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Journal of Clinical and Experimental... Dec 2023Metacognition provides a lens through which individuals experience, interpret, and respond to their affective states and behavior; it might thus influence complex...
INTRODUCTION
Metacognition provides a lens through which individuals experience, interpret, and respond to their affective states and behavior; it might thus influence complex neuropsychiatric conditions such as functional seizures - events characterized by states of heightened affective arousal and the disinhibition of prepotent behavior. In this pilot study, we aimed to establish a better understanding of the role of metacognition in functional seizures and its relationship to affective arousal and behavioral disinhibition (i.e., problems in suppressing prepared behavior). We hypothesized that affective arousal is related to higher behavioral disinhibition as well as slower reaction times, that affect and action (performing vs. not performing a movement) are related to memory and metacognition, and that metacognition is related to illness characteristics.
METHODS
We used a combination of an emotional go/no-go and a metacognitive recognition task with affectively valenced and neutral images in 18 patients with functional seizures. We compared markers of behavioral inhibition as well as indices for memory and metacognitive performance between affective (vs. neutral) and action/go (vs. inhibition/no-go) conditions.
RESULTS
Contrary to our hypothesis, behavioral disinhibition was not different between conditions. However, we found slower reaction times for affectively valenced stimuli. Memory performance and metacognition were better for affectively valenced pictures and for pictures used in go trials (i.e., associated with action/performing the movement). Illness factors (illness duration, seizure frequency, levels of self-reported anxiety) were correlated with aspects of metacognition.
CONCLUSIONS
This pilot study offers first insights into alterations in metacognition related to action and affect in patients with functional seizures; specifically, that affectively valenced stimuli and active engagement are related to enhanced memory and metacognition. This relationship was also found with respect to illness factors. These results provide insight into potentially underlying pathomechanisms, although the lack of a control group limits evaluating the specificity of these findings.
Topics: Humans; Male; Female; Adult; Seizures; Metacognition; Reaction Time; Middle Aged; Pilot Projects; Inhibition, Psychological; Affect; Neuropsychological Tests; Young Adult
PubMed: 38007609
DOI: 10.1080/13803395.2023.2287778 -
British Journal of Hospital Medicine... Oct 2023The National Confidential Enquiry into Patient Outcome and Death reviewed the quality of care provided to adults who presented to hospital following an epileptic...
The National Confidential Enquiry into Patient Outcome and Death reviewed the quality of care provided to adults who presented to hospital following an epileptic seizure. Clinical and organisational changes are highlighted that aim to improve patient care and outcomes.
Topics: Adult; Humans; Epilepsy; Hospitals; Seizures
PubMed: 37906066
DOI: 10.12968/hmed.2023.0283 -
Epilepsy Research Sep 2023Cenobamate was approved by the US Food and Drug Administration (FDA) based on studies of adjunctive therapy in patients with focal epilepsy. To support the use of...
OBJECTIVE
Cenobamate was approved by the US Food and Drug Administration (FDA) based on studies of adjunctive therapy in patients with focal epilepsy. To support the use of cenobamate monotherapy, this pharmacokinetic (PK)-based simulation analysis evaluated the predicted PK exposure of cenobamate when used as monotherapy versus adjunctive therapy.
METHODS
A population pharmacokinetic (PopPK) model of cenobamate was developed using pooled human data from eight phase 1 studies in healthy subjects or special populations, and three phase 2 and 3 studies in patients with focal seizures (N = 960). Concomitant antiseizure medications (ASMs) with a statistically significant effect on the apparent systemic clearance (CL/F) of cenobamate in the PopPK model were used to compare simulated patient plasma exposures (area under the plasma concentration vs time curve [AUC]) following monotherapy versus adjunctive therapy. Treatment equivalence between monotherapy and adjunctive therapy was concluded if the 90% confidence interval (CI) of the geometric mean AUC ratio was within 0.8-1.25.
RESULTS
In the PopPK model, statistically significant effects on cenobamate CL/F were shown for clobazam (decreased cenobamate CL/F by 19%) and carbamazepine (increased cenobamate CL/F by 15%); these differences were not considered clinically meaningful. Other ASMs (lacosamide, lamotrigine, levetiracetam, oxcarbazepine, topiramate, and valproate) when coadministered with cenobamate did not have significant effects on the disposition (ie, PK or efficacy) of cenobamate. The geometric mean ratio (90% CIs) of cenobamate AUC for adjunctive therapy/monotherapy was 0.87 (0.816-0.925) for adjunctive carbamazepine and 1.24 (1.147-1.339) for adjunctive clobazam. The 90% CI was within the no-effect limits (90% CIs 0.8-1.25) for adjunctive carbamazepine and partially exceeding no-effect limits for adjunctive clobazam.
CONCLUSIONS
Based on the results from this PopPK analysis, cenobamate monotherapy can be expected to result in comparable exposures to those that have been demonstrated to be safe and effective when used as adjunctive therapy for the treatment of focal seizures, supporting the use of cenobamate as monotherapy in these patients.
Topics: Humans; Clobazam; Anticonvulsants; Seizures; Carbamazepine; Benzodiazepines
PubMed: 37429218
DOI: 10.1016/j.eplepsyres.2023.107185 -
Journal of the American Veterinary... Aug 2023
Topics: Cats; Animals; Seizures; Cat Diseases
PubMed: 36933208
DOI: 10.2460/javma.23.01.0015 -
BMC Veterinary Research Sep 2023Idiopathic epilepsy (IE) is a common, chronic brain dysfunction in dogs. Recently, the effect of feeding a diet enriched with medium-chain triglycerides (MCTs) on...
Efficacy evaluation of a commercially available MCT enriched therapeutic diet on dogs with idiopathic epilepsy treated with zonisamide: a prospective, randomized, double-blinded, placebo-controlled, crossover dietary preliminary study.
BACKGROUND
Idiopathic epilepsy (IE) is a common, chronic brain dysfunction in dogs. Recently, the effect of feeding a diet enriched with medium-chain triglycerides (MCTs) on seizure frequency has been evaluated in several studies in dogs with IE. However, most dogs with IE in previous studies were treated with phenobarbital as the main antiseizure medication (ASM). In Japan, zonisamide (ZNS) is the most prescribed ASM for dogs with IE. The interaction between ZNS and various nutrients including MCTs and the potential effects on treatment efficacy resulting from combining these therapies have not been previously studied. A prospective, randomized, double-blinded, placebo-controlled, crossover dietary study was conducted. Dogs (n = 7) treated with ZNS were fed either a placebo diet (PL) or Purina ProPlan Veterinary Diet NeuroCare (NC) for 3 months, after which treatments were crossed over and continued for another 3 months. Seizure frequency (seizures/month; sz/m), blood tests including concentrations of ZNS and β-hydroxybutyric acid, and owner's visual analogue scale score were collected from all dogs for both treatment periods.
RESULTS
There was no significant difference in the seizure frequency between PL (2.95 ± 0.80 sz/m) and NC (1.90 ± 0.57 sz/m) during the 6 months of trial. Three of 7 dogs showed ≥ 50% seizure reduction, and 1 of those 3 dogs achieved seizure freedom in NC period. However, 2 of 7 dogs had no changes in epileptic seizure frequency, 2 of 7 dogs had a deterioration in seizure frequency in the NC period. Feeding the MCT diet concurrent with ZNS showed no apparent adverse effects and did not affect ZNS concentration.
CONCLUSIONS
This study indicated that the commercially available MCT-enriched diet (NC) can be safely used concurrently with ZNS for dogs with IE.
Topics: Dogs; Animals; Zonisamide; Prospective Studies; Epilepsy; Seizures; Diet; Triglycerides; Dog Diseases
PubMed: 37674206
DOI: 10.1186/s12917-023-03710-4 -
Epilepsy & Behavior : E&B Oct 2023Seizure clustering, is the most frequently reported adverse event in epilepsy monitoring unit (EMU) safety studies which, can also potentiate other adverse events, such...
INTRODUCTION
Seizure clustering, is the most frequently reported adverse event in epilepsy monitoring unit (EMU) safety studies which, can also potentiate other adverse events, such as falls, status epilepticus, and increased length of stay. The purpose of this study is to determine variables associated with increased risk of seizure clustering among patients admitted to the EMU.
METHODS
A retrospective review of patients admitted to the EMU over a two-year period was completed. Data collected included patient demographics, types of epilepsy, seizure frequency, anti-seizure medications (ASMs) and hospital and EMU course including incidence of seizure clustering.
RESULTS
Two hundred seven patients were included in our study; of these, ninety patients experienced two or more seizures in a 24-hour period (24SC), and 68 patients experienced two or more seizures in a 4-hour period (4SC). Logistic regression analysis associated the absence of long-acting ASM with increased clustering within the 4SC group (p = 0.038). For every additional ASM taken by a patient at home, the odds of seizure clustering increased by 81% in the 4SC group (p = 0.009) and by 61% in the 24SC group (p = 0.022). In addition, patients with a diagnosis of temporal lobe epilepsy had some association with clustering in the 24SC group (p = 0.061).
CONCLUSION
Our data showed that long-acting ASMs can be protective against seizure clustering. Furthermore, patients with temporal lobe epilepsy, and those on increased numbers of ASMs, were more likely to experience seizure clustering when undergoing medication withdrawal during an EMU evaluation.
Topics: Humans; Epilepsy, Temporal Lobe; Electroencephalography; Epilepsy; Status Epilepticus; Retrospective Studies; Cluster Analysis
PubMed: 37717459
DOI: 10.1016/j.yebeh.2023.109433 -
Neurobiology of Disease Aug 2023Low-voltage-activated or T-type Ca channels play a key role in the generation of seizures in absence epilepsy. We have described a homozygous, gain of function...
RATIONALE
Low-voltage-activated or T-type Ca channels play a key role in the generation of seizures in absence epilepsy. We have described a homozygous, gain of function substitution mutation (R1584P) in the Ca3.2 T-type Ca channel gene (Cacna1h) in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS). The non-epileptic control (NEC) rats, derived from the same original Wistar strains as GAERS but selectively in-breed not to express seizures, are null for the R1584P mutation. To study the effects of this mutation in rats who otherwise have a GAERS or NEC genetic background, we bred congenic GAERS-Cacna1hNEC (GAERS null for R1584P mutation) and congenic NEC-Cacna1hGAERS (NEC homozygous for R1584P mutation) and evaluated the seizure and behavioral phenotype of these strains in comparison to the original GAERS and NEC strains.
METHODS
To evaluate seizure expression in the congenic strains, EEG electrodes were implanted in NEC, GAERS, GAERS without the R1584P mutation, and NEC with the R1584P mutation rats. In the first study, continuous EEG recordings were acquired from week 4 (when seizures begin to develop in GAERS) to week 14 of age (when GAERS display hundreds of seizures per day). In the second study, the seizure and behavioral phenotype of GAERS and NEC strains were evaluated during young age (6 weeks of age) and adulthood (16 weeks of age) of GAERS, NEC, GAERS and NEC. The Open field test (OFT) and sucrose preference test (SPT) were performed to evaluate anxiety-like and depressive-like behavior, respectively. This was followed by EEG recordings at 18 weeks of age to quantify the seizures, and spike-wave discharge (SWD) cycle frequency. At the end of the study, the whole thalamus was collected for T-type calcium channel mRNA expression analysis.
RESULTS
GAERS had a significantly shorter latency to first seizures and an increased number of seizures per day compared to GAERS. On the other hand, the presence of the R1584P mutation in the NEC was not enough to generate spontaneous seizures in their seizure-resistant background. 6 and 16-week-old GAERS and GAERS rats showed anxiety-like behavior in the OFT, in contrast to NEC and NEC. Results from the SPT showed that the GAERS developed depressive-like in the SPT compared to GAERS, NEC, and NEC. Analysis of the EEG at 18 weeks of age showed that the GAERS had an increased number of seizures per day, increased total seizure duration and a higher cycle frequency of SWD relative to GAERS. However, the average seizure duration was not significantly different between strains. Quantitative real-time PCR showed that the T-type Ca channel isoform Ca3.2 channel expression was significantly increased in GAERS compared to NEC, GAERS and NEC. The presence of the R1584P mutation increased the total ratio of Ca3.2 + 25/-25 splice variants in GAERS and NEC compared to NEC and GAERS.
DISCUSSION
The data from this study demonstrate that the R1584P mutation in isolation on a seizure-resistant NEC genetic background was insufficient to generate absence seizures, and that a GAERS genetic background can cause seizures even without the mutation. However, the study provides evidence that the R1584P mutation acts as a modulator of seizures development and expression, and depressive-like behavior in the SPT, but not the anxiety phenotype of the GAERS model of absence epilepsy.
Topics: Animals; Rats; Calcium Channels, T-Type; Disease Models, Animal; Electroencephalography; Epilepsy, Absence; Mutation; Rats, Wistar; Seizures
PubMed: 37391087
DOI: 10.1016/j.nbd.2023.106217 -
Archives of Disease in Childhood. Fetal... Nov 2023
Topics: Infant, Newborn; Humans; Seizures; Infant, Newborn, Diseases; Neonatology
PubMed: 37527943
DOI: 10.1136/archdischild-2023-325324 -
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 -
Respiratory Physiology & Neurobiology May 2024This study investigated the respiratory activity in adult Wistar rats across different behavioral seizure severity induced by pentylenetetrazole (PTZ). Animals underwent...
This study investigated the respiratory activity in adult Wistar rats across different behavioral seizure severity induced by pentylenetetrazole (PTZ). Animals underwent surgery for electrodes implantation, allowing simultaneous EEG and diaphragm EMG (DIA) recordings and the respiratory frequency and DIA amplitude were measured. Seizures were acutely induced through PTZ injection and classified based on a pre-established score, with absence-like seizures (spike wave discharge (SWD) events on EEG) representing the lowest score. The respiratory activity was grouped into the different seizure severities. During absence-like and myoclonic jerk seizures, the breathing frequency decreased significantly (∼50% decrease) compared to pre- and post-ictal periods. Pronounced changes occurred with more severe seizures (clonic and tonic) with periods of apnea, especially during tonic seizures. Apnea duration was significantly higher in tonic compared to clonic seizures. Notably, during PTZ-induced tonic seizures the apnea events were marked by tonic DIA contraction (tonic-phase apnea). In the majority of animals (5 out of 7) this was a fatal event in which the seizure-induced respiratory arrest preceded the asystole. In conclusion, we provide an assessment of the respiratory activity in the PTZ-induced acute seizures and showed that breathing dysfunction is more pronounced in seizures with higher severity.
Topics: Rats; Animals; Pentylenetetrazole; Apnea; Rats, Wistar; Seizures; Respiratory Rate
PubMed: 38307440
DOI: 10.1016/j.resp.2024.104229