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Journal of Veterinary Internal Medicine 2024Seizure emergencies (ie, status epilepticus [SE] and cluster seizures [CS]), are common challenging disorders with complex pathophysiology, rapidly progressive...
BACKGROUND
Seizure emergencies (ie, status epilepticus [SE] and cluster seizures [CS]), are common challenging disorders with complex pathophysiology, rapidly progressive drug-resistant and self-sustaining character, and high morbidity and mortality. Current treatment approaches are characterized by considerable variations, but official guidelines are lacking.
OBJECTIVES
To establish evidence-based guidelines and an agreement among board-certified specialists for the appropriate management of SE and CS in dogs and cats.
ANIMALS
None.
MATERIALS AND METHODS
A panel of 5 specialists was formed to assess and summarize evidence in the peer-reviewed literature with the aim to establish consensus clinical recommendations. Evidence from veterinary pharmacokinetic studies, basic research, and human medicine also was used to support the panel's recommendations, especially for the interventions where veterinary clinical evidence was lacking.
RESULTS
The majority of the evidence was on the first-line management (ie, benzodiazepines and their various administration routes) in both species. Overall, there was less evidence available on the management of emergency seizure disorders in cats in contrast to dogs. Most recommendations made by the panel were supported by a combination of a moderate level of veterinary clinical evidence and pharmacokinetic data as well as studies in humans and basic research studies.
CONCLUSIONS AND CLINICAL RELEVANCE
Successful management of seizure emergencies should include an early, rapid, and stage-based treatment approach consisting of interventions with moderate to preferably high ACVIM recommendations; management of complications and underlying causes related to seizure emergencies should accompany antiseizure medications.
Topics: Cats; Dogs; Animals; Humans; Emergencies; Cat Diseases; Dog Diseases; Status Epilepticus; Epilepsy; Anticonvulsants
PubMed: 37921621
DOI: 10.1111/jvim.16928 -
Drugs Jul 2023Fenfluramine (Fintepla) is an oral anti-seizure medication (ASM) with a novel mechanism of action consisting of activity in the serotonergic system coupled with positive... (Review)
Review
Fenfluramine (Fintepla) is an oral anti-seizure medication (ASM) with a novel mechanism of action consisting of activity in the serotonergic system coupled with positive allosteric modulation effects at sigma-1 receptors. Originally approved for use at high doses as an appetite suppressant, it was subsequently withdrawn after being linked to valvular heart disease (VHD) and pulmonary arterial hypertension (PAH), before being investigated for use at low doses as an adjunctive ASM in patients with developmental epileptic encephalopathies, including Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) who have pharmacoresistant seizures. In clinical trials, treatment with adjunctive fenfluramine markedly reduced convulsive seizure frequency in patients with DS that were sustained for up to 3 years, and reduced drop seizure frequency in patients with LGS that were sustained for up to 1 year. Notably, fenfluramine was also associated with clinically meaningful improvements in aspects of everyday executive functioning (EF) not entirely explainable by seizure reduction alone. Furthermore, it was generally well tolerated with, importantly, no reports of VHD or PAH. Thus, adjunctive fenfluramine is a novel and effective treatment for pharmacoresistant seizures associated with DS and LGS that may also improve aspects of everyday EF in some patients.
Topics: Humans; Lennox Gastaut Syndrome; Fenfluramine; Epilepsies, Myoclonic; Treatment Outcome; Seizures; Anticonvulsants
PubMed: 37316680
DOI: 10.1007/s40265-023-01881-w -
Cell Stem Cell Oct 2023Mesial temporal lobe epilepsy (MTLE) is the most common focal epilepsy. One-third of patients have drug-refractory seizures and are left with suboptimal therapeutic...
Mesial temporal lobe epilepsy (MTLE) is the most common focal epilepsy. One-third of patients have drug-refractory seizures and are left with suboptimal therapeutic options such as brain tissue-destructive surgery. Here, we report the development and characterization of a cell therapy alternative for drug-resistant MTLE, which is derived from a human embryonic stem cell line and comprises cryopreserved, post-mitotic, medial ganglionic eminence (MGE) pallial-type GABAergic interneurons. Single-dose intrahippocampal delivery of the interneurons in a mouse model of chronic MTLE resulted in consistent mesiotemporal seizure suppression, with most animals becoming seizure-free and surviving longer. The grafted interneurons dispersed locally, functionally integrated, persisted long term, and significantly reduced dentate granule cell dispersion, a pathological hallmark of MTLE. These disease-modifying effects were dose-dependent, with a broad therapeutic range. No adverse effects were observed. These findings support an ongoing phase 1/2 clinical trial (NCT05135091) for drug-resistant MTLE.
Topics: Mice; Animals; Humans; Hippocampus; Epilepsy, Temporal Lobe; Seizures; Interneurons; Brain
PubMed: 37802038
DOI: 10.1016/j.stem.2023.08.013 -
Medical Science Monitor : International... Jul 2023Eclampsia is the most serious pregnancy complication and one of the main causes of death of pregnant and delivering women. The mortality rate of young mothers is 5-20%,... (Review)
Review
Eclampsia is the most serious pregnancy complication and one of the main causes of death of pregnant and delivering women. The mortality rate of young mothers is 5-20%, emphasizing the severity of this pregnancy-related disorder. Today many centers have only rare opportunities to see and deal with eclampsia cases; therefore, it is very important to bring this emergency medical condition to the attention of attending physicians. All patients with eclampsia, and after eclamptic seizures, should be treated in an intensive care unit. However, taking into account clinical realities, especially in developing countries, this is not always possible. It is necessary for all gynecologists-obstetricians to be fully prepared for eclampsia, although its occurrence is very rare. Drug treatment aims to stop eclampsia seizures and prevent reoccurrence of convulsions and complications. Magnesium sulphate is the drug of first choice used in treatment of eclampsia seizure, whereas treatment with the use of antihypertensive drugs and proper blood pressure control is one of the most important factors effectively reducing the risk of deaths or acute complications and poor pregnancy outcomes. The most urgent part of the treatment is the lifesaving procedure involving airways patency assessment, maintenance of breathing and blood circulation of the mother, securing an adequate oxygen level of the mother and thereby of the fetus, and prevention of injuries. This review aims to present an overview of the current prevalence, diagnosis, and management of eclampsia and the need for improved maternal care.
Topics: Pregnancy; Female; Humans; Eclampsia; Magnesium Sulfate; Pregnancy Complications; Pregnancy Outcome; Seizures; Pre-Eclampsia
PubMed: 37415326
DOI: 10.12659/MSM.939919 -
Nature Communications Jun 2023Autism spectrum disorders (ASD) represent neurodevelopmental disorders characterized by social deficits, repetitive behaviors, and various comorbidities, including...
Autism spectrum disorders (ASD) represent neurodevelopmental disorders characterized by social deficits, repetitive behaviors, and various comorbidities, including epilepsy. ANK2, which encodes a neuronal scaffolding protein, is frequently mutated in ASD, but its in vivo functions and disease-related mechanisms are largely unknown. Here, we report that mice with Ank2 knockout restricted to cortical and hippocampal excitatory neurons (Ank2-cKO mice) show ASD-related behavioral abnormalities and juvenile seizure-related death. Ank2-cKO cortical neurons show abnormally increased excitability and firing rate. These changes accompanied decreases in the total level and function of the Kv7.2/KCNQ2 and Kv7.3/KCNQ3 potassium channels and the density of these channels in the enlengthened axon initial segment. Importantly, the Kv7 agonist, retigabine, rescued neuronal excitability, juvenile seizure-related death, and hyperactivity in Ank2-cKO mice. These results suggest that Ank2 regulates neuronal excitability by regulating the length of and Kv7 density in the AIS and that Kv7 channelopathy is involved in Ank2-related brain dysfunctions.
Topics: Animals; Mice; Epilepsy; KCNQ Potassium Channels; KCNQ2 Potassium Channel; KCNQ3 Potassium Channel; Neurons; Seizures
PubMed: 37321992
DOI: 10.1038/s41467-023-39203-z -
Brain : a Journal of Neurology Jul 2023Neuromodulation of the anterior nuclei of the thalamus (ANT) has shown to be efficacious in a subset of patients with refractory focal epilepsy. One important...
Neuromodulation of the anterior nuclei of the thalamus (ANT) has shown to be efficacious in a subset of patients with refractory focal epilepsy. One important uncertainty is to what extent thalamic subregions other than the ANT could be recruited more prominently in the propagation of focal onset seizures. We designed the current study to simultaneously monitor the engagement of the ANT, mediodorsal (MD) and pulvinar (PUL) nuclei during seizures in patients who could be candidates for thalamic neuromodulation. We studied 11 patients with clinical manifestations of presumed temporal lobe epilepsy (TLE) undergoing invasive stereo-encephalography (sEEG) monitoring to confirm the source of their seizures. We extended cortical electrodes to reach the ANT, MD and PUL nuclei of the thalamus. More than one thalamic subdivision was simultaneously interrogated in nine patients. We recorded seizures with implanted electrodes across various regions of the brain and documented seizure onset zones (SOZ) in each recorded seizure. We visually identified the first thalamic subregion to be involved in seizure propagation. Additionally, in eight patients, we applied repeated single pulse electrical stimulation in each SOZ and recorded the time and prominence of evoked responses across the implanted thalamic regions. Our approach for multisite thalamic sampling was safe and caused no adverse events. Intracranial EEG recordings confirmed SOZ in medial temporal lobe, insula, orbitofrontal and temporal neocortical sites, highlighting the importance of invasive monitoring for accurate localization of SOZs. In all patients, seizures with the same propagation network and originating from the same SOZ involved the same thalamic subregion, with a stereotyped thalamic EEG signature. Qualitative visual reviews of ictal EEGs were largely consistent with the quantitative analysis of the corticothalamic evoked potentials, and both documented that thalamic nuclei other than ANT could have the earliest participation in seizure propagation. Specifically, pulvinar nuclei were involved earlier and more prominently than ANT in more than half of the patients. However, which specific thalamic subregion first demonstrated ictal activity could not be reliably predicted based on clinical semiology or lobar localization of SOZs. Our findings document the feasibility and safety of bilateral multisite sampling from the human thalamus. This may allow more personalized thalamic targets to be identified for neuromodulation. Future studies are needed to determine if a personalized thalamic neuromodulation leads to greater improvements in clinical outcome.
Topics: Humans; Seizures; Brain; Epilepsy, Temporal Lobe; Electroencephalography; Drug Resistant Epilepsy; Anterior Thalamic Nuclei; Electrodes, Implanted
PubMed: 37137813
DOI: 10.1093/brain/awad121 -
Drugs Oct 2023Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy characterized by drug-resistant, lifelong seizures. The management of seizures in DS has... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy characterized by drug-resistant, lifelong seizures. The management of seizures in DS has changed in recent years with the approval of new antiseizure medications (ASMs).
OBJECTIVE
The aim of this study was to estimate the comparative efficacy and tolerability of the ASMs for the treatment of seizures associated with DS using a network meta-analysis (NMA).
METHODS
Studies were identified by conducting a systematic search (week 4, January 2023) of the MEDLINE (accessed by PubMed), EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and US National Institutes of Health Clinical Trials Registry ( http://www.
CLINICALTRIALS
gov ) databases. Any randomized, controlled, double- or single-blinded, parallel-group study comparing at least one ASM therapy against placebo, another ASM, or a different dose of the same ASM in participants with a diagnosis of DS was identified. The efficacy outcomes were the proportions of participants with ≥ 50% (seizure response) and 100% reduction (seizure freedom) in baseline convulsive seizure frequency during the maintenance period. The tolerability outcomes included the proportions of patients who withdrew from treatment for any reason and who experienced at least one adverse event (AE). Effect sizes were estimated by network meta-analyses within a frequentist framework.
RESULTS
Eight placebo-controlled trials were included, and the active add-on treatments were stiripentol (n = 2), pharmaceutical-grade cannabidiol (n = 3), fenfluramine hydrochloride (n = 2), and soticlestat (n = 1). The studies recruited 680 participants, of whom 409 were randomized to active treatments (stiripentol = 33, pharmaceutical-grade cannabidiol = 228, fenfluramine hydrochloride = 122, and soticlestat = 26) and 271 to placebo. Pharmaceutical-grade cannabidiol was associated with a lower rate of seizure response than fenfluramine hydrochloride (odds ratio [OR] 0.20, 95% confidence interval [CI] 0.07-0.54), and stiripentol was associated with a higher seizure response rate than pharmaceutical-grade cannabidiol (OR 14.07, 95% CI 2.57-76.87). No statistically significant differences emerged across the different ASMs for the seizure freedom outcome. Stiripentol was associated with a lower probability of drug discontinuation for any reason than pharmaceutical-grade cannabidiol (OR 0.45, 95% CI 0.04-5.69), and pharmaceutical-grade cannabidiol was associated with a lower proportion of participants experiencing any AE than fenfluramine hydrochloride (OR 0.22, 95% CI 0.06-0.78). Stiripentol had a higher risk of AE occurrence than pharmaceutical-grade cannabidiol (OR 75.72, 95% CI 3.59-1598.58). The study found high-quality evidence of efficacy and tolerability of the four ASMs in the treatment of convulsive seizures in DS.
CONCLUSIONS
There exists first-class evidence that documents the efficacy and tolerability of stiripentol, pharmaceutical-grade cannabidiol, fenfluramine hydrochloride, and soticlestat for the treatment of seizures associated with DS, and allows discussion about the expected outcomes regarding seizure frequency reduction and tolerability profiles.
Topics: Humans; Anticonvulsants; Cannabidiol; Network Meta-Analysis; Randomized Controlled Trials as Topic; Seizures; Epilepsies, Myoclonic; Fenfluramine; Pharmaceutical Preparations
PubMed: 37695433
DOI: 10.1007/s40265-023-01936-y -
Epilepsia Open Sep 2023This study investigated early, real-world outcomes with cenobamate (CNB) in a large series of patients with highly drug-resistant epilepsy within a Spanish Expanded... (Observational Study)
Observational Study
OBJECTIVE
This study investigated early, real-world outcomes with cenobamate (CNB) in a large series of patients with highly drug-resistant epilepsy within a Spanish Expanded Access Program (EAP).
METHOD
This was a multicenter, retrospective, observational study in 14 hospitals. Inclusion criteria were age ≥18 years, focal seizures, and EAP authorization. Data were sourced from patient clinical records. Primary effectiveness endpoints included reductions (100%, ≥90%, ≥75%, and ≥50%) or worsening in seizure frequency at 3-, 6-, and 12-month visits and at the last visit. Safety endpoints included rates of adverse events (AEs) and AEs leading to discontinuation.
RESULTS
The study included 170 patients. At baseline, median epilepsy duration was 26 years and median number of seizures/month was 11.3. The median number of prior antiseizure medications (ASMs) and concomitant ASMs were 12 and 3, respectively. Mean CNB dosages/day were 176 mg, 200 mg, and 250 mg at 3, 6, and 12 months. Retention rates were 98.2%, 94.5%, and 87% at 3, 6, and 12 months. At last available visit, the rate of seizure freedom was 13.3%; ≥90%, ≥75%, and ≥50% responder rates were 27.9%, 45.5%, and 63%, respectively. There was a significant reduction in the number of seizures per month (mean: 44.6%; median: 66.7%) between baseline and the last visit (P < 0.001). Responses were maintained regardless of the number of prior or concomitant ASMs. The number of concomitant ASMs was reduced in 44.7% of patients. The cumulative percentage of patients with AEs and AEs leading to discontinuation were 68.2% and 3.5% at 3 months, 74.1% and 4.1% at 6 months, and 74.1% and 4.1% at 12 months. The most frequent AEs were somnolence and dizziness.
SIGNIFICANCE
In this highly refractory population, CNB showed a high response regardless of prior and concomitant ASMs. AEs were frequent but mostly mild-to-moderate, and few led to discontinuation.
Topics: Humans; Adolescent; Anticonvulsants; Retrospective Studies; Treatment Outcome; Seizures; Epilepsy
PubMed: 37149853
DOI: 10.1002/epi4.12757 -
Seizure Dec 2023The typical adult patient presenting with a first seizure has a normal clinical examination, uninformative investigations, and often has no witness to their episode. The... (Review)
Review
The typical adult patient presenting with a first seizure has a normal clinical examination, uninformative investigations, and often has no witness to their episode. The assessing clinician, therefore, has one primary source of information to guide their assessment; the patient's experience. However, seizure phenomenology - the subjective seizure experience - has received relatively less attention by researchers than objective semiology or investigations. This essay reviews the clinical importance of seizure phenomenology, and the challenges clinicians face in eliciting accurate and clinically relevant descriptions of ictal experience. I conclude by discussing tools that clinicians may use to support the clinical application of seizure phenomenology, and exploring the subjectivity of epilepsy more broadly.
Topics: Adult; Humans; Electroencephalography; Seizures; Epilepsy; Physical Examination
PubMed: 37976801
DOI: 10.1016/j.seizure.2023.11.008 -
Journal of Neuroinflammation Jul 2023Impaired activation and regulation of the extinction of inflammatory cells and molecules in injured neuronal tissues are key factors in the development of epilepsy....
Impaired activation and regulation of the extinction of inflammatory cells and molecules in injured neuronal tissues are key factors in the development of epilepsy. SerpinA3N is mainly associated with the acute phase response and inflammatory response. In our current study, transcriptomics analysis, proteomics analysis, and Western blotting showed that the expression level of Serpin clade A member 3N (SerpinA3N) is significantly increased in the hippocampus of mice with kainic acid (KA)-induced temporal lobe epilepsy, and this molecule is mainly expressed in astrocytes. Notably, in vivo studies using gain- and loss-of-function approaches revealed that SerpinA3N in astrocytes promoted the release of proinflammatory factors and aggravated seizures. Mechanistically, RNA sequencing and Western blotting showed that SerpinA3N promoted KA-induced neuroinflammation by activating the NF-κB signaling pathway. In addition, co-immunoprecipitation revealed that SerpinA3N interacts with ryanodine receptor type 2 (RYR2) and promotes RYR2 phosphorylation. Overall, our study reveals a novel SerpinA3N-mediated mechanism in seizure-induced neuroinflammation and provides a new target for developing neuroinflammation-based strategies to reduce seizure-induced brain injury.
Topics: Animals; Mice; Astrocytes; Epilepsy, Temporal Lobe; Hippocampus; Kainic Acid; Neuroinflammatory Diseases; NF-kappa B; Ryanodine Receptor Calcium Release Channel; Seizures; Signal Transduction; Serpins
PubMed: 37422673
DOI: 10.1186/s12974-023-02840-8