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Epilepsy & Behavior : E&B Jun 2024To evaluate the clinical predictors of positive genetic investigation in developmental and epileptic encephalopathies, beyond the influence of Dravet Syndrome.
OBJECTIVE
To evaluate the clinical predictors of positive genetic investigation in developmental and epileptic encephalopathies, beyond the influence of Dravet Syndrome.
METHODS
The study included 98 patients diagnosed with developmental and epileptic encephalopathies. The patients underwent Sanger sequencing of SCN1A, Chromosomal Microarray Analysis, and Whole Exome Sequencing. The association of clinical variables with a positive genetic test was investigated using univariate and multivariate analysis.
RESULTS
Genetic diagnosis was identified in 47 (48 %) patients with developmental and epileptic encephalopathies. Beyond Dravet Syndrome influence, first seizure in the context of fever (p < 0.01), seizures precipitated by temperature (p = 0.04), cognitive regression (p = 0.04), hypotonia (p < 0.01), and focal seizures (p = 0.03) increased the chances of a positive genetic investigation. In contrast, atonic seizures (p = 0.01) and generalized discharges on electroencephalogram (p = 0.02) decreased the chances. Dravet Syndrome was positively associated with a genetic developmental and epileptic encephalopathies etiology (p < 0.01), whereas epilepsy with myoclonic-atonic seizures (p = 0.01), developmental and epileptic encephalopathies with spike-wave activation in sleep (p = 0.04), and Lennox-Gastaut syndrome (p = 0.03) were negatively associated. In multivariate analysis, the first seizure in the context of fever (p < 0.01) and hypotonia (p = 0.02) were positively, and atonic seizures (p = 0.01) were negatively and independently associated with a genetic etiology.
CONCLUSION
The predictive variables of genetic investigation in developmental and epileptic encephalopathies are first seizure in the context of fever and hypotonia, whereas atonic seizures decrease the chances of finding a genetic cause for developmental and epileptic encephalopathies. Regarding epileptic syndromes, Dravet Syndrome is highly associated with a positive genetic test, whereas epilepsy with myoclonic-atonic seizures, developmental and epileptic encephalopathies with spike-wave activation in sleep, and Lennox-Gastaut syndrome are rarely associated with a positive genetic investigation.
Topics: Humans; Male; Female; Child; Child, Preschool; Epilepsies, Myoclonic; NAV1.1 Voltage-Gated Sodium Channel; Infant; Adolescent; Electroencephalography; Genetic Testing; Adult; Epilepsy; Young Adult; Exome Sequencing; Lennox Gastaut Syndrome
PubMed: 38636144
DOI: 10.1016/j.yebeh.2024.109762 -
Annals of Neurology Jun 2024The objective was to analyze seizure semiology in pediatric frontal lobe epilepsy patients, considering age, to localize the seizure onset zone for surgical resection in...
OBJECTIVE
The objective was to analyze seizure semiology in pediatric frontal lobe epilepsy patients, considering age, to localize the seizure onset zone for surgical resection in focal epilepsy.
METHODS
Fifty patients were identified retrospectively, who achieved seizure freedom after frontal lobe resective surgery at Great Ormond Street Hospital. Video-electroencephalography recordings of preoperative ictal seizure semiology were analyzed, stratifying the data based on resection region (mesial or lateral frontal lobe) and age at surgery (≤4 vs >4).
RESULTS
Pediatric frontal lobe epilepsy is characterized by frequent, short, complex seizures, similar to adult cohorts. Children with mesial onset had higher occurrence of head deviation (either direction: 55.6% vs 17.4%; p = 0.02) and contralateral head deviation (22.2% vs 0.0%; p = 0.03), ictal body-turning (55.6% vs 13.0%; p = 0.006; ipsilateral: 55.6% vs 4.3%; p = 0.0003), and complex motor signs (88.9% vs 56.5%; p = 0.037). Both age groups (≤4 and >4 years) showed hyperkinetic features (21.1% vs 32.1%), contrary to previous reports. The very young group showed more myoclonic (36.8% vs 3.6%; p = 0.005) and hypomotor features (31.6% vs 0.0%; p = 0.003), and fewer behavioral features (36.8% vs 71.4%; p = 0.03) and reduced responsiveness (31.6% vs 78.6%; p = 0.002).
INTERPRETATION
This study presents the most extensive semiological analysis of children with confirmed frontal lobe epilepsy. It identifies semiological features that aid in differentiating between mesial and lateral onset. Despite age-dependent differences, typical frontal lobe features, including hyperkinetic seizures, are observed even in very young children. A better understanding of pediatric seizure semiology may enhance the accuracy of onset identification, and enable earlier presurgical evaluation, improving postsurgical outcomes. ANN NEUROL 2024;95:1138-1148.
Topics: Humans; Child; Male; Female; Epilepsy, Frontal Lobe; Child, Preschool; Electroencephalography; Retrospective Studies; Adolescent; Seizures; Infant; Frontal Lobe; Video Recording
PubMed: 38624073
DOI: 10.1002/ana.26922 -
Neurologia May 2024In the present study, anticonvulsant effects of aqueous extract (AE), hydro-alcoholic crude extract (HE), and its fractions (F-CHCl, F-EtOAc, F-MeOH) of Paeonia daurica...
INTRODUCTION
In the present study, anticonvulsant effects of aqueous extract (AE), hydro-alcoholic crude extract (HE), and its fractions (F-CHCl, F-EtOAc, F-MeOH) of Paeonia daurica subsp. macrophylla (P. daurica ssp. macrophylla) root examined by using a pentylenetetrazol-induced model (PTZ) on mice.
METHODS
HE and its fractions as well as AE, in concentrations of (100, 200 and 400mg/kg), valproate (Val) (100 and 200mg/kg), and saline (negative control) (10mg/kg) were injected intraperitoneally (i.p.) 30min before PTZ (80mg/kg, i.p.). The time taken before the onset of myoclonic convulsions (MC), MC duration, time taken before the onset of generalized tonic-clonic seizures (GTCS), the duration of GTCS, and the percentage of GTCS and mortality protection recorded. The plant's anticonvulsant mechanisms were assessed using flumazenil (5mg/kg, i.p.) before AE (100, 200, and 400mg/kg, i.p.) injection. GraphPad Prism software was used to compare the differences between various treatment groups with one-way analysis of variance (ANOVA) followed by Tukey-Krammer multiple comparison tests.
RESULTS
All the plant samples except F-EtOAc significantly delayed the onset and decreased the duration of PTZ-induced MCS and GTCS, and significantly reduced the GTCS and mortality rate. Pretreatment with flumazenil diminished the significant anticonvulsant effects of AE against PTZ-induced seizures.
CONCLUSIONS
It can report that extract of P. daurica ssp. macrophylla might be a helpful guide for future studies in the treatment of epilepsy.
Topics: Animals; Mice; Anticonvulsants; Pentylenetetrazole; Paeonia; Flumazenil; Seizures
PubMed: 38616060
DOI: 10.1016/j.nrleng.2021.08.004 -
Prostaglandins & Other Lipid Mediators Jun 2024Dravet syndrome is an intractable epilepsy with a high seizure burden that is resistant to current anti-seizure medications. There is evidence that neuroinflammation...
Dravet syndrome is an intractable epilepsy with a high seizure burden that is resistant to current anti-seizure medications. There is evidence that neuroinflammation plays a role in epilepsy and seizures, however few studies have specifically examined neuroinflammation in Dravet syndrome under conditions of a higher seizure burden. Here we used an established genetic mouse model of Dravet syndrome (Scn1a mice), to examine whether a higher seizure burden impacts the number and morphology of microglia in the hippocampus. Moreover, we examined whether a high seizure burden influences classical inflammatory mediators in this brain region. Scn1a mice with a high seizure burden induced by thermal priming displayed a localised reduction in microglial cell density in the granule cell layer and subgranular zone of the dentate gyrus, regions important to postnatal neurogenesis. However, microglial cell number and morphology remained unchanged in other hippocampal subfields. The high seizure burden in Scn1a mice did not affect hippocampal mRNA expression of classical inflammatory mediators such as interleukin 1β and tumour necrosis factor α, but increased cyclooxygenase 2 (COX-2) expression. We then quantified hippocampal levels of prostanoids that arise from COX-2 mediated metabolism of fatty acids and found that Scn1a mice with a high seizure burden displayed increased hippocampal concentrations of numerous prostaglandins, notably PGF, PGE, PGD, and 6-K-PGF, compared to Scn1a mice with a low seizure burden. In conclusion, a high seizure burden increased hippocampal concentrations of various prostaglandin mediators in a mouse model of Dravet syndrome. Future studies could interrogate the prostaglandin pathways to further better understand their role in the pathophysiology of Dravet syndrome.
Topics: Animals; Epilepsies, Myoclonic; Mice; Hippocampus; NAV1.1 Voltage-Gated Sodium Channel; Disease Models, Animal; Seizures; Prostaglandins; Male; Microglia
PubMed: 38599513
DOI: 10.1016/j.prostaglandins.2024.106836 -
Epilepsia Jun 2024
Topics: Humans; Intellectual Disability; Epilepsies, Myoclonic
PubMed: 38597521
DOI: 10.1111/epi.17919 -
Epilepsia Jun 2024Sudden unexpected death in epilepsy (SUDEP) is an underestimated complication of epilepsy. Previous studies have demonstrated that enhancement of serotonergic...
OBJECTIVE
Sudden unexpected death in epilepsy (SUDEP) is an underestimated complication of epilepsy. Previous studies have demonstrated that enhancement of serotonergic neurotransmission suppresses seizure-induced sudden death in evoked seizure models. However, it is unclear whether elevated serotonin (5-HT) function will prevent spontaneous seizure-induced mortality (SSIM), which is characteristic of human SUDEP. We examined the effects of 5-HT-enhancing agents that act by three different pharmacological mechanisms on SSIM in Dravet mice, which exhibit a high incidence of SUDEP, modeling human Dravet syndrome.
METHODS
Dravet mice of both sexes were evaluated for spontaneous seizure characterization and changes in SSIM incidence induced by agents that enhance 5-HT-mediated neurotransmission. Fluoxetine (a selective 5-HT reuptake inhibitor), fenfluramine (a 5-HT releaser and agonist), SR 57227 (a specific 5-HT receptor agonist), or saline (vehicle) was intraperitoneally administered over an 8-day period in Dravet mice, and the effect of these treatments on SSIM was examined.
RESULTS
Spontaneous seizures in Dravet mice generally progressed from wild running to tonic seizures with or without SSIM. Fluoxetine at 30 mg/kg, but not at 20 or 5 mg/kg, significantly reduced SSIM compared with the vehicle control. Fenfluramine at 1-10 mg/kg, but not .2 mg/kg, fully protected Dravet mice from SSIM, with all mice surviving. Compared with the vehicle control, SR 57227 at 20 mg/kg, but not at 10 or 5 mg/kg, significantly lowered SSIM. The effect of these drugs on SSIM was independent of sex.
SIGNIFICANCE
Our data demonstrate that elevating serotonergic function by fluoxetine, fenfluramine, or SR 57227 significantly reduces or eliminates SSIM in Dravet mice in a sex-independent manner. These findings suggest that deficits in serotonergic neurotransmission likely play an important role in the pathogenesis of SSIM, and fluoxetine and fenfluramine, which are US Food and Drug Administration-approved medications, may potentially prevent SUDEP in at-risk patients.
Topics: Animals; Mice; Male; Fluoxetine; Female; Epilepsies, Myoclonic; Fenfluramine; Seizures; Serotonin; Selective Serotonin Reuptake Inhibitors; Disease Models, Animal; Sudden Unexpected Death in Epilepsy; Serotonin Receptor Agonists; Mice, Transgenic; NAV1.1 Voltage-Gated Sodium Channel
PubMed: 38593237
DOI: 10.1111/epi.17966 -
PloS One 2024Juvenile Myoclonic Epilepsy (JME) is a prevalent form of epileptic disorder, specifically categorized within the realm of Genetic Generalized Epilepsy (GGE). Its... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Juvenile Myoclonic Epilepsy (JME) is a prevalent form of epileptic disorder, specifically categorized within the realm of Genetic Generalized Epilepsy (GGE). Its hallmark features encompass unprovoked bilateral myoclonus and tonic-clonic seizures that manifest during adolescence. While most JME patients respond favorably to anti-seizure medication (ASM), a subset experiences refractory JME, a condition where seizures persist despite rigorous ASM treatment, often termed "Drug-Resistant Epilepsy" (DRE). This systematic review and meta-analysis aims to determine the prevalence of refractory JME, and further to identify socio-demographic, electrophysiological and clinical risk factors associated with its occurrence. Pinpointing these factors is crucial as it offers the potential to predict ASM responsiveness, enabling early interventions and tailored care strategies for patients.
MATERIAL AND METHODS
The systematic review and meta-analysis followed the Cochrane Handbook and adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The study evaluated outcomes post ASM treatment in JME cohorts by searching papers published up to September 2023 in PubMed/MEDLINE, Scopus, and Google Scholar databases. Predefined inclusion criteria were met by 25 eligible studies, forming the basis for analysis.
RESULTS
A total of 22 potential risk factors for refractory JME were documented. Notably, robust risk factors for treatment resistance included Psychiatric Disorder (Odds Ratio (OR), 3.42 [2.54, 4.61] (95% Confidence Inverval (Cl)), Febrile Seizures (OR, 1.83 [1.14, 2.96] (95% Cl)), Alcohol Consumption (OR, 16.86 [1.94, 146.88] (95%Cl)), Aura (OR, 2.15 [1.04, 4.47] (95%Cl)), childhood absence epilepsy (CAE) evolving into JME (OR, 4.54 [1.61, 12.78] (95%CI)), occurrence of three seizure types (OR, 2.96 [1.96, 4.46] (95%CI)), and Focal EEG abnormalities (OR, 1.85 [1.13, 3.01] (95%Cl)). In addition, there were some non-significant risk factors for DRE because of noticeable heterogeneity.
CONCLUSION
In aggregate, over 36% of JME patients demonstrated drug resistance, with seven significant risk factors closely linked to this refractoriness. The interplay between these factors and whether they denote treatment non-response or heightened disease burden remains an open question and more studies would be required to fully examine their influence.
Topics: Adolescent; Humans; Child; Myoclonic Epilepsy, Juvenile; Epilepsy, Absence; Seizures; Drug Resistant Epilepsy; Risk Factors; Electroencephalography; Anticonvulsants
PubMed: 38593118
DOI: 10.1371/journal.pone.0300930 -
The Journal of Biological Chemistry May 2024Lafora disease (LD) is an autosomal recessive myoclonus epilepsy with onset in the teenage years leading to death within a decade of onset. LD is characterized by the...
Lafora disease (LD) is an autosomal recessive myoclonus epilepsy with onset in the teenage years leading to death within a decade of onset. LD is characterized by the overaccumulation of hyperphosphorylated, poorly branched, insoluble, glycogen-like polymers called Lafora bodies. The disease is caused by mutations in either EPM2A, encoding laforin, a dual specificity phosphatase that dephosphorylates glycogen, or EMP2B, encoding malin, an E3-ubiquitin ligase. While glycogen is a widely accepted laforin substrate, substrates for malin have been difficult to identify partly due to the lack of malin antibodies able to detect malin in vivo. Here we describe a mouse model in which the malin gene is modified at the C-terminus to contain the c-myc tag sequence, making an expression of malin-myc readily detectable. Mass spectrometry analyses of immunoprecipitates using c-myc tag antibodies demonstrate that malin interacts with laforin and several glycogen-metabolizing enzymes. To investigate the role of laforin in these interactions we analyzed two additional mouse models: malin-myc/laforin knockout and malin-myc/LaforinCS, where laforin was either absent or the catalytic Cys was genomically mutated to Ser, respectively. The interaction of malin with partner proteins requires laforin but is not dependent on its catalytic activity or the presence of glycogen. Overall, the results demonstrate that laforin and malin form a complex in vivo, which stabilizes malin and enhances interaction with partner proteins to facilitate normal glycogen metabolism. They also provide insights into the development of LD and the rescue of the disease by the catalytically inactive phosphatase.
Topics: Lafora Disease; Animals; Mice; Ubiquitin-Protein Ligases; Protein Tyrosine Phosphatases, Non-Receptor; Humans; Dual-Specificity Phosphatases; Disease Models, Animal; Glycogen
PubMed: 38588813
DOI: 10.1016/j.jbc.2024.107271 -
MedRxiv : the Preprint Server For... Mar 2024Cognitive impairment is prevalent among individuals with epilepsy, and it is possible that genetic factors can underlie this relationship. Here, we investigated the...
OBJECTIVE
Cognitive impairment is prevalent among individuals with epilepsy, and it is possible that genetic factors can underlie this relationship. Here, we investigated the potential shared genetic basis of common epilepsies and general cognitive ability (COG).
METHODS
We applied linkage disequilibrium score (LDSC) regression, MiXeR and conjunctional false discovery rate (conjFDR) to analyze different aspects of genetic overlap between COG and epilepsies. We used the largest available genome-wide association study data on COG ( = 269,867) and common epilepsies ( = 27,559 cases, 42,436 controls), including the broad phenotypes 'all epilepsy', focal epilepsies and genetic generalized epilepsies (GGE), and as well as specific subtypes. We functionally annotated the identified loci using a variety of biological resources and validated the results in independent samples.
RESULTS
Using MiXeR, COG (11.2k variants) was estimated to be almost four times more polygenic than 'all epilepsy', GGE, juvenile myoclonic epilepsy (JME), and childhood absence epilepsy (CAE) (2.5k - 2.9k variants). The other epilepsy phenotypes were insufficiently powered for analysis. We show extensive genetic overlap between COG and epilepsies with significant negative genetic correlations (-0.23 to -0.04). COG was estimated to share 2.9k variants with both GGE and 'all epilepsy', and 2.3k variants with both JME and CAE. Using conjFDR, we identified 66 distinct loci shared between COG and epilepsies, including novel associations for GGE (27), 'all epilepsy' (5), JME (5) and CAE (5). The implicated genes were significantly expressed in multiple brain regions. The results were validated in independent samples (COG: = 1.0 × 10; 'all epilepsy': = 5.6 × 10).
SIGNIFICANCE
Our study demonstrates a substantial genetic basis shared between epilepsies and COG and identifies novel overlapping genomic loci. Enhancing our understanding of the relationship between epilepsies and COG may lead to the development of novel comorbidity-targeted epilepsy treatments.
PubMed: 38585944
DOI: 10.1101/2024.03.25.24304773 -
Neurology. Clinical Practice Apr 2024Clonic seizures are currently defined as repetitive and rhythmic contractions of a specific body part, producing twitching movements at a frequency of 0.2-5 Hz. There...
BACKGROUND AND OBJECTIVES
Clonic seizures are currently defined as repetitive and rhythmic contractions of a specific body part, producing twitching movements at a frequency of 0.2-5 Hz. There are few studies in the literature that have reported a detailed analysis of the semiology, neurophysiology, and lateralizing value of clonic seizures. In this article, we aim to report our findings from a retrospective review of 39 patients.
METHODS
We identified 39 patients (48 seizures) from our center who had been admitted with clonic seizures between 2016 and 2022. We performed a retrospective review of their video-EEG recordings for semiology and ictal EEG findings. Seventeen patients also had simultaneous surface-EMG (sEMG) electrodes placed on affected body parts, which were analyzed as well.
RESULTS
The most common initial affected body parts were face, arm, and hand. In most of the cases, seizures propagated from lower face to upper face and distal hand to proximal arm. The most common seizure-onset zone was the perirolandic region, and the most common EEG seizure pattern was paroxysmal rhythmic monomorphic activity. The lateralizing value for EEG seizure onset to contralateral hemisphere in unilateral clonic seizures (n = 39) was 100%. All seizures recorded with sEMG electrodes demonstrated synchronous brief tetanic contractions of agonists and antagonists, alternating with synchronous silent periods. Arrhythmic clonic seizures were associated with periodic epileptiform discharges on the EEG, whereas rhythmic clonic seizures were associated with paroxysmal rhythmic monomorphic activity. Overall, the most common etiology was cerebrovascular injuries, followed by tumors.
DISCUSSION
Clonic seizures are characterized by synchronized brief tetanic contractions of agonist and antagonistic muscles alternating with synchronized silent periods, giving rise to the visible twitching. The most common seizure onset zone is in the perirolandic region, which is consistent with the symptomatogenic zone being in the primary motor area. The lateralizing value of unilateral clonic seizures for seizure onset in the contralateral hemisphere is 100%.
PubMed: 38585439
DOI: 10.1212/CPJ.0000000000200252