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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 -
Annals of Clinical and Translational... Aug 2023Infection-triggered encephalopathy syndromes (ITES) are potentially devastating neuroinflammatory conditions. Although some ITES syndromes have recognisable MRI...
OBJECTIVE
Infection-triggered encephalopathy syndromes (ITES) are potentially devastating neuroinflammatory conditions. Although some ITES syndromes have recognisable MRI neuroimaging phenotypes, there are otherwise few biomarkers of disease. Early detection to enable immune modulatory treatments could improve outcomes.
METHODS
We measured CSF neopterin, quinolinic acid, kynurenine and kynurenine/tryptophan ratio using a liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) system. The CSF of 18 children with ITES were compared with acute encephalitis (n = 20), and three control groups, namely epilepsy (n = 20), status epilepticus (n = 18) and neurogenetic controls (n = 20).
RESULTS
The main ITES phenotypes in 18 patients were acute encephalopathy with biphasic seizures and late restricted diffusion (AESD, n = 4), febrile infection-related epilepsy syndrome (FIRES n = 4) and other ITES phenotypes. Influenza A was the most common infectious trigger (n = 5), and 50% of patients had a preceding notable neurodevelopmental or family history. CSF neopterin, quinolinic acid and kynurenine were elevated in ITES group compared to the three control groups (all p < 0.0002). The ROC (area under curve) for CSF neopterin (99.3%, CI 98.1-100) was significantly better than CSF pleocytosis (87.3% CI 76.4-98.2) (p = 0.028). Elevated CSF neopterin could discriminate ITES from other causes of seizures, status epilepticus and febrile status epilepticus (all p < 0.0002). The elevated CSF metabolites normalised during longitudinal testing in two patients with FIRES.
INTERPRETATION
CSF neopterin and quinolinic acid are neuroinflammatory and excitotoxic metabolites. This CSF metabolomic inflammatory panel can discriminate ITES from other causes of new onset seizures or status epilepticus, and rapid results (4 h) may facilitate early immune modulatory therapy.
Topics: Humans; Neopterin; Quinolinic Acid; Kynurenine; Syndrome; Neuroinflammatory Diseases; Chromatography, Liquid; Tandem Mass Spectrometry; Brain Diseases; Seizures; Status Epilepticus; Encephalitis; Biomarkers
PubMed: 37340737
DOI: 10.1002/acn3.51832 -
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 -
Epilepsia Open Dec 2023Wearable seizure detection devices have the potential to address unmet needs of people with epilepsy. A recently published evidence-based international guideline...
Wearable seizure detection devices have the potential to address unmet needs of people with epilepsy. A recently published evidence-based international guideline recommends using such devices for safety indications in patients with tonic-clonic seizures (TCS). Our objective was to map existing guidelines and clinical practices at national level. We conducted a survey of the International League Against Epilepsy (ILAE) chapters regarding national recommendations and practical circumstances for prescribing seizure detection devices, and another survey of physicians in the ILAE constituency anywhere in the world, concerning their views and practices regarding recommendations for and prescription of such devices. Fifty-eight ILAE chapters (response rate 48%) and 157 physicians completed the surveys. More than two-thirds of responding countries do not have standards on wearables for seizure detection, although they indicated availability of such devices. The most often recognized indications were safety and objective seizure quantification. In nearly half of countries, devices are purchased by patients or caregivers, and either lack a uniform reimbursement scheme (41%) or patients pay the full cost for the device (48%). Tonic-clonic seizure frequency, nocturnal seizures, and previous injuries were the main factors that influenced the surveyed physicians to recommend wearable seizure detection devices. Our results document the need to implement international clinical practice guidelines at national level and to consider these when deciding upon reimbursement of seizure detection devices.
Topics: Humans; Sudden Unexpected Death in Epilepsy; Seizures; Surveys and Questionnaires; Wearable Electronic Devices; Epilepsy, Reflex
PubMed: 37567865
DOI: 10.1002/epi4.12801 -
Paediatric Drugs Jan 2024Epilepsy is a common pediatric neurological condition, affecting approximately 470,000 children in the USA and having a prevalence of 0.9% in the global population of... (Review)
Review
Practical Questions About Rescue Medications for Acute Treatment of Seizure Clusters in Children and Adolescents with Epilepsy in the USA: Expanding Treatment Options to Address Unmet Needs.
Epilepsy is a common pediatric neurological condition, affecting approximately 470,000 children in the USA and having a prevalence of 0.9% in the global population of approximately 2.6 billion children. Epilepsy is associated with disruptions in several areas of a child's life, including medical burden, quality of life, cognitive outcomes, and higher risk of mortality. Additionally, some pediatric patients may experience acute seizure emergencies such as seizure clusters (also called acute repetitive seizures), which are intermittent increases in seizure activity that differ from the patient's usual seizure pattern and may occur despite daily antiseizure drug administration. Seizure clusters increase a patient's risk for status epilepticus and emergency room visits. Benzodiazepines are the main category of drugs used as acute seizure therapies for seizure clusters. This narrative review provides a practical discussion of care for pediatric patients with epilepsy and seizure clusters exploring such topics as details about the US Food and Drug Administration-approved acute seizure therapies, safety and ease of use of these medications, benefits of seizure action plans to help ensure optimal treatment, and considerations for transitioning a pediatric patient with acute seizure therapy to adult healthcare management.
Topics: Adult; Humans; Adolescent; Child; Anticonvulsants; Quality of Life; Seizures; Epilepsy; Status Epilepticus
PubMed: 37902940
DOI: 10.1007/s40272-023-00601-x -
Clinical Neurophysiology : Official... Dec 2023Epilepsy surgery requires localization of the seizure onset zone (SOZ). Today this can only be achieved by intracranial electroencephalography (iEEG). The iEEG electrode...
OBJECTIVE
Epilepsy surgery requires localization of the seizure onset zone (SOZ). Today this can only be achieved by intracranial electroencephalography (iEEG). The iEEG electrode placement is guided by findings from non-invasive modalities that cannot themselves detect SOZ-generated initial seizure activity. On scalp magnetoencephalography (osMEG), with sensors placed on the scalp, demonstrates higher sensitivity than conventional MEG (convMEG) and could potentially detect early seizure activity. Here, we modeled EEG, convMEG and osMEG to compare the modalities' ability to localize SOZ activity and to detect epileptic spikes.
METHODS
We modeled seizure propagation within ten epileptic networks located in the mesial and lateral temporal lobe; basal, dorsal, central and frontopolar frontal lobe; parietal and occipital lobe as well as insula and cingulum. The networks included brain regions often involved in focal epilepsy. 128-channel osMEG, convMEG, EEG and combined osMEG + EEG and convMEG + EEG were modeled, and the SOZ source estimation accuracy was quantified and compared using Student's t-test.
RESULTS
OsMEG was significantly (p-value <0.01) better than both convMEG and EEG at detecting the earliest SOZ-generated seizure activity and epileptic spikes, and better at localizing seizure activity from all epileptic networks (p < 0.01).
CONCLUSIONS
Our modeling results clearly show that osMEG has an unsurpassed potential to detect both epileptic spikes and seizure activity from all simulated anatomical sites.
SIGNIFICANCE
No clinically available non-invasive technique can detect SOZ activity from all brain regions. Our study indicates that osMEG has the potential to become an important clinical tool, improving both non-invasive SOZ localization and iEEG electrode placement accuracy.
Topics: Humans; Magnetoencephalography; Scalp; Epilepsy; Seizures; Brain; Electroencephalography
PubMed: 37951041
DOI: 10.1016/j.clinph.2023.10.006 -
Epilepsia Open Feb 2024Apart from seizure freedom, the presence of comorbidities related to neurological, cardiovascular, or psychiatric disorders is the largest determinant of a reduced... (Review)
Review
Apart from seizure freedom, the presence of comorbidities related to neurological, cardiovascular, or psychiatric disorders is the largest determinant of a reduced health-related quality of life in people with epilepsy (PwE). However, comorbidities are often underrecognized and undertreated, and clinical management of comorbid conditions can be challenging. The focus of a comprehensive treatment regimen should maximize seizure control while optimizing clinical management of treatable comorbidities to improve a person's quality of life and overall health. A panel of four European epileptologists with expertise in their respective fields of epilepsy-related comorbidities combined the latest available scientific evidence with clinical expertise and collaborated to provide consensus practical advice to improve the identification and management of comorbidities in PwE. This review provides a critical evaluation for the diagnosis and management of sleep-wake disorders, cardiovascular diseases, cognitive dysfunction, and depression in PwE. Whenever possible, clinical data have been provided. The PubMed database was the main search source for the literature review. The deleterious pathophysiological processes underlying neurological, cardiovascular, or psychiatric comorbidities in PwE interact with the processes responsible for generating seizures to increase cerebral and physiological dysfunction. This can increase the likelihood of developing drug-resistant epilepsy; therefore, early identification of comorbidities and intervention is imperative. The practical evidence-based advice presented in this article may help clinical neurologists and other specialist physicians responsible for the care and management of PwE.
Topics: Humans; Quality of Life; Expert Testimony; Epilepsy; Comorbidity; Seizures
PubMed: 37876310
DOI: 10.1002/epi4.12851 -
Epilepsia Open Apr 2024Alcohol-related seizures (ARS) are one of the most important consequences of alcohol withdrawal syndrome (AWS). However, demographic and clinical characteristics, and...
OBJECTIVE
Alcohol-related seizures (ARS) are one of the most important consequences of alcohol withdrawal syndrome (AWS). However, demographic and clinical characteristics, and furthermore, the relationship of ARS with delirium tremens (DT), have not yet been evaluated in detail. Therefore, the aim of the present study was to reveal the correlates of ARS and examine the interaction of ARS with the occurrence of DT and with the severity of AWS.
METHODS
In the retrospective study (Study 1) 2851 medical charts of inpatient admissions characterized by AWS and DT were listed. Demographic and clinical variables of ARS were assessed. In the follow-up study (Study 2), patients admitted with AWS without (N = 28) and with (N = 18) ARS were enrolled. Study 1 was performed between 2008 and 2023, and Study 2 was performed in 2019 in Hungary. To determine the severity of AWS, the Clinical Institute Withdrawal Assessment Scale for Alcohol, Revised (CIWA-Ar) was used. ARS is a provoked, occasional seizure; therefore, patients with epilepsy syndrome were excluded from the two studies. Statistical analyses were performed by the means of chi-square tests, multinomial logistic regressions, mixed ANOVA, and derivation.
RESULTS
The occurrence of DT, the history of ARS, and somatic co-morbidities were found to be risk factors for the appearance of ARS. ARS was proved to be a risk factor for the development of DT. In the follow-up study, there was no difference in the decrease of CIWA-Ar scores between the groups.
SIGNIFICANCE
Our present findings support the likelihood of kindling, which is one of the most important mechanisms underlying the development of ARS, but do not directly prove its presence. Additionally, our results revealed that the severity of AWS is not influenced by the presence of ARS.
PLAIN LANGUAGE SUMMARY
Provoked, occasional seizures during AWS are defined as ARS. In the present study, predictors and interactions of these seizures with DT-the most severe form of withdrawal-and with the severity of withdrawal were examined in retrospective and follow-up studies. The present study shows that a history of withdrawal seizures, the occurrence of DT, and somatic comorbidities are predictors of the development of seizures. Furthermore, our findings suggest that the presence of seizures does not influence the severity of withdrawal.
Topics: Humans; Substance Withdrawal Syndrome; Alcohol Withdrawal Seizures; Retrospective Studies; Alcoholism; Alcohol Withdrawal Delirium; Follow-Up Studies; Ethanol; Seizures
PubMed: 38279829
DOI: 10.1002/epi4.12906 -
Medical Archives (Sarajevo, Bosnia and... 2024Levetiracetam (LEV) is a broad spectrum second-generation antiepileptic drug (AED). (Observational Study)
Observational Study
BACKGROUND
Levetiracetam (LEV) is a broad spectrum second-generation antiepileptic drug (AED).
OBJECTIVE
The objective of the study was to investigate the efficacy and safety of levetiracetam for childhood epilepsies.
METHODS
This is single, tertiary centre observational, prospective study, that included paediatric patients who were treated with levetiracetam at Paediatric hospital University Clinical Centre Sarajevo, during the period of 15 years (2008-2022). Inclusion criteria were: paediatric patients age > 1 month, diagnosed with epilepsy according to International League Against Epilepsy. After the introduction of levetiracetam, each patient has been followed up at least 12 months. According to the outcome the patients were divided into 5 groups: seizure reduction >50%, seizure reduction <50%, complete seizure freedom, the same number of seizures and increased number of seizures. From these groups two intergroups have been formed: responders (seizure reduction >50% and complete seizure freedom) and non-responders (seizure reduction <50%, the same number of seizures and increased number of seizures).
RESULTS
The study enrolled 259 patients (141 female and 118 male), with mean age 7 years (3,0-12.0). Comorbidities were present at 129/259 (49.8%) patients. After 12 months of treatment, 25/259 (9.7%) patients had seizure reduction >50%, 30/259 (11.6%) patients had seizure reduction <50%, 154/259 (56.5%) patients had achieved seizure freedom, 31/259 (12%) patients had same number of seizures, while 19/259 (7.3%) patients had increased number of seizures. Seizure frequency between responders and non-responders, before treatment and after 12 months of treatment was statistically significant (p<0.001).
DISCUSSION
Non responders had the best outcome with ditherapy (30/79; 38%), while responders had the best outcome with monotherapy (161/180;89.4%).
CONCLUSION
Levetiracetam is efficient antiepileptic drug for different types of epilepsies in childhood, used as mono, di or polytherapy.
Topics: Child; Female; Humans; Male; Anticonvulsants; Epilepsy; Levetiracetam; Prospective Studies; Seizures; Treatment Outcome; Child, Preschool
PubMed: 38566869
DOI: 10.5455/medarh.2024.78.122-126 -
Neurobiology of Disease Oct 2023Acute organophosphate (OP) intoxication can trigger seizures that progress to status epilepticus (SE), and survivors often develop chronic morbidities, including...
Acute organophosphate (OP) intoxication can trigger seizures that progress to status epilepticus (SE), and survivors often develop chronic morbidities, including spontaneous recurrent seizures (SRS). The pathogenic mechanisms underlying OP-induced SRS are unknown, but increased BBB permeability is hypothesized to be involved. Previous studies reported BBB leakage following OP-induced SE, but key information regarding time and regional distribution of BBB impairment during the epileptogenic period is missing. To address this data gap, we characterized the spatiotemporal progression of BBB impairment during the first week post-exposure in a rat model of diisopropylfluorophosphate-induced SE, using MRI and albumin immunohistochemistry. Increased BBB permeability, which was detected at 6 h and persisted up to 7 d post-exposure, was most severe and persistent in the piriform cortex and amygdala, moderate but persistent in the thalamus, and less severe and transient in the hippocampus and somatosensory cortex. The extent of BBB leakage was positively correlated with behavioral seizure severity, with the strongest association identified in the piriform cortex and amygdala. These findings provide evidence of the duration, magnitude and spatial breakdown of the BBB during the epileptogenic period following OP-induced SE and support BBB regulation as a viable therapeutic target for preventing SRS following acute OP intoxication.
Topics: Rats; Animals; Blood-Brain Barrier; Rats, Sprague-Dawley; Organophosphates; Status Epilepticus; Seizures; Brain
PubMed: 37797902
DOI: 10.1016/j.nbd.2023.106316