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Brain Communications 2024Juvenile myoclonic epilepsy is an idiopathic generalized epilepsy syndrome associated with photosensitivity in approximately 30-40% of cases. Microstates consist of a...
Juvenile myoclonic epilepsy is an idiopathic generalized epilepsy syndrome associated with photosensitivity in approximately 30-40% of cases. Microstates consist of a brief period of time during which the topography of the whole resting-state electroencephalography signal is characterized by a specific configuration. Previous neurophysiological and neuroimaging studies have suggested that Microstate B may represent activity within the visual network. In this case-control study, we aimed to investigate whether anatomical and functional alterations in the visual network observed in individuals with photosensitivity could lead to changes in Microstate B dynamics in photosensitive patients with juvenile myoclonic epilepsy. Resting-state electroencephalography microstate analysis was performed on 28 patients with juvenile myoclonic epilepsy. Of these, 15 patients exhibited photosensitivity, while the remaining 13 served as non-photosensitive controls. The two groups were carefully matched in terms of age, sex, seizure control and anti-seizure medications. Multivariate analysis of variance and repeated-measures analysis of variance were performed to assess significant differences in microstate metrics and syntax between the photosensitive and the non-photosensitive group. false discovery rate adjusted unpaired -tests were used to determine differences in specific microstate classes between the two groups. The four classical microstates (Classes A, B, C and D) accounted for 72.8% of the total electroencephalography signal variance in the photosensitive group and 75.64% in the non-photosensitive group. Multivariate analysis of variance revealed a statistically significant class-group interaction on microstate temporal metrics ( = 0.021). False discovery rate adjusted univariate analyses of variance indicated a significant class-group interaction for both mean occurrence ( = 0.002) and coverage ( = 0.03), but not for mean duration ( = 0.14). false discovery rate adjusted unpaired -tests showed significantly higher coverage ( = 0.02) and occurrence ( = 0.04) of Microstate B in photosensitive patients compared with non-photosensitive participants, along with an increased probability of transitioning from Microstates C ( = 0.04) and D ( = 0.02) to Microstate B. No significant differences were found concerning the other microstate classes between the two groups. Our study provides novel insights on resting-state electroencephalography microstate dynamics underlying photosensitivity in patients with juvenile myoclonic epilepsy. The increased representation of Microstate B in these patients might reflect the resting-state overactivation of the visual system underlying photosensitivity. Further research is warranted to investigate microstate dynamics in other photosensitive epilepsy syndromes.
PubMed: 38444911
DOI: 10.1093/braincomms/fcae054 -
Advances in Therapy Apr 2024Stiripentol (Diacomit) (STP) is an orally active antiseizure medication (ASM) indicated as adjunctive therapy, for the treatment of seizures associated with Dravet... (Review)
Review
Stiripentol (Diacomit) (STP) is an orally active antiseizure medication (ASM) indicated as adjunctive therapy, for the treatment of seizures associated with Dravet syndrome (DS), a severe form of childhood epilepsy, in conjunction with clobazam and, in some regions valproic acid. Since the discovery of STP, several mechanisms of action (MoA) have been described that may explain its specific effect on seizures associated with DS. STP is mainly considered as a potentiator of gamma-aminobutyric acid (GABA) neurotransmission: (i) via uptake blockade, (ii) inhibition of degradation, but also (iii) as a positive allosteric modulator of GABA receptors, especially those containing α3 and δ subunits. Blockade of voltage-gated sodium and T-type calcium channels, which is classically associated with anticonvulsant and neuroprotective properties, has also been demonstrated for STP. Finally, several studies indicate that STP could regulate glucose energy metabolism and inhibit lactate dehydrogenase. STP is also an inhibitor of several cytochrome P450 enzymes involved in the metabolism of other ASMs, contributing to boost their anticonvulsant efficacy as add-on therapy. These different MoAs involved in treatment of DS and recent data suggest a potential for STP to treat other neurological or non-neurological diseases.
Topics: Humans; Anticonvulsants; Dioxolanes; Seizures; Epilepsies, Myoclonic; gamma-Aminobutyric Acid
PubMed: 38443647
DOI: 10.1007/s12325-024-02813-0 -
JACC. Clinical Electrophysiology May 2024Sudden unexpected death in epilepsy (SUDEP) is a fatal complication experienced by otherwise healthy epilepsy patients. Dravet syndrome (DS) is an inherited epileptic...
BACKGROUND
Sudden unexpected death in epilepsy (SUDEP) is a fatal complication experienced by otherwise healthy epilepsy patients. Dravet syndrome (DS) is an inherited epileptic disorder resulting from loss of function of the voltage-gated sodium channel, Na 1.1, and is associated with particularly high SUDEP risk. Evidence is mounting that Nas abundant in the brain also occur in the heart, suggesting that the very molecular mechanisms underlying epilepsy could also precipitate cardiac arrhythmias and sudden death. Despite marked reduction of Na 1.1 functional expression in DS, pathogenic late sodium current (I) is paradoxically increased in DS hearts. However, the mechanisms by which DS directly impacts the heart to promote sudden death remain unclear.
OBJECTIVES
In this study, the authors sought to provide evidence implicating remodeling of Na - and Ca -handling machinery, including Na 1.6 and Na/Caexchanger (NCX) within transverse (T)-tubules in DS-associated arrhythmias.
METHODS
The authors undertook scanning ion conductance microscopy (SICM)-guided patch clamp, super-resolution microscopy, confocal Ca imaging, and in vivo electrocardiography studies in Scn1a haploinsufficient murine model of DS.
RESULTS
DS promotes I in T-tubular nanodomains, but not in other subcellular regions. Consistent with increased Na activity in these regions, super-resolution microscopy revealed increased Na 1.6 density near Carelease channels, the ryanodine receptors (RyR2) and NCX in DS relative to WT hearts. The resulting I in these regions promoted aberrant Ca release, leading to ventricular arrhythmias in vivo. Cardiac-specific deletion of Na 1.6 protects adult DS mice from increased T-tubular late Na activity and the resulting arrhythmias, as well as sudden death.
CONCLUSIONS
These data demonstrate that Na 1.6 undergoes remodeling within T-tubules of adult DS hearts serving as a substrate for Ca -mediated cardiac arrhythmias and may be a druggable target for the prevention of SUDEP in adult DS subjects.
Topics: Animals; Female; Humans; Male; Mice; Arrhythmias, Cardiac; Calcium; Epilepsies, Myoclonic; Mice, Knockout; Myocytes, Cardiac; NAV1.6 Voltage-Gated Sodium Channel; Sodium-Calcium Exchanger; Sudden Unexpected Death in Epilepsy
PubMed: 38430092
DOI: 10.1016/j.jacep.2024.01.003 -
Epilepsia Open Apr 2024Stiripentol, fenfluramine, and cannabidiol are licensed add-on therapies to treat seizures in Dravet Syndrome (DS). There are no direct or indirect comparisons assessing... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
Stiripentol, fenfluramine, and cannabidiol are licensed add-on therapies to treat seizures in Dravet Syndrome (DS). There are no direct or indirect comparisons assessing their full licensed dose regimens, across different jurisdictions, as first-line add-on therapies in DS.
METHODS
We conducted a systematic review and frequentist network meta-analysis (NMA) of randomized controlled trial (RCT) data for licensed add-on DS therapies. We compared the proportions of patients experiencing: reductions from baseline in monthly convulsive seizure frequency (MCSF) of ≥50% (clinically meaningful), ≥75% (profound), and 100% (seizure-free); serious adverse events (SAEs); discontinuations due to AEs.
RESULTS
We identified relevant data from two placebo-controlled RCTs for each drug. Stiripentol 50 mg/kg/day and fenfluramine 0.7 mg/kg/day had similar efficacy in achieving ≥50% (clinically meaningful) and ≥75% (profound) reductions from baseline in MCSF (absolute risk difference [RD] for stiripentol versus fenfluramine 1% [95% confidence interval: -20% to 22%; p = 0.93] and 6% [-15% to 27%; p = 0.59], respectively), and both were statistically superior (p < 0.05) to licensed dose regimens of cannabidiol (10 or 20 mg/kg/day, with/irrespective of clobazam) for these outcomes. Stiripentol was statistically superior in achieving seizure-free intervals compared to fenfluramine (RD = 26% [CI: 8% to 44%; p < 0.01]) and licensed dose regimens of cannabidiol. There were no significant differences in the proportions of patients experiencing SAEs. The risk of discontinuations due to AEs was lower for stiripentol, although the stiripentol trials were shorter.
SIGNIFICANCE
This NMA of RCT data indicates stiripentol, as a first-line add-on therapy in DS, is at least as effective as fenfluramine and both are more effective than cannabidiol in reducing convulsive seizures. No significant difference in the incidence of SAEs between the three add-on agents was observed, but stiripentol may have a lower risk of discontinuations due to AEs. These results may inform clinical decision-making and the continued development of guidelines for the treatment of people with DS.
PLAIN LANGUAGE SUMMARY
This study compared three drugs (stiripentol, fenfluramine, and cannabidiol) used alongside other medications for managing seizures in a severe type of epilepsy called DS. The study found that stiripentol and fenfluramine were similarly effective in reducing seizures and both were more effective than cannabidiol. Stiripentol was the best drug for stopping seizures completely based on the available clinical trial data. All three drugs had similar rates of serious side effects, but stiripentol had a lower chance of being stopped due to side effects. This information can help guide treatment choices for people with DS.
Topics: Humans; Cannabidiol; Anticonvulsants; Fenfluramine; Network Meta-Analysis; Seizures; Epilepsies, Myoclonic; Randomized Controlled Trials as Topic; Dioxolanes
PubMed: 38427284
DOI: 10.1002/epi4.12923 -
Brain Communications 2023Voltage-gated sodium channel β1 subunits are essential proteins that regulate excitability. They modulate sodium and potassium currents, function as cell adhesion...
Voltage-gated sodium channel β1 subunits are essential proteins that regulate excitability. They modulate sodium and potassium currents, function as cell adhesion molecules and regulate gene transcription following regulated intramembrane proteolysis. Biallelic pathogenic variants in , encoding β1, are linked to developmental and epileptic encephalopathy 52, with clinical features overlapping Dravet syndrome. A recessive variant, c.265C>T, predicting -p.R89C, was homozygous in two children of a non-consanguineous family. One child was diagnosed with Dravet syndrome, while the other had a milder phenotype. We identified an unrelated biallelic c.265C>T patient with a clinically more severe phenotype than Dravet syndrome. We used CRISPR/Cas9 to knock-in p.R89C to the mouse locus (). We then rederived the line on the C57BL/6J background to allow comparisons between and littermates with and mice, which are congenic on C57BL/6J, to determine whether the c.265C>T variant results in loss-of-function. mice have normal body weights and ∼20% premature mortality, compared with severely reduced body weight and 100% mortality in mice. β1-p.R89C polypeptides are expressed in brain at comparable levels to wild type. In heterologous cells, β1-p.R89C localizes to the plasma membrane and undergoes regulated intramembrane proteolysis similar to wild type. Heterologous expression of β1-p.R89C results in sodium channel α subunit subtype specific effects on sodium current. mRNA abundance of , , and was increased in somatosensory cortex, with no changes in . In contrast, mouse somatosensory cortex is haploinsufficient for , suggesting an additive mechanism for the severity of the null model via disrupted regulation of another Dravet syndrome gene. mice are more susceptible to hyperthermia-induced seizures at post-natal Day 15 compared with littermates. EEG recordings detected epileptic discharges in young adult mice that coincided with convulsive seizures and myoclonic jerks. We compared seizure frequency and duration in a subset of adult mice that had been exposed to hyperthermia at post-natal Day 15 versus a subset that were not hyperthermia exposed. No differences in spontaneous seizures were detected between groups. For both groups, the spontaneous seizure pattern was diurnal, occurring with higher frequency during the dark cycle. This work suggests that the c.265C>T variant does not result in complete loss-of-function. mice more accurately model -linked variants with incomplete loss-of-function compared with mice, which model complete loss-of-function, and thus add to our understanding of disease mechanisms as well as our ability to develop new therapeutic strategies.
PubMed: 38425576
DOI: 10.1093/braincomms/fcad283 -
Progressive Myoclonus Epilepsy: A Scoping Review of Diagnostic, Phenotypic and Therapeutic Advances.Genes Jan 2024The progressive myoclonus epilepsies (PME) are a diverse group of disorders that feature both myoclonus and seizures that worsen gradually over a variable timeframe.... (Review)
Review
The progressive myoclonus epilepsies (PME) are a diverse group of disorders that feature both myoclonus and seizures that worsen gradually over a variable timeframe. While each of the disorders is individually rare, they collectively make up a non-trivial portion of the complex epilepsy and myoclonus cases that are seen in tertiary care centers. The last decade has seen substantial progress in our understanding of the pathophysiology, diagnosis, prognosis, and, in select disorders, therapies of these diseases. In this scoping review, we examine English language publications from the past decade that address diagnostic, phenotypic, and therapeutic advances in all PMEs. We then highlight the major lessons that have been learned and point out avenues for future investigation that seem promising.
Topics: Humans; Myoclonus; Myoclonic Epilepsies, Progressive
PubMed: 38397161
DOI: 10.3390/genes15020171 -
Revue Neurologique Apr 2024In childhood absence epilepsy, pharmaco-resistance occurs in 20-30% of patients. In that situation, glucose transporter type 1 deficiency has to be ruled out, especially... (Review)
Review
In childhood absence epilepsy, pharmaco-resistance occurs in 20-30% of patients. In that situation, glucose transporter type 1 deficiency has to be ruled out, especially if absences started before the age of four years and if neurological signs are present. If ethosuximide, valproate and lamotrigine have failed in monotherapy or in association, there are currently no valuable therapeutic options. The same rules apply for epilepsy with myoclonic absences. Importantly, arguments supporting that making the patient seizure-free will improve eventual associated cognitive deficits such as attention deficit are very weak. Therefore, limiting the cognitive side effects of the anti-epileptic drugs has always to be a priority when faced with typical refractory absences in childhood. In epilepsy with eyelid myoclonia, the majority of patients are pharmaco-resistant. However, absence seizures, if present, tend to be very brief, and seizures are limited in many patients to eyelid myoclonia that eventually do not affect their quality of life and are well attenuated by wearing blue lenses. Atypical absences occurring in the course a developmental and/or epileptic encephalopathy are often pharmaco-resistant. In that situation, characterizing the type of epilepsy syndrome and searching for a specific genetic or structural etiology are needed to offer the best therapeutic options to the patient.
Topics: Humans; Epilepsy, Absence; Child; Anticonvulsants; Drug Resistant Epilepsy; Child, Preschool; Seizures
PubMed: 38388226
DOI: 10.1016/j.neurol.2024.01.002 -
Cell Reports. Medicine Feb 2024Progressive myoclonus epilepsy type 7, a debilitating neurological disorder, is caused by a loss-of-function mutation in the K3.1 channel. Exciting work by Feng et al....
Progressive myoclonus epilepsy type 7, a debilitating neurological disorder, is caused by a loss-of-function mutation in the K3.1 channel. Exciting work by Feng et al. utilizes a new knockin mouse model to identify a potential therapeutic intervention.
Topics: Animals; Mice; Myoclonic Epilepsies, Progressive; Mutation
PubMed: 38382469
DOI: 10.1016/j.xcrm.2024.101425