Mechanisms of neurodevelopmental toxicity of topiramate.

Prescriptions for antiseizure medications (ASMs) have been rapidly growing over the last several decades due, in part, to an expanding list of clinical indications for which they are now prescribed. This trend has raised concern for potential adverse neurodevelopmental outcomes in ASM-exposed pregnancies. Recent large scale population studies have suggested that the use of topiramate (TOPAMAX, Janssen-Cilag), when prescribed for seizure control, migraines, and/or weight management, is associated with an increased risk for autism spectrum disorder (ASD), intellectual disability, and attention-deficit/hyperactivity disorder (ADHD) in exposed offspring. Here, we critically review epidemiologic evidence demonstrating the neurobehavioral teratogenicity of topiramate and speculate on the neuromolecular mechanisms by which prenatal exposure may perturb neurocognitive development. Specifically, we explore the potential role of topiramate's pharmacological interactions with ligand- and voltage-gated ion channels, especially GABAergic signaling, its effects on DNA methylation and histone acetylation, whether topiramate induces oxidative stress, and its association with fetal growth restriction as possible mechanisms contributing to neurodevelopmental toxicity. Resolving this biology will be necessary to reduce the risk of adverse pregnancy outcomes caused by topiramate or other ASMs.

Benzodiazepines for pediatric epilepsies and their risks in a cohort within the French health care data.

OBJECTIVE: The management of antiseizure treatment in patients with epilepsy relies on the benefit-risk ratio. Data on antiseizure medication (ASM) use in children are limited. We described antiseizure medication use in children with epilepsy (CwE) in France, with a focus on the chronic use of benzodiazepines and related implications. METHODS: We conducted a 5-year cohort study from January 2012, using data from the French national health care data system (Système National des Données de Santé). We included CwE identified through International Classification of Diseases, 10th Revision codes and medications from January 2012 to December 2015 and followed them until December 2016. We described ASMs and assessed whether the risk of initiating a polytherapy after a bitherapy depends on whether benzodiazepine was included in the bitherapy. RESULTS: We identified 62 885 CwE. Valproate was the most reimbursed ASM (40%), followed by lamotrigine (17.6%), levetiracetam (9.3%), clobazam (6.1%), and carbamazepine (5.8%). Prescriptions were initiated at the hospital in 74.5% of CwE. We observed a decrease in the number of CwE with at least one benzodiazepine reimbursement from 15.3% in 2013 to 10.1% in 2016 (p < .0001). The prevalence of CwE with levetiracetam reimbursements increased, whereas that of CwE with valproate decreased. A switch from a bitherapy to a polytherapy was more likely when the bitherapy included a benzodiazepine (subdistribution hazard ratio [sHR] = 1.20 [1.03-1.39]). SIGNIFICANCE: The prevalence of CwE with at least one benzodiazepine reimbursement decreased during the study period. Benzodiazepines were associated with an increased use of subsequent ASM polytherapy.

Which terms should be used to describe medications used in the treatment of seizure disorders? An ILAE position paper.

A variety of terms, such as "antiepileptic," "anticonvulsant," and "antiseizure" have been historically applied to medications for the treatment of seizure disorders. Terminology is important because using terms that do not accurately reflect the action of specific treatments may result in a misunderstanding of their effects and inappropriate use. The present International League Against Epilepsy (ILAE) position paper used a Delphi approach to develop recommendations on English-language terminology applicable to pharmacological agents currently approved for treating seizure disorders. There was consensus that these medications should be collectively named "antiseizure medications". This term accurately reflects their primarily symptomatic effect against seizures and reduces the possibility of health care practitioners, patients, or caregivers having undue expectations or an incorrect understanding of the real action of these medications. The term "antiseizure" to describe these agents does not exclude the possibility of beneficial effects on the course of the disease and comorbidities that result from the downstream effects of seizures, whenever these beneficial effects can be explained solely by the suppression of seizure activity. It is acknowledged that other treatments, mostly under development, can exert direct favorable actions on the underlying disease or its progression, by having "antiepileptogenic" or "disease-modifying" effects. A more-refined terminology to describe precisely these actions needs to be developed.

Long-term physical and psychiatric morbidities and mortality of untreated, deferred, and immediately treated epilepsy.

OBJECTIVE: In Australia, 30% of newly diagnosed epilepsy patients were not immediately treated at diagnosis. We explored health outcomes between patients receiving immediate, deferred, or no treatment, and compared them to the general population. METHODS: Adults with newly diagnosed epilepsy in Western Australia between 1999 and 2016 were linked with statewide health care data collections. Health care utilization, comorbidity, and mortality at up to 10 years postdiagnosis were compared between patients receiving immediate, deferred, and no treatment, as well as with age- and sex-matched population controls. RESULTS: Of 603 epilepsy patients (61% male, median age = 40 years) were included, 422 (70%) were treated immediately at diagnosis, 110 (18%) received deferred treatment, and 71 (12%) were untreated at the end of follow-up (median = 6.8 years). Immediately treated patients had a higher 10-year rate of all-cause admissions or emergency department presentations than the untreated (incidence rate ratio [IRR] = 2.0, 95% confidence interval [CI] = 1.4-2.9) and deferred treatment groups (IRR = 1.7, 95% CI = 1.0-2.8). They had similar 10-year risks of mortality and developing new physical and psychiatric comorbidities compared with the deferred and untreated groups. Compared to population controls, epilepsy patients had higher 10-year mortality (hazard ratio = 2.6, 95% CI = 2.1-3.3), hospital admissions (IRR = 2.3, 95% CI = 1.6-3.3), and psychiatric outpatient visits (IRR = 3.2, 95% CI = 1.6-6.3). Patients with epilepsy were also 2.5 (95% CI = 2.1-3.1) and 3.9 (95% CI = 2.6-5.8) times more likely to develop a new physical and psychiatric comorbidity, respectively. SIGNIFICANCE: Newly diagnosed epilepsy patients with deferred or no treatment did not have worse outcomes than those immediately treated. Instead, immediately treated patients had greater health care utilization, likely reflecting more severe underlying epilepsy etiology. Our findings emphasize the importance of individualizing epilepsy treatment and recognition and management of the significant comorbidities, particularly psychiatric, that ensue following a diagnosis of epilepsy.

Effect of drug treatment changes and seizure outcomes on depression and suicidality in adults with drug-resistant focal epilepsy.

OBJECTIVE: To investigate changes in depressive and suicidality status and their relationship with seizure outcomes after the addition or substitution of another antiseizure medication (ASM) in adults with drug-resistant focal epilepsy. METHODS: Seven hundred seventy consecutively enrolled patients were assessed and followed prospectively for seizure outcome and depressive status over a 6-month period after starting treatment with a newly introduced ASM. The Neurological Disorders Depression Inventory for Epilepsy (NDDIE) was used to screen for depression and suicidality. Correlations of NDDIE results with clinical and treatment-related variables were assessed by using a stepwise logistic regression model. RESULTS: At baseline, 50% of patients had a positive screening test result for depression and 13% had a positive screening test result for suicidal ideation. A psychiatric comorbidity at baseline was associated with a 2.3 times increased risk of an initially negative NDDIE screening result becoming positive at re-assessment after 6 months. In addition, the number of ASMs taken at baseline correlated with an increased risk of a change in depression screening test results from negative to positive during follow-up, whereas no association was identified with sociodemographic and epilepsy-related variables, including seizure outcomes. Approximately 6% of patients who were initially negative at screening for suicidal ideation became positive at the 6-month re-assessment. The risk of switch from a negative to a positive screening test result for suicidal ideation was increased more than two-fold in individuals who screened positive for depression at baseline, and was unrelated to the type of ASM introduced, sociodemographic variables, or seizure outcomes. SIGNIFICANCE: Almost 1 in 5 adults with drug-resistant focal epilepsy who screen negative for depression become positive when re-assessed 6 months after a treatment change. At re-assessment 6 months later, 6.1% who screen initially negative for passive suicidal ideation become positive. These changes in screening status are independent of type of ASM introduced or seizure outcomes but correlate with psychiatric status at baseline.

The risk of unprovoked seizure occurrence after status epilepticus in adults.

OBJECTIVE: Status epilepticus (SE) may lead to long-term consequences. This study evaluated the risk and predictors of seizure occurrence after SE, with a focus on SE due to acute symptomatic etiologies. METHODS: Prospectively collected data about adults surviving a first non-hypoxic SE were reviewed. The outcome was the occurrence of unprovoked seizures during the follow-up. Kaplan-Meier survival curve analysis and log-rank test were used to analyze the time to seizure occurrence and determine the statistical significance between etiological groups. Three subcategories within acute etiology were considered according to the presence of the following: (1) structural lesion (acute-primary); (2) brain involvement during systemic disorders (acute-secondary); and (3) drug or alcohol intoxication/withdrawal (acute-toxic). Cox proportional hazards model was adopted to estimate hazard ratios (HRs) with the 95% confidence intervals (CIs). RESULTS: Two hundreds fifty-seven individuals were included. Fifty-four subjects (21.0%) developed seizures after a median of 9.9 (interquartile range 4.3-21.7) months after SE. The estimated 1-, 2-, and 5-year rates of seizure occurrence according to acute SE etiologies were 19.4%, 23.4%, and 30.1%, respectively, for acute-primary central nervous system (CNS) pathology; 2.2%, 2.2%, and 8.7%, respectively, for acute-secondary CNS pathology; and 0%, 9.1%, and 9.1%, respectively, for acute-toxic causes. Five-year rates of seizure occurrence for non-acute SE causes were 33.9% for remote, 65.7% for progressive, and 25.9% for unknown etiologies. In multivariate Cox regression model, progressive etiology (adjusted HR [adjHR] 2.27, 95% CI 1.12-4.58), SE with prominent motor phenomena evolving in non-convulsive SE (adjHR 3.17, 95% CI 1.38-7.25), and non-convulsive SE (adjHR 2.38, 95% CI 1.16-4.90) were independently associated with higher hazards of unprovoked seizures. Older people (adjHR .98, 95% CI .96-.99) and people with SE due to acute-secondary CNS pathology (adjHR .18, 95% CI .04-.82) were at decreased risk of seizure occurrence. SIGNIFICANCE: SE carries a risk of subsequent seizures. Both the underlying cause and epileptogenic effects of SE are likely to contribute.

Lacosamide and pregnancy: Data from spontaneous and solicited reports.

OBJECTIVE: In pregnancy, it is important to balance the risks of uncontrolled epileptic seizures to the mother and fetus against the potential teratogenic effects of antiseizure medications. Data are limited on pregnancy outcomes among patients taking lacosamide (LCM), particularly when taken as monotherapy. The objective of this analysis was to evaluate the pregnancy outcomes of LCM-exposed pregnancies. METHODS: This analysis included all reports in the UCB Pharma pharmacovigilance database of exposure to LCM during pregnancy from spontaneous sources (routine clinical settings) or solicited reports from interventional clinical studies and noninterventional postmarketing studies. Prospective and retrospective reports were analyzed separately. RESULTS: At the data cutoff (August 31, 2021), there were 202 prospective pregnancy cases with maternal exposure to LCM and known outcomes. Among these cases, 44 (21.8%) patients received LCM monotherapy and 158 (78.2%) received LCM polytherapy. Most patients received LCM during the first trimester (LCM monotherapy: 39 [88.6%]; LCM polytherapy: 143 [90.5%]). From the prospective pregnancy cases with maternal LCM exposure, there were 204 reported outcomes (two twin pregnancies occurred in the polytherapy group). The proportion of live births was 84.1% (37/44) in patients who received LCM as monotherapy, and 76.3% (122/160) for LCM polytherapy. The overall proportion of abortions (for any reason) was 15.9% (7/44) with LCM monotherapy, and 22.5% (36/160) with LCM polytherapy. Congenital malformations were reported in 2.3% (1/44) of known pregnancy outcomes with maternal exposure to LCM monotherapy, and 6.9% (11/160) with polytherapy. SIGNIFICANCE: Our preliminary data do not raise major concerns on the use of LCM during pregnancy. Most pregnancies with LCM exposure resulted in healthy live births, and no new safety issues were identified. These findings should be interpreted with caution, as additional data are needed to fully evaluate the safety profile of LCM in pregnancy.

Challenges and directions in epilepsy diagnostics and therapeutics: Proceedings of the 17th Epilepsy Therapies and Diagnostics Development conference.

Substantial efforts are underway toward optimizing the diagnosis, monitoring, and treatment of seizures and epilepsy. We describe preclinical programs in place for screening investigational therapeutic candidates in animal models, with particular attention to identifying and eliminating drugs that might paradoxically aggravate seizure burden. After preclinical development, we discuss challenges and solutions in the design and regulatory logistics of clinical trial execution, and efforts to develop disease biomarkers and interventions that may be not only seizure-suppressing, but also disease-modifying. As disease-modifying treatments are designed, there is clear recognition that, although seizures represent one critical therapeutic target, targeting nonseizure outcomes like cognitive development or functional outcomes requires changes to traditional designs. This reflects our increasing understanding that epilepsy is a disease with profound impact on quality of life for the patient and caregivers due to both seizures themselves and other nonseizure factors. This review examines selected key challenges and future directions in epilepsy diagnostics and therapeutics, from drug discovery to translational application.

Current state of the epilepsy drug and device pipeline.

The field of epilepsy has undergone substantial advances as we develop novel drugs and devices. Yet considerable challenges remain in developing broadly effective, well-tolerated treatments, but also precision treatments for rare epilepsies and seizure-monitoring devices. We summarize major recent and ongoing innovations in diagnostic and therapeutic products presented at the seventeenth Epilepsy Therapies & Diagnostics Development (ETDD) conference, which occurred May 31 to June 2, 2023, in Aventura, Florida. Therapeutics under development are targeting genetics, ion channels and other neurotransmitters, and many other potentially first-in-class interventions such as stem cells, glycogen metabolism, cholesterol, the gut microbiome, and novel modalities for delivering electrical neuromodulation.

First unprovoked seizures among soldiers recruited to the Israeli Defense Forces during 10 consecutive years: A population-based study.

OBJECTIVE: The management of patients after a first unprovoked seizure (FUS) can benefit from stratification of the average 50% risk for further seizures. We characterized subjects with FUSs, out of a large generally healthy homogenous population of soldiers recruited by law to the Israeli Defense Forces, to investigate the role of the type of service, as a trigger burden surrogate, in the risk for additional seizures. METHODS: Soldiers recruited between 2005 and 2014, who experienced an FUS during their service, were identified from military records. Subjects with a history of epilepsy or lack of documentation of FUS characteristics were excluded from the study. Data on demographics and military service and medical details were extracted for the eligible soldiers. RESULTS: Of 816 252 newly recruited soldiers, representing 2 138 000 person-years, 346 had an FUS, indicating an incidence rate of 16.2 per 100 000 person-years. The FUS incidence rate was higher in combat versus noncombat male and female soldiers (p < .0001). Most subjects (75.7%) were prescribed antiseizure medications (ASMs), and 29.2% had additional seizures after the FUS. Service in combat units, abnormal magnetic resonance imaging, and being prescribed ASMs were correlated with a lower risk of having multiple seizures (95% confidence interval [CI] = .48-.97, .09-.86, .15-.28, respectively). On multivariate analysis, service in combat units (odds ratio [OR] = .48 for seizure recurrence, 95% CI = .26-.88) and taking medications (OR = .46, 95% CI = .24-.9) independently predicted not having additional seizures. SIGNIFICANCE: FUS incidence rate was higher in combat soldiers, but they had a twofold lower risk of additional seizures than noncombat soldiers, emphasizing the value of strenuous triggers as negative predictors for developing epilepsy. This suggests a shift in the perception of epilepsy from a "yes or no" condition to a continuous trend of predisposition to seizures, warranting changes in the ways etiologies of epilepsy are weighted and treatments are delivered.

Safety and efficacy of concomitant treatment with non-vitamin K antagonist oral anticoagulants and antiseizure medications: A propensity score matching cohort study.

Research on cerebrovascular events in atrial fibrillation (AF) patients taking non-vitamin K antagonist oral anticoagulants (NOACs) with antiseizure medications (ASMs) is limited, highlighting a significant gap in literature. We assessed thrombotic and hemorrhagic risks in patients on NOACs and ASMs versus those on NOACs or ASMs alone. We analyzed a retrospective cohort from five centers, including AF and epilepsy patients on both medications (n = 188), AF patients on NOACs (n = 298), and epilepsy patients on ASMs (n = 50), with a 3-year follow-up. Propensity score matching adjusted for cardiovascular risk differences. The primary outcomes were ischemic stroke, transient ischemic attack, and major bleeding. Results showed the ASM+NOAC group had a higher risk of primary outcomes compared to the NOAC-only group (5.68% vs. 1.18%, hazard ratio = 5.72, 95% confidence interval = 2.22-14.73), with no events in the ASM-only group. This suggests an increased risk for patients on combined NOAC and ASM therapy, underlining the need for careful drug interaction consideration.

Progress report on new medications for seizures and epilepsy: A summary of the 17th Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVII). II. Drugs in more advanced clinical development.

The 17th Eilat Conference on New Antiepileptic Drugs and Devices took place in Madrid, Spain on May 5-8, 2024. As usual, the core part of the conference consisted of presentations on investigational drugs at various stages of development for epilepsy-related indications. Summaries of information on compounds in preclinical or early clinical development are included in an accompanying publication (Part I). In this article, we provide summaries for five compounds in more advanced clinical development, i.e. compounds for which some information on antiseizure activity in individuals with epilepsy is available. These investigational treatments include azetukalner (XEN1101), a potent, KV7.2/7.3-specific potassium channel opener in development for the treatment of focal seizures, generalized tonic-clonic seizures, and major depressive disorder; bexicaserin (LP352), a selective 5-HT2C receptor superagonist in development for the treatment of seizures associated with developmental and epileptic encephalopathies; radiprodil, a selective negative allosteric modulator of NR2B subunit-containing N-methyl-D-aspartate glutamate receptors, in development for the treatment of seizures and behavior manifestations associated with disorders caused by gain-of-function mutations in the GRIN1, -2A, -2B, or -2D genes; soticlestat (TAK-935), a selective inhibitor of cholesterol 24-hydroxylase in development for the treatment of seizures associated with Dravet syndrome and Lennox-Gastaut syndrome; and STK-001, an antisense oligonucleotide designed to upregulate Nav1.1 protein expression and improve outcomes in individuals with Dravet syndrome. The diversity in mechanisms of action of these agents illustrates different approaches being pursued in the discovery of novel treatments for seizures and epilepsy. For two of the compounds discussed in this report (azetukalner and soticlestat), clinical evidence of efficacy has already been obtained in a randomized placebo-controlled adjunctive-therapy trial. For the other compounds, adequately powered placebo-controlled efficacy trials have not been completed to date.

Progress report on new medications for seizures and epilepsy: A summary of the 17th Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVII). I. Drugs in preclinical and early clinical development.

For >30 years, the Eilat Conference on New Antiepileptic Drugs and Devices has provided a forum for the discussion of advances in the development of new therapies for seizures and epilepsy. The EILAT XVII conference took place in Madrid, Spain, on May 5-8, 2024. Participants included basic scientists and clinical investigators from industry and academia, other health care professionals, and representatives from lay organizations. We summarize in this article information on treatments in preclinical and in early clinical development discussed at the conference. These include AMT-260, a gene therapy designed to downregulate the expression of Glu2K subunits of kainate receptors, in development for the treatment of drug-resistant seizures associated with mesial temporal sclerosis; BHV-7000, a selective activator of heteromeric Kv7.2/7.3 potassium channels, in development for the treatment of focal epilepsy; ETX101, a recombinant adeno-associated virus serotype 9 designed to increase NaV1.1 channel density in inhibitory γ-aminobutyric acidergic (GABAergic) neurons, in development for the treatment of SCN1A-positive Dravet syndrome; GAO-3-02, a compound structurally related to synaptamide, which exerts antiseizure activity at least in part through an action on cannabinoid type 2 receptors; LRP-661, a structural analogue of cannabidiol, in development for the treatment of seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex; OV329, a selective inactivator of GABA aminotransferase, in development for the treatment of drug-resistant seizures; PRAX-628, a functionally selective potent sodium channel modulator with preference for the hyperexcitable state of sodium channels, in development for the treatment of focal seizures; RAP-219, a selective negative allosteric modulator of transmembrane α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor regulatory protein γ-8, in development for the treatment of focal seizures; and rozanolixizumab, a humanized anti-neonatal Fc receptor monoclonal antibody, in development for the treatment of LGI1 autoimmune encephalitis. Treatments in more advanced development are summarized in Part II of this report.

Psychiatric implications of anti-seizure medications in epileptic population.

BACKGROUND AND OBJECTIVE: Epilepsy is a prevalent neurological disorder that affects a significant number of individuals globally. This condition is associated with a high occurrence of psychiatric comorbidities, which can significantly affect the quality of life of individuals affected. The aim of this study was to investigate the association between antiseizure therapies and the likelihood of psychiatric comorbidities in individuals with epilepsy. METHODOLOGY: Data for this study was gathered from the Neurology referral center in Islamabad, Pakistan. A standardized questionnaire was utilized to gather data from 120 individuals diagnosed with epilepsy. The survey consisted of inquiries regarding the management of seizures, the utilization of anti-seizure medications, and the presence of psychiatric comorbidities. The data was analyzed using the Statistical Package for the Social Sciences (SPSS). RESULTS: The findings indicated that individuals who were using multiple antiseizure medications had a notably higher likelihood of having psychiatric comorbidities in comparison to those who were on mono therapy (p = 0.010). suggests that patients with unsuccessful seizure control are more probable to have psychiatric comorbidities as compared to those with good seizure control (p = 0.029). CONCLUSION: To conclude poor seizure control and poly therapy are associated with increased risk of psychiatric comorbidities.

Authors reply.

(There is no abstract) for this article type.

Trends in enzyme-inducing antiseizure medication use: A retrospective analysis among adults with epilepsy.

BACKGROUND: Enzyme-inducing antiseizure medications (EIASMs) were associated with drug interactions and long-term adverse effects. Therefore, it was suggested that epilepsy treatment should be started with non-EIASMs, and in patients treated with EIASMs, replacement with non-EIASMs should be evaluated OBJECTIVE: To assess potent EIASM use among patients with epilepsy at their first visit in our epilepsy outpatient clinic. METHODS: We retrospectively reviewed the computerized database and the medical records of all the patients who had their first visit in our outpatient epilepsy clinic during a 10-year period (2012-2021). Of 730 patients with ASM treated epilepsy, 243 (33%) were receiving potent EIASMs. RESULTS: The annual potent EIASM use decreased from 35.1 % in 2012 to 11.8 % in 2021. Most of the patients who received potent EIASM had their first visit during 2012-2015 compared to the following years (56.8 % vs 43.2 %) (p = 0.0001). Patients with epilepsy receiving potent EIASMs were older (44.3 vs 34.7) (p = 0.0001), more likely men (60.9 % vs 47.2 %) (p = 0.001), with longer disease duration (13 vs 9.3 y) (p = 0.0001), higher rate of neuropsychiatric comorbidity (37 % vs 27.9 %) (p = 0.014), and were treated with more ASMs (1.6 vs 1.3) (p = 0.0001) compared to patients receiving non-EIASMs. CONCLUSIONS: Potent EIASM use has been declining over the past decade. Additional efforts to further decrease EIASM use should be exerted among all patients with ASM-treated epilepsy, with emphasis on men with focal epilepsy and epilepsy duration > 10 years.

Advances in serum thyroid hormone levels and seizures.

Epilepsy, a common neurological disorder, is characterized by paroxysmal, short-term, repetitive, and stereotypical features, significantly impacting patients' quality of life. Currently, the pathogenesis of epilepsy remains incompletely understood. Changes in neuronal excitability, imbalances in glutamate and gamma-aminobutyric acid (GABA) levels, alterations in the activity of GABA receptors, and dysfunction of GABA receptors are considered closely related to its occurrence. Thyroid hormones, vital for human growth and development, also play a crucial role in the nervous system. They mediate oxidative stress, influence reactive oxygen species production, affect mitochondrial function and neuronal excitability, and modulate glutamate and GABA levels. Also, they combine with thyroid hormone receptors and exert genomic effects by regulating the expression of numerous genes. However, once there are defects in thyroid hormone signaling, these defects may lead to severe neurodevelopmental disorders that are associated with an increased frequency of seizures. The impact of antiseizure medications (ASMs) on serum thyroid hormone levels, particularly traditional ASMs, has been extensively studied. It is reported that conventional ASMs such as phenobarbital, phenytoin sodium, carbamazepine, and valproate sodium were more likely to induce subclinical hypothyroidism (elevated TSH with normal FT4) or isolated hypothyroidism (decreased FT4 with normal TSH). However, the new ASMs, such as levetiracetam, have no effect on thyroid hormone levels. Together, seizures not only affect thyroid hormone levels, but abnormal thyroid hormone levels can also influence seizures. However, the precise mechanism underlying the interaction between serum thyroid hormone levels and seizures remains unclear. This review aims to explore the relationship between thyroid hormone levels and seizures, along with the underlying mechanisms.

Why have status epilepticus trials failed: Wrong drugs or wrong trials?

Despite burgeoning interest in trials in status epilepticus over the last 20 years, outcomes have yet to improve and a number of high profile studies have failed to deliver for a range of reasons. The range of reasons a trial may fail to meet the intended outcomes are discussed. Recent well designed, adequately powered studies in established status epilepticus failed to meet primary endpoints, but are nonetheless influencing practice, reflecting the importance of interpreting results in the context of broader literature, safety and practical considerations. Studies in refractory and super-refractory status epilepticus have yet to do so, frequently failing to deliver as hoped despite huge financial and human cost. The importance of reviewing regulatory frameworks, and our approach to trial design to address important clinical questions is reviewed, reflecting on lessons from the COVID-19 RECOVERY trials, and other disease areas, together with the potential associated with the use artificial intelligence tools. This paper is based on a presentation made at the 9th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures in April 2024.

Efficacy of verbal suggestion, verbal suggestion with a tuning fork, and verbal suggestion with a cotton swab for inducing the paroxysmal event during video-EEG recording in children with suspected psychogenic nonepileptic seizures.

INTRODUCTION: Video-electroencephalogram (EEG) with suggestion is widely considered the gold standard for diagnosing psychogenic nonepileptic seizures (PNES). However, ethical concerns and uncertainties persist regarding the most minimally invasive and least deceptive suggestion approach. MATERIALS AND METHODS: In an open-label randomized controlled trial, we evaluated the effectiveness of three suggestion methods (verbal suggestion, verbal suggestion with a tuning fork, and verbal suggestion with a cotton swab) during short-term video-EEG (STVEEG) recordings to induce PNES in children aged 5-18 years. If the paroxysmal event couldn't be elicited with the assigned method, alternative techniques were employed. RESULTS: Out of 97 initially screened children, 75 were enrolled, with 25 in each group. The efficacy of all three suggestion methods was comparable in reproducing paroxysmal events (success rate of 16/25, 17/25 and 17/25 in verbal suggestion only, verbal suggestion with tuning fork and sterile cotton swab group respectively, p = 0.83) and the time required for induction (median of 2, 3 and 3 min respectively, p = 0.21). After trying alternative methods, 20 %, 12 %, and 12 % more patients in these three groups, respectively, were able to reproduce the paroxysmal event, with the differences not reaching statistical significance (p = 0.74). The assigned induction method or the success/failure of event reproduction did not significantly impact clinical outcomes at 12 weeks, and none of the patients in whom PNES could not be reproduced during STVEEG were later found to have an organic cause. Only the presence of psychiatric comorbidity independently predicted successful event reproduction during STVEEG, with statistical significance even after adjusting for other variables (p = 0.03). CONCLUSION: The efficacy of verbal suggestion alone in inducing paroxysmal nonepileptic seizures is on par with using a tuning fork or cotton swab in conjunction with verbal suggestion during STVEEG.

Pregnancy, antiseizure medications and unexplained intrauterine foetal death.

OBJECTIVE: To assess the role of antiseizure medication (ASM) regimens and other factors in relation to the occurrence of intrauterine foetal death (IUFD) in pregnant women with epilepsy (WWE) enrolled in the Raoul Wallenberg Australian Pregnancy Register of Antiepileptic Drugs (APR). RESULTS: IUFDs occurred in 70 (3.01 %) of 2,323 prospective pregnancies from WWE with known outcomes in the APR. Factors associated with IUFD occurrence included older maternal age, enrolment in the APR at an earlier stage of pregnancy, history of pregnancies which did not result in livebirths, parental history of foetal malformations, and maternal use of carbamazepine, lamotrigine or ethosuximide. Individual ASM dosages were not associated with IUFD occurrence. Relative to no exposure, the risk of IUFD increased with the increasing number of ASMs used in combination (2 ASMs: relative risk, RR = 5.45 [95 % CI: 0.73-41.80]; 3 ASMs: RR = 10.70 [95 % CI: 1.27-90.17]), >3 ASMs: RR = 10.70 [95 % CI: 1.27-90.17]), but this finding was attenuated after adjusting for other factors implicated in IUFD occurrence. Several ASM pairs were associated with an increased risk of IUFD relative to no exposure, but these associations were lost after accounting for confounders. CONCLUSIONS: Although it is possible that prenatal ASM exposure may increase the risk of IUFD, other non-pharmacological factors are more relevant to the occurrence to IUFD in pregnant WWE.