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Epilepsy & Behavior : E&B Jul 2024Dravet syndrome is a rare, early childhood-onset epileptic and developmental encephalopathy. Responses to placebo in clinical trials for epilepsy therapies range widely,... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Dravet syndrome is a rare, early childhood-onset epileptic and developmental encephalopathy. Responses to placebo in clinical trials for epilepsy therapies range widely, but factors influencing placebo response remain poorly understood. This study explored placebo response and its effects on safety, efficacy, and quality of life outcomes in patients with Dravet syndrome.
METHODS
We performed exploratory post-hoc analyses of pooled data from placebo-treated patients from the GWPCARE 1B and GWPCARE 2 randomized controlled phase III trials, comparing cannabidiol and matched placebo in 2-18 year old Dravet syndrome patients. All patients had ≥4 convulsive seizures during a baseline period of 4 weeks.
RESULTS
124 Dravet syndrome-treated patients were included in the analysis (2-5 years: n = 35; 6-12 years: n = 52; 13-18 years: n = 37). Convulsive seizures were experienced by all placebo group patients at all timepoints, with decreased median convulsive seizure frequency during the treatment period versus baseline; the number of convulsive seizure-free days was similar to baseline. Convulsive seizure frequency had a nominally significant positive correlation with age and a nominally significant negative correlation with body mass index. Most placebo-treated patients experienced a treatment-emergent adverse event; however, most resolved quickly, and serious adverse events were infrequent. Placebo treatment had very little effect on reported Caregiver Global Impression of Change outcomes versus baseline.
INTERPRETATION
Placebo had little impact on convulsive seizure-free days and Caregiver Global Impression of Change versus baseline, suggesting that these metrics may help differentiate placebo and active treatment effects in future studies. However, future research should further assess placebo responses to confirm these results.
Topics: Humans; Epilepsies, Myoclonic; Adolescent; Child; Female; Male; Cannabidiol; Child, Preschool; Placebo Effect; Anticonvulsants; Quality of Life; Treatment Outcome; Double-Blind Method
PubMed: 38677101
DOI: 10.1016/j.yebeh.2024.109805 -
International Journal of Molecular... Apr 2024An important component contributing to the onset of epilepsy is the death of hippocampal neurons. Several studies have shown that Dravet syndrome model mice: KO mice...
An important component contributing to the onset of epilepsy is the death of hippocampal neurons. Several studies have shown that Dravet syndrome model mice: KO mice have a high number of apoptotic neurons following seizures, but the precise mechanism underlying this remains unclear. The aim of this research was to elucidate the potential molecular mechanism of neuronal apoptosis in KO mice by integrating proteomics and transcriptomics, with the ultimate goal of offering better neuroprotection. We found that apoptotic processes were enriched in both proteomic and transcriptomic GO analyses, and KEGG results also indicated that differential proteins and genes play a role in neurotransmission, the cell cycle, apoptosis, and neuroinflammation. Then, we examined the upstream and downstream KGML interactions of the pathways to determine the relationship between the two omics, and we found that the HIF-1 signaling pathway plays a significant role in the onset and apoptosis of epilepsy. Meanwhile, the expression of the apoptosis-related protein VHL decreased in this pathway, and the expression of p21 was upregulated. Therefore, this study suggests that VHL/HIF-1α/p21 might be involved in the apoptosis of hippocampal neurons in KO mice.
Topics: Animals; Epilepsies, Myoclonic; Hippocampus; Apoptosis; Mice; Neurons; Disease Models, Animal; NAV1.1 Voltage-Gated Sodium Channel; Proteomics; Mice, Knockout; Transcriptome; Signal Transduction; Gene Expression Profiling; Hypoxia-Inducible Factor 1, alpha Subunit
PubMed: 38674042
DOI: 10.3390/ijms25084457 -
Cells Apr 2024It has been known for a long time that epileptic seizures provoke brain neuroinflammation involving the activation of microglial cells. However, the role of these cells...
It has been known for a long time that epileptic seizures provoke brain neuroinflammation involving the activation of microglial cells. However, the role of these cells in this disease context and the consequences of their inflammatory activation on subsequent neuron network activity remain poorly understood so far. To fill this gap of knowledge and gain a better understanding of the role of microglia in the pathophysiology of epilepsy, we used an established zebrafish Dravet syndrome epilepsy model based on Scn1Lab sodium channel loss-of-function, combined with live microglia and neuronal Ca imaging, local field potential (LFP) recording, and genetic microglia ablation. Data showed that microglial cells in -deficient larvae experiencing epileptiform seizures displayed morphological and biochemical changes characteristic of M1-like pro-inflammatory activation; i.e., reduced branching, amoeboid-like morphology, and marked increase in the number of microglia expressing pro-inflammatory cytokine Il1β. More importantly, LFP recording, Ca imaging, and swimming behavior analysis showed that microglia-depleted -KD larvae displayed an increase in epileptiform seizure-like neuron activation when compared to that seen in -KD individuals with microglia. These findings strongly suggest that despite microglia activation and the synthesis of pro-inflammatory cytokines, these cells provide neuroprotective activities to epileptic neuronal networks, making these cells a promising therapeutic target in epilepsy.
Topics: Animals; Zebrafish; Microglia; Epilepsies, Myoclonic; Disease Models, Animal; Neurons; NAV1.1 Voltage-Gated Sodium Channel; Interleukin-1beta; Larva; Calcium; Zebrafish Proteins
PubMed: 38667299
DOI: 10.3390/cells13080684 -
Journal of Medical Case Reports Apr 2024Dravet syndrome is an infantile-onset developmental and epileptic encephalopathy (DEE) characterized by drug resistance, intractable seizures, and developmental...
BACKGROUND
Dravet syndrome is an infantile-onset developmental and epileptic encephalopathy (DEE) characterized by drug resistance, intractable seizures, and developmental comorbidities. This article focuses on manifestations in two Indonesian children with Javanese ethnicity who experienced Dravet syndrome with an SCN1A gene mutation, presenting genetic analysis findings using next-generation sequencing.
CASE PRESENTATION
We present a case series involving two Indonesian children with Javanese ethnicity whom had their first febrile seizure at the age of 3 months, triggered after immunization. Both patients had global developmental delay and intractable seizures. We observed distinct genetic findings in both our cases. The first patient revealed heterozygous deletion mutation in three genes (TTC21B, SCN1A, and SCN9A). In our second patient, previously unreported mutation was discovered at canonical splice site upstream of exon 24 of the SCN1A gene. Our patient's outcomes improved after therapeutic evaluation based on mutation findings When comparing clinical manifestations in our first and second patients, we found that the more severe the genetic mutation discovered, the more severe the patient's clinical manifestations.
CONCLUSION
These findings emphasize the importance of comprehensive genetic testing beyond SCN1A, providing valuable insights for personalized management and tailored therapeutic interventions in patients with Dravet syndrome. Our study underscores the potential of next-generation sequencing in advancing genotype-phenotype correlations and enhancing diagnostic precision for effective disease management.
Topics: Humans; Epilepsies, Myoclonic; NAV1.1 Voltage-Gated Sodium Channel; Male; Female; Infant; NAV1.7 Voltage-Gated Sodium Channel; Indonesia; Anticonvulsants; Mutation; Genetic Testing; High-Throughput Nucleotide Sequencing; Child, Preschool
PubMed: 38649973
DOI: 10.1186/s13256-024-04514-2 -
Epilepsy & Behavior : E&B Jun 2024Dravet syndrome is a rare developmental epilepsy syndrome associated with severe, treatment-resistant seizures. Since seizures and seizure clusters are linked to... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Dravet syndrome is a rare developmental epilepsy syndrome associated with severe, treatment-resistant seizures. Since seizures and seizure clusters are linked to morbidity, reduced quality of life, and premature mortality, a greater understanding of these outcomes could improve trial designs. This analysis explored seizure types, seizure clusters, and factors affecting seizure cluster variability in Dravet syndrome patients.
METHODS
Pooled post-hoc analyses were performed on data from placebo-treated patients in GWPCARE 1B and GWPCARE 2 randomized controlled phase III trials comparing cannabidiol and placebo in Dravet syndrome patients aged 2-18 years. Multivariate stepwise analysis of covariance of log-transformed convulsive seizure cluster frequency was performed, body weight and body mass index z-scores were calculated, and incidence of adverse events was assessed. Data were summarized in three age groups.
RESULTS
We analyzed 124 placebo-treated patients across both studies (2-5 years: n = 35; 6-12 years: n = 52; 13-18 years: n = 37). Generalized tonic-clonic seizures followed by myoclonic seizures were the most frequent seizure types. Mean and median convulsive seizure cluster frequency overall decreased between baseline and maintenance period but did not change significantly during the latter; variation in convulsive seizure cluster frequency was observed across age groups. Multivariate analysis suggested correlations between convulsive seizure cluster frequency and age (positive), and body mass index (BMI) (negative).
INTERPRETATION
Post-hoc analyses suggested that potential relationships could exist between BMI, age and convulsive seizure cluster variation. Results suggested that seizure cluster frequency may be a valuable outcome in future trials. Further research is needed to confirm our findings.
Topics: Humans; Adolescent; Child; Epilepsies, Myoclonic; Female; Male; Seizures; Child, Preschool; Cannabidiol; Anticonvulsants; Cluster Analysis; Double-Blind Method
PubMed: 38643658
DOI: 10.1016/j.yebeh.2024.109774 -
Brain Communications 2024[This corrects the article DOI: 10.1093/braincomms/fcae054.].
[This corrects the article DOI: 10.1093/braincomms/fcae054.].
PubMed: 38638151
DOI: 10.1093/braincomms/fcae125 -
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 -
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