neurological patients. We analyzed whether epilepsy heightens the negative effect of PI on long-term face memory. PI was induced by a list of 20 faces learned 24 hours prior to a target list of 20 faces. We tested immediate and 24-hour recognition for both lists. Twelve healthy controls and 42 patients with generalized epilepsy or temporal lobe epilepsy (TLE) were studied. PI led to a decrease in 24-hour recognition in patients with generalized epilepsy and TLE but not in controls. Thus, PI may cause long-term memory disturbances in epilepsy patients. PI was also associated with decreased short-term memory, but only in right TLE. This confirms the dominant role of the right temporal lobe in short-term face memory. [Copyright &y& Elsevier]

• Bilateral RFA of the CMN reduce the frequency of seizures in patients with refractory epilepsy. • It may improve neuropsychological deficits by reducing the frequency seizures. • It appears to be just as effective as other palliative epilepsy surgical methods. To determine the usefulness and efficacy of radiofrequency ablations (RFA) of the Centromedian thalamic nucleus (CMN) to control primarily generalized or multifocal seizures in refractory epilepsy. Six patients with clinical diagnosis of multifocal or primarily generalized drug-resistant epilepsy were included. Bilateral RFA of the CMN was performed through a monopolar 1.8 mm. tip electrode with a temperature of 80 °C during 90 seconds. Patients were followed in every 3 months visit for 20 to 36 months and kept a monthly seizure count calendar. We also compared maximal paroxysmal electroencephalogram (EEG) activity and neuropsychological evaluation pre and 6 months postoperatively. A significant reduction in the number of generalized seizures was observed in all subjects in the range of 79–98%, starting the first post-operative month. Although focal aware seizures remained unchanged throughout follow-up, there was an important reduction on paroxysmal activity between the pre and postoperative EEG. No major changes on cognitive status were detected. There was post-operative dysphagia and odynophagia lasting one week and there was no mortality in this group of patients. Preliminary results of CMN RFA suggest safety and a trend toward reduction of some seizure types, it may reduce the seizure frequency like other palliative procedures since the first post-operative month, but a larger, controlled study would be needed to establish the value of this therapy. [ABSTRACT FROM AUTHOR]

Abstract: The coexistence of focal and idiopathic generalized epilepsy (IGE) is rarely observed, and the mechanism underlying this situation remains unknown. We report a 13-year-old girl with well-controlled generalized epilepsy and medically-refractory left temporal lobe epilepsy. She underwent intracranial EEG recording, which demonstrated two characteristic seizure patterns of generalized ictal onset and left mesial temporal onset. In addition, two types of interictal spike distribution, including the left mesial temporal region and generalized spikes, were also supportive of the coexistence of left mesial temporal lobe epilepsy and IGE. Thereafter, a left anterior temporal lobectomy and post-surgical medication significantly improved her seizure outcome. This case illustrates the importance of considering surgical management for patients with medically-intractable focal epilepsy coexisting with generalized epilepsy. [Copyright &y& Elsevier]

Abstract: The characterization of a seizure as generalized or focal onset depends on a basic knowledge of the underlying pathophysiology. Recently, an uncommon phenomenon in generalized epilepsy—evolution of seizures from generalized to focal followed by secondary generalization—was reported for the first time. We describe a 15-year-old boy, initially classified as having partial epilepsy, who had a typical absence seizure that became focal with second secondary generalization (double generalization). On the basis of these findings his epilepsy was classified as juvenile absence epilepsy and his treatment was changed, resulting in seizure freedom. This is the first report of this unusual electroclinical evolution in a patient with juvenile absence epilepsy. The recognition of this particular pattern allows correct classification and impacts both treatment and prognosis. [Copyright &y& Elsevier]

The aim of this study was to gather the expert opinions of Korean epileptologists regarding the treatment of adult patients with epilepsy. A total of 42 neurologists who specialized in epilepsy were surveyed. They completed an online questionnaire describing multiple patient scenarios. Using these scenarios, they evaluated treatment strategies and gave their preference for specific antiepileptic drugs (AEDs) used to treat genetically mediated generalized epilepsy and focal epilepsy. Initial AED monotherapy, followed by a second form of alternative monotherapy or an add-on combination therapy, was the preferred treatment strategy. The experts reached consensus for 87.2% of the items. The most commonly selected AEDs for the initial monotherapy for patients with generalized epilepsy were levetiracetam or valproate. For those with focal epilepsy, levetiracetam, oxcarbazepine, or lamotrigine were the most popular selections. Ethosuximide was the treatment of choice only for patients with generalized epilepsy with prominent absence seizures. Levetiracetam was preferred as an add-on therapy for both generalized and focal epilepsy. For special populations of patients, such as elderly adults or those with comorbid diseases, levetiracetam or lamotrigine was selected as the treatment of choice. Most of the survey results were in accordance with the US expert opinion survey published in 2016. This survey can assist clinicians in making clinical decisions when treating individual adult patients with epilepsy. • We surveyed 42 Korean experts for their opinions on adult epilepsy treatment. • The consensus was reached for 87.2% of items. • The results were in accordance with those of the US expert opinion survey of 2016. • No consensus between the experts was reached on newly licensed or on old AEDs. [ABSTRACT FROM AUTHOR]

Epilepsy is a common neurological disorder characterized by recurrent seizures, along with comorbid cognitive and psychosocial impairment. Current gold standards of assessment can quantify cognitive and motor performance, but may not capture all subtleties of behavior. Here, we study the feasibility of assessing various upper limb sensorimotor and cognition functions in people with epilepsy using the Kinarm robotic assessment system. We quantify performance across multiple behavioral domains and additionally consider the possible effects of epilepsy subtype and medication. We recruited individuals with a variety of epilepsy subtypes. Participants performed 8 behavioral tasks that tested motor, cognitive, and sensory domains. We collected data on the same tasks from a group of control participants that had no known neurological impairments. We quantified performance using Task Scores, which provide a composite measure of overall performance on a given task and are adjusted for age, sex, and handedness. We collected data from 46 individuals with epilepsy and 92 control participants. The assessment was well-tolerated, with no adverse events recorded. Cognitive tasks testing spatial working memory, executive function, and motor response inhibition were the most frequently impaired in the epilepsy cohort, with 33/46 (72%) being outside the normal range on at least one of these tasks. Additionally, 29/46 (63%) were impaired on at least one task testing primarily motor skill, and 14/46 (30%) were impaired on a proprioceptive sensory task. People with either focal epilepsy or generalized epilepsy performed significantly worse on both motor and cognitive tasks than control participants after correcting for multiple comparisons. There were no statistical differences between generalized and focal epilepsy groups on Task Scores. Finally, individuals taking topiramate trended toward having worse performance on a spatial working memory task than other individuals with epilepsy who were not taking topiramate. Kinarm robotic assessment is feasible in individuals with epilepsy and is well-tolerated. Our robotic paradigm can detect impairments in various sensorimotor and cognitive functions across the population with epilepsy. Future studies will explore the role of epilepsy subtype and medications. • Kinarm robotic assessment is feasible to use with people who have epilepsy • Almost 3/4 of people with epilepsy were impaired on at least one robotic test of cognition, and almost 2/3 were impaired on at least 1 test of motor • People with epilepsy frequently had deficits on tests of processing speed as well as quick and accurate movement [ABSTRACT FROM AUTHOR]

Praxis induction (PI) is a reflex trait defined as the precipitation of epileptic discharges (ED) or seizures by cognition-guided tasks that often involve visuomotor coordination and decision-making. This is a characteristic of genetic generalized epilepsy (GGE), and especially of juvenile myoclonic epilepsy (JME). Additionally, several studies have described dysexecutive traits in these patients. Our objective was to analyze PI in the different syndromes of GGE and explore the relationship between PI and cognitive performance. Sixty-one adult patients with GGE underwent video-electroencephalograph (EEG) during which a neuropsychological activation protocol (NPAP) was performed: reading, writing, calculations, crosswords, and tangram. Praxis induction was defined by the presence of ED during the NPAP with a persistence of at least twice seen on the basal EEG. All patients also underwent a comprehensive cognitive evaluation. We observed PI in 22 out of 61 patients (36%). Grouped by syndrome, PI was more frequent in adult patients with persistent childhood or juvenile absence epilepsy (JAE, 60%), followed by JME (42.1%) and in a lesser grade in patients with only tonic–clonic generalized seizures (9%). Patients classified as having PI did not obtain worse results in the cognitive evaluation. The presence of ED during the performance of a test was associated with a trend to lower results in that specific test. Our study showed a relevant presence of PI in patients whose absence epilepsy persists into adulthood, and not only in JME, the syndrome classically associated with PI. According to our results, PI as a reflex trait does not imply necessarily a poorer cognitive phenotype, but the induction of frequent ED during the tasks could be associated with transient cognitive impairment. • PI was frequent in adults with persistent childhood/juvenile absence epilepsy (60%). • It was even more frequent than in juvenile myoclonic epilepsy (42%). • Having this reflex trait did not imply necessarily a poorer cognitive phenotype. [ABSTRACT FROM AUTHOR]