Trials Of Antiepileptic Drugs Research Articles

Tracing topics and trends in drug-resistant epilepsy research using a natural language processing-based topic modeling approach.

Epilepsy is a common neurological disorder affecting over 70 million people worldwide. Although many patients achieve seizure control with anti-epileptic drugs (AEDs), 30%-40% develop drug-resistant epilepsy (DRE), where seizures persist despite adequate trials of AEDs. DRE is associated with reduced quality of life, increased mortality and morbidity, and greater socioeconomic challenges. The continued intractability of DRE has fueled exponential growth in research that aims to understand and treat this serious condition. However, synthesizing this vast and continuously expanding DRE literature to derive insights poses considerable difficulties for investigators and clinicians. Conventional review methods are often prolonged, hampering the timely application of findings. More-efficient approaches to analyze the voluminous research are needed. In this study, we utilize a natural language processing (NLP)-based topic modeling approach to examine the DRE publication landscape, uncovering key topics and trends. Documents were retrieved from Scopus, preprocessed, and modeled using BERTopic. This technique employs transformer models like BERT (Bidirectional Encoder Representations from Transformers) for contextual understanding, thereby enabling accurate topic categorization. Analysis revealed 18 distinct topics spanning various DRE research areas. The 10 most common topics, including "AEDs," "Neuromodulation Therapy," and "Genomics," were examined further. "Cannabidiol," "Functional Brain Mapping," and "Autoimmune Encephalitis" emerged as the hottest topics of the current decade, and were examined further. This NLP methodology provided valuable insights into the evolving DRE research landscape, revealing shifting priorities and declining interests. Moreover, we demonstrate an efficient approach to synthesizing and visualizing patterns within extensive literature that could be applied to other research fields.

The need for an individualized approach to what is considered a clinically significant reduction in seizure frequency: A patient's perspective.

The need for an individualized approach to what is considered a clinically significant reduction in seizure frequency: A patient's perspective.

Disruption of hippocampal neuronal circuit function depends upon behavioral state in the APP/PS1 mouse model of Alzheimer’s disease

The Alzheimer’s disease-associated peptide amyloid-beta (Aβ) has been associated with neuronal hyperactivity under anesthesia, but clinical trials of anticonvulsants or neural system suppressors have, so far, failed to improve symptoms in AD. Using simultaneous hippocampal calcium imaging and electrophysiology in freely moving mice expressing human Aβ, here we show that Aβ aggregates perturbed neural systems in a state-dependent fashion, driving neuronal hyperactivity in exploratory behavior and slow wave sleep (SWS), yet suppressing activity in quiet wakefulness (QW) and REM sleep. In exploratory behavior and REM sleep, Aβ impaired hippocampal theta–gamma phase-amplitude coupling and altered neuronal synchronization with theta. In SWS, Aβ reduced cortical slow oscillation (SO) power, the coordination of hippocampal sharp wave-ripples with both the SO and thalamocortical spindles, and the coordination of calcium transients with the sharp wave-ripple. Physostigmine improved Aβ-associated hyperactivity in exploratory behavior and hypoactivity in QW and expanded the range of gamma that coupled with theta phase, but exacerbated hypoactivity in exploratory behavior. Together, these findings show that the effects of Aβ alone on hippocampal circuit function are profoundly state dependent and suggest a reformulation of therapeutic strategies aimed at Aβ induced hyperexcitability.

TH-206. EEG response to anti-epileptic drug trial in critically ill patients with generalized periodic discharges

TH-206. EEG response to anti-epileptic drug trial in critically ill patients with generalized periodic discharges

When the rhythm moves you

A 47-year-old lady presented with a 6-year history of increasing refractory seizures and scoliosis despite trials of multiple anti-epileptic drugs(AEDs). She described seizures of temporal lobe(TLE) semiology provoked mainly by music which evoked elation. These musicogenic reflex seizures (MRS) were occurring up to twice weekly.CT and MRI brain, paraspinal EMG, and routine EEG were unremarkable. Provoked EEG captured a gen- eralised seizure with focal left mid-anterior temporal focus with rapid bilateral spreading within 2 minutes of playing a piece of music and lasted for 90 seconds, followed by a prolonged post-ictal phase. Auto- antibody screen revealed persistently elevated and rising serum GAD-Ab(glutamic acid decarboxylase antibodies) at 11618 U/mL with GAD positive on CSF testing. CT body, PET and transvaginal ultrasound revealed no significant abnormalities. Plasmapheresis was trialled with some effect.We present a rare case of GAD-Ab mediated MRS. MRS are well described, with 9% mediated by GAD-Ab. This mechanistically accounts for the limbic MRS semiology. We highlight the importance of GAD-Ab screening for refractory new onset TLE in an adult, with high serum GAD-Ab titre (≥2000 U/mL) and evidence of intrathecal synthesis. Unlike other immune-mediated epilepsies, GAD-Ab-mediated epilepsy responds poorly to AEDs and may require immunosuppression with rituximab or cyclophosphamide.

The Significance of Subclinical Epileptiform Activity in Alzheimer's Disease: A Review.

Hyperexcitability is a recently recognized contributor to the pathophysiology of Alzheimer's disease (AD). Subclinical epileptiform activity (SEA) is a neurophysiological sign of cortical hyperexcitability; however, the results of the studies in this field vary due to differences in the applied methodology. The aim of this review is to summarize the results of the related studies aiming to describe the characteristic features and significance of subclinical epileptiform discharges in the pathophysiologic process of AD from three different directions: (1) what SEA is; (2) why we should diagnose SEA, and (3) how we should diagnose SEA. We scrutinized both the completed and ongoing antiepileptic drug trials in AD where SEA served as a grouping variable or an outcome measure. SEA seems to appear predominantly in slow-wave sleep and in the left temporal region and to compromise cognitive functions. We clarify using supportive literature the high sensitivity of overnight electroencephalography (EEG) in the detection of epileptiform discharges. Finally, we present the most important research questions around SEA and provide an overview of the possible solutions.

Referral practices for epilepsy surgery in pediatric patients: A North American Study.

Patients with epilepsy who do not respond to two trials of appropriate antiepileptic drugs are considered to have drug-resistant epilepsy (DRE). The International League Against Epilepsy recommends patients with DRE be referred for surgical evaluation; however, prior literature suggeststhis is an underutilized intervention, especially in the pediatric setting. This study capturespractices of North American pediatric neurologists regarding the management of DREand factors that maypromoteor limitreferrals for epilepsy surgical evaluation. A REDCap survey was distributed via the Child Neurology Society mailing list to pediatric neurologists practicing in North America. Ethics approval from the Children's Hospital of Eastern Ontario Research Ethics Board was granted prior to the start of data collection. Ninety-eight responses were included in the analysis; 77% of participants currently practice in the United States; 73.5% of respondents reported they would refer a patient for surgical consultation after two failed medications.Of all potential predictors tested in a binary logisticregressionmodel, only annual referral volume predicted whether participants refer patients after three or more failed medications. Centers with high referral volume were 37% more likely to adhere to the guideline of referral after two failed medications. Pediatric neurologists demonstrate fair knowledge of formal recommendations to refer patients for surgical evaluation after two failed medication trials, although referral rates remain unacceptably low. Participants continue to report that they would not refer patients with generalized electroencephalographic findings for surgical evaluation; this should continue to be addressed. Other modifiable factors reported, especiallyfamily perceptions of epilepsy surgery, should be prioritized when developing tools to enhance effective referrals and increase utilization of epilepsy surgery in the management of pediatric DRE.

Practical Drug Treatment Recommendations on the Drug Refractory Epilepsy Patients: 2021 Clinical Guideline Subcommittee for Epilepsy in the Korean Neurological Association

One third of the overall epilepsy population are estimated to be a drug refractory epilepsy (DRE), defined as the patients who failed to control seizure reduction, even tried two or more appropriate antiepileptic drugs (AEDs) trials. Those people need additional AEDs trials or other treatment options (resective surgery, neuromoulation, etc.). Here, we, clinical guideline committee of the Korean Neurological Association (KNA) introduce the recommendations of AEDs treatments including not only old and new AEDs currently available in Korea but also AEDs planned to be launched in the new future for DRE patients with literature review to help efficient decision of the clinician. The authors reviewed literatures and assessed efficacy and tolerability on 12 currently available and four newly introduced/or planned AEDs applied to DRE patients, published from November 2015 to July 2021. Brivaracetam, eslicarbazepine, canabidiol and cenobamate are the four AEDs that are newly introduced or planned to be launched soon. The reviewed articles are publications after November 2015, 2018 American Association of Neurology guideline, new AEDs which were introduced or planned to be launched as of 2021. All AEDs are classified based on the therapeutic rating scheme, generating recommendations. Overall 173 papers have been reviewed and analyzed for recommendation rationales. KNA introduce additional add-on treatment or conversional monotherapy guidelines on the drug refractory focal and generalized epilepsy. We hope these guidelines or recommendations to help clinical decision for the treatment of drug refractory epilepsy patients

Treating Seizures after Hypoxic-Ischemic Encephalopathy-Current Controversies and Future Directions.

Seizures are common in newborn infants with hypoxic-ischemic encephalopathy and are highly associated with adverse neurodevelopmental outcomes. The impact of seizure activity on the developing brain and the most effective way to manage these seizures remain surprisingly poorly understood, particularly in the era of therapeutic hypothermia. Critically, the extent to which seizures exacerbate brain injury or merely reflect the underlying evolution of injury is unclear. Current anticonvulsants, such as phenobarbital and phenytoin have poor efficacy and preclinical studies suggest that most anticonvulsants are associated with adverse effects on the developing brain. Levetiracetam seems to have less potential neurotoxic effects than other anticonvulsants but may not be more effective. Given that therapeutic hypothermia itself has significant anticonvulsant effects, randomized controlled trials of anticonvulsants combined with therapeutic hypothermia, are required to properly determine the safety and efficacy of these drugs. Small clinical studies suggest that prophylactic phenobarbital administration may improve neurodevelopmental outcomes compared to delayed administration; however, larger high-quality studies are required to confirm this. In conclusion, there is a distinct lack of high-quality evidence for whether and to what extent neonatal seizures exacerbate brain damage after hypoxia-ischemia and how best to manage them in the era of therapeutic hypothermia.

A multivariable prediction model of a major treatment response for focal-onset seizures: A post-hoc analysis of Phase III trials of perampanel

ObjectiveAlthough 50 % reduction in seizure frequency is a common efficacy endpoint in clinical trials of antiepileptic drugs (AEDs), 75 % or greater reductions may be required to improve patients’ health-related quality of life. Identification of clinical factors that are associated with high responder rates may help to inform clinicians on which patients may optimally benefit from treatment. We evaluated potential predictive factors for achieving major treatment responses (≥75 % reduction in seizure frequency per 28 days from study baseline) in patients with drug-resistant focal-onset seizures, with/without focal to bilateral tonic-clonic (FBTC) seizures in perampanel trials designed for regulatory approval. MethodsUnivariate analyses using logistic regression were performed using data from three double-blind, placebo-controlled Phase III studies of adjunctive perampanel (Studies 304 [NCT00699972], 305 [NCT00699582], 306 [NCT00700310]), and their open-label extension study (OLEx; Study 307 [NCT00735397]). For the double-blind studies, baseline seizure frequency, number of baseline AEDs, baseline seizure type, baseline concomitant enzyme-inducing AEDs (EIAEDs), baseline carbamazepine, lamotrigine, or valproic acid, age at diagnosis, time since diagnosis, etiology, and perampanel plasma concentration were included individually with study treatment. The same factors were included for the OLEx analysis except for plasma concentration and treatment. Variables found to be significant predictors for a major treatment response in univariate analyses were subsequently included in multivariable analyses using backwards and forwards selection. ResultsIn the double-blind studies, 175/1374 patients had a major response to placebo (n = 25) or perampanel (n = 150). The best predictors of a major treatment response in multivariable models with forwards and backwards selection were: the presence of FBTC seizures during baseline (P = 0.0002), higher perampanel plasma concentration (P < 0.0001), older age at diagnosis (P = 0.0024 and 0.0045, respectively), and lower baseline seizure frequency (P = 0.0364 and 0.0127, respectively). In the OLEx, 217/1090 patients had a major treatment response. The best predictors of a major treatment response in the final multivariable model, regardless of backwards or forwards selection, were a lower baseline seizure frequency (P = 0.0022), the absence of focal impaired awareness seizures during baseline (P = 0.0011), the presence of FBTC seizures during baseline (P = 0.0164), lower number(s) of baseline AEDs (P = 0.0002), the absence of EIAEDs during baseline (P = 0.0059), an older age at diagnosis (P = 0.0054), and absence of structural etiologies (P = 0.0138). SignificanceThese analyses of placebo-controlled and long-term extension trial data identified a number of potential predictive factors for patients with focal-onset seizures achieving a major treatment response. These factors may help guide clinicians when predicting a patient’s response to treatment and optimizing individual treatment regimens.

Analyses of seizure responses supportive of a novel trial design to assess efficacy of antiepileptic drugs in infants and young children with epilepsy: Post hoc analyses of pediatric levetiracetam and lacosamide trials.

ObjectiveRecently, a novel trial design has been proposed to overcome challenges with traditional placebo‐controlled trials of antiepileptic drugs in infants and young children (≥1 month of age) (Auvin S, et al. Epilepsia Open 2019;4:537‐43). The proposed time‐to‐event trial design involves seizure counting by caregivers and allows adjustment of the duration of the baseline period and duration of exposure to placebo or potentially ineffective treatment based on the patient's seizure burden and response. We performed post hoc analyses to mimic this trial design and evaluate its viability. As these analyses required trials with prolonged baseline and treatment periods and diary data, which is not a typical design of trials in infants and young children (1 month to <4 years of age), data from two trials in pediatric patients (4‐16 years of age) were used.MethodsWe performed post hoc analyses of two randomized, double‐blind, placebo‐controlled trials of adjunctive levetiracetam (N159; NCT00615615) and lacosamide (SP0969; NCT01921205) in children and adolescents (4‐16 years of age) with focal‐onset seizures. In these analyses, patients were followed until they completed the 10‐week maintenance period, discontinued during the maintenance period, or reached their “nth” seizure (n = number of seizures patient had during baseline). Efficacy was assessed by determining time to nth seizure.ResultsIn the analyses of both trials, patients on levetiracetam or lacosamide had a 34% lower risk of reaching their baseline seizure count during their 10‐week maintenance period than patients on placebo. The previously published primary results of these trials also demonstrated efficacy of adjunctive levetiracetam and lacosamide.SignificanceAlthough these were post hoc analyses of trials in older children (4‐16 years of age), our results provide supportive evidence for the utility of the novel time‐to‐event trial design for future trials in infants and young children (1 month to <4 years of age).

The Efficacy, Adverse Events, and Withdrawal Rates of the Pharmacological Management of Chronic Spinal Cord Injury Pain: A Systematic Review and Meta-Analysis.

To establish the efficacy of medications, incidence of adverse events (AEs), and withdrawal rates associated with the pharmacological management of chronic spinal cord injury pain. PubMed, MEDLINE, Embase, CINAHL, Web of Science, CENTRAL, and PsycINFO were searched (November 2017) and updated (January 2020). Two independent review authors screened and identified papers for inclusion. Twenty-one studies met inclusion requirements for efficacy analysis and 17 for AE and withdrawal rate analysis; no additional papers were included from the updated 2020 search. Treatments were divided into six categories: anticonvulsants (n = 6), antidepressants (n = 3), analgesics (n = 8), anti-spasticity medications (n = 2), cannabinoids (n = 1), and other (n = 2). Trials of anticonvulsants, antidepressants, and cannabinoids included long-term follow-up trials (2 weeks to 4 months), and trials of analgesics and anti-spasticity medications, among others, were short-term trials (0-2 days). Effectiveness for neuropathic pain was found for pregabalin (3/3 studies) and lidocaine (2/3 studies). Studies using ketamine also reported effectiveness (2/2), but the quality of these papers was rated as poor. The most frequently reported AEs included dizziness, dry mouth, nausea, and constipation. Pregabalin was associated with a higher risk of somnolence (risk ratio [RR] 3.15, 95% confidence interval [CI]: 2.00-4.98) and dizziness (RR 2.9, 95% CI: 1.58-5.30). Ketamine was associated with a higher risk of reduced vision (RR 9.00, 95% CI: 0.05-146.11), dizziness (RR 8.33, 95% CI: 1.73-40.10), and somnolence (RR 7.00, 95% CI: 1.73-40.1). Withdrawal rates ranged from 18.4% for antidepressants to 0-30% for anticonvulsants, 0-10% for anti-spasticity medications, 0-48% for analgesics, 28.6% for cannabinoids, and 0-22.2% for other medications. Pregabalin was found to be effective for neuropathic pain vs placebo. Cannabinoids were ineffective for neuropathic pain. AEs are a common cause for withdrawal. The nature of AEs was poorly reported, and AE reporting should be improved in future randomized controlled trials.

The association between MDR1 C3435T genetic polymorphism and the risk of multidrug-resistant epilepsy in Egyptian children

BackgroundEpilepsy is a chronic disease affecting about 2% of the population and is considered a serious neurological disease. Despite its good prognosis, 20–30% of epileptic patients were not cured of their seizures even with the many trials of antiepileptic drug (AED) therapy. The resistance mechanism is still unclear, maybe due to the effect of the genetic factors on the bioavailability of the drugs. Consequently, the association between therapy resistance and the presence of a gene called “multidrug resistance 1 (MDR1)” had been proposed. Thus, the present study aimed to understand the relationship between the genetic polymorphism of MDR1C3435T and the resistance to AEDs.ResultA non-significant association was found between MDR1 C3435T single-nucleotide polymorphism (SNP) and drug-resistant epilepsy. However, there was statistical significance in the association between the drug type and the genotype distribution, in cases that were maintained on sodium valproate and MDR1C3435T genotype.ConclusionPossible involvement of the MDR1 gene C 3435T polymorphism with sodium valproate resistance clarifies the importance of genetic variability in response to the drug and may help to find novel genetic therapy for epilepsy, by targeting the biological mechanisms responsible for epilepsy in each specific individual. Future studies with bigger sample sizes and in other racial populations will be necessary.

A meta-analysis: efficacy and safety of anti-epileptic drugs prescribed in Korea as monotherapy and adjunctive treatment for patients with focal epilepsy.

Focal epilepsy is the most common type of epilepsy in Korea, and anti-epileptic drugs (AEDs) are the main treatment option for patients. This study aimed to compare the efficacy and safety of AEDs for focal epilepsy through a meta-analysis. The AEDs prescribed in Korea as monotherapy and adjunctive treatment for patients with focal epilepsy were included for analysis. Relevant articles were searched for randomized clinical trials of AEDs and treatment outcomes were analyzed on the basis of the 50% responder rate, seizure-free rate, treatment withdrawal rate, and emergence rates of adverse events (AEs). The odds ratios (ORs) and their 95% confidence intervals (CI) of study outcome were calculated using combined data from multiple studies. A total of 47 studies were included in the meta-analysis. The seizure-free rate, treatment withdrawal rate, and AE rate were not significantly different among the AEDs recommended for monotherapy. Among the AEDs recommended for adjunctive treatment, topiramate and oxcarbazepine yielded the highest OR in comparison with placebo for each efficacy parameter: the 50% responder rate for topiramate = 6.42 (3.76–11.6) and the seizure-free rate for oxcarbazepine = 32.7 (6.05–899). The third-generation AEDs (brivaracetam and perampanel) yielded relatively better safety outcomes than other AEDs. In general, the 50% responder rate and treatment withdrawal rate tended to increase as the dose of the AEDs increased. The results from the current meta-analysis of the efficacy and safety data of various AEDs may provide insight into optimal pharmacotherapy for the treatment of focal epilepsy.

The association between toll-like receptor 4 (TLR4) genotyping and the risk of epilepsy in children

BackgroundEpilepsy is one of the most widely recognized neurological disorders; unfortunately, twenty to thirty percent of patients do not get cured from epilepsy, despite many trials of antiepileptic drug (AED) therapy. Immunotherapy may be a viable treatment strategy in a subset of epileptic patients. The association between Toll-like receptor polymorphisms and epilepsy clarifies the role of the immune system in epilepsy and its response to the drug. Thus, this study will focus on the relation between TLR4 rs1927914, rs11536858, rs1927911SNPs, and epilepsy in an Egyptian case-control study to assess their link to antiepileptic drug response.ResultsAccording to TLR4 rs1927914, there is a significant association between the SNP and the development of epilepsy, as CC genotype is 15.3 times more at risk for developing epilepsy than TT genotype, and CT is 11.1 times more at risk for developing epilepsy than TT. Also, patients with CC genotypes are 6.3 times more at risk for developing primary epilepsy than TT genotype.According to rs11536858, there is a significant association between cases and control groups, as AA genotypes are found to be more at risk for developing epilepsy than GG genotypes. Also, there is a statistically significant association between clonazepam resistance and rs11536858, as p value < 0.001* with the highest frequency of TT genotypes at 4.3%.According to rs1927911, there are no significant results between the cases and the control groups or between drug-responsive and drug resistance.ConclusionPossible involvement of the Toll-like receptor clarifies the importance of innate immunity in initiating seizures and making neuronal hyperexcitability. In this work, multiple significant associations between TLR SNPs and epilepsy, epileptic phenotype, and drug-resistant epilepsy have been found. More studies with bigger sample sizes and different techniques with different SNPs are recommended to find the proper immunotherapy for epilepsy instead of the treatment by antiepileptic drugs.

Cardiogenic paroxysmal autonomic events mimicking complex partial seizures

A cardiogenic paroxysmal autonomic event (CPAE), including swallow syncope, can be mistaken for an epileptic seizure. In the case of a CPAE, an underlying cardiac pathology should rapidly be considered as delayed treatment of the underlying cardiac condition poses a significant mortality risk, including the risk of sudden cardiac death (SCD). Further, when CPAE is misdiagnosed as an epileptic seizure and is treated by enrollment in antiepileptic drug (AED) trials, cardiac bradyarrhythmia can be aggravated by some ion channel active AEDs; because of this, care must be taken, as a hasty diagnosis of epilepsy can have significant psychosocial consequences.

Pharmacological Management of Neuropsychiatric Symptoms of Dementia.

Neuropsychiatric symptoms are universal across all stages and types of dementia and can cause significant challenges for patients and caregivers. While there are currently no approved medications for treatment of neuropsychiatric symptoms of dementia, a variety of psychotropic medications such as antipsychotics, benzodiazepines, anticonvulsants, and antidepressants are used off-label to treat these symptoms. This systematic review evaluated the available evidence for effectiveness and tolerability of pharmacologic treatments in addressing behavioral disturbances in dementia. Inclusion criteria were placebo-controlled, randomized controlled clinical trials (RCTs) or meta-analyses; a total of 38 studies and 3 meta-analyses representing an additional 27 RCTs met the inclusion criteria. Of the medication classes evaluated, atypical antipsychotics had the greatest available evidence for use, however, the treatment effect size was modest. Nine trials of antidepressants were included; 3 trials supported use in dementia. Eight trials of anticonvulsants were included; only one showed benefit. For benzodiazepines, 2 RCTs were included; only one trial of lorazepam showed improvement. Six trials of melatonin agonists were included; none showed efficacy outside of improved sleep measures. Evidence for effectiveness of pimavanserin and dextromethorphan-quinidine was limited to one study each, both of which showed benefit. Despite the widespread off-label use of psychotropic medications for treatment of neuropsychiatric symptoms in dementia, there are relatively few RCTs to evaluate their use with treatment effect sizes absent or modest for most medication classes. Of the medication classes reviewed, atypical antipsychotics have the best evidence for effectiveness, however, the overall magnitude of treatment effect is modest and must be balanced with risk of serious adverse events including death.

Modelling seizure rates rather than time to an event within clinical trials of antiepileptic drugs

BackgroundPredictive models within epilepsy are frequently developed via Cox’s proportional hazards models. These models estimate risk of a specified event such as 12-month remission. They are relatively simple to produce, have familiar output, and are useful to answer questions about short-term prognosis. However, the Cox model only considers time to first event rather than all seizures after starting treatment for example. This makes assessing change in seizure rates over time difficult. Variants to the Cox model exist enabling recurrent events to be modelled. One such variant is the Prentice, Williams and Peterson – Total Time (PWP-TT) model. An alternative is the negative binomial model for event counts. This study aims to demonstrate the differences between the three approaches, and to consider the benefits of the PWP-TT approach for assessing change in seizure rates over time.MethodsTime to 12-month remission and time to first seizure after randomisation were modelled using the Cox model. Risk of seizure recurrence was modelled using the PWP-TT model, including all seizures across the whole follow-up period. Seizure counts were modelled using negative binomial regression. Differences between the approaches were demonstrated using participants recruited to the UK-based multi-centre Standard versus New Antiepileptic Drug (SANAD) study.ResultsResults from the PWP-TT model were similar to those from the conventional Cox and negative binomial models. In general, the direction of effect was consistent although the variables included in the models and the significance of the predictors varied. The confidence intervals obtained via the PWP-TT model tended to be narrower due to the increase in statistical power of the model.ConclusionsThe Cox model is useful for determining the initial response to treatment and potentially informing when the next intervention may be required. The negative binomial model is useful for modelling event counts. The PWP-TT model extends the Cox model to all included events. This is useful in determining the longer-term effects of treatment policy. Such a model should be considered when designing future clinical trials in medical conditions typified by recurrent events to improve efficiency and statistical power as well as providing evidence regarding changes in event rates over time.

Gender and Racial Disparity in Antiepileptic Drug(AED) Trials– A metaanalysis and systematic review of AED randomized controlled trials and open labels studies (274)

Gender and Racial Disparity in Antiepileptic Drug(AED) Trials– A metaanalysis and systematic review of AED randomized controlled trials and open labels studies (274)

Clinical outcomes and treatments effectiveness in status epilepticus resolved by antiepileptic drugs: A five-year observational study.

ObjectiveTo evaluate clinical outcomes and treatment effectiveness of status epilepticus finally resolved by nonbenzodiazepine antiepileptic drugs (AEDs).MethodsAll consecutive SE episodes observed from September 1, 2013, to September 1, 2018, and resolved by AEDs were considered. Diagnosis and classification of SE followed the 2015 ILAE proposal. Nonconvulsive status (NCSE) diagnosis was confirmed according to the Salzburg EEG criteria. The modified Rankin Scale and deaths at 30 days from onset were used to evaluate outcomes.ResultsA total of 277 status episodes (mean age 71 years; 61% female) were treated and resolved by antiepileptic drugs after 382 treatment trials. 68% of the SE resolved after AED use as first/second treatment line, while subsequent trials with AEDs gave an additional 32% resolution. A return to baseline conditions was observed in 48% of the patients, while overall mortality was 19% without significant changes across the study years. Mortality was higher in NCSE than in convulsive SE (22.5% vs 12.9%; P < .05), while mortality did not differ in SE episodes resolved by a first/second AED trial (17.2%) versus SE resolved by successive treatment trials (18.9%). The resolution rate of intravenous AEDs was 82% for valproate, 77% for lacosamide, 71% for phenytoin, and 62% for levetiracetam. No significant differences were found in head‐to‐head comparison, but for the valproate‐levetiracetam one that was related to NCSE episodes in which valproate resulted to be effective in 86% of the trials while levetiracetam in 62% (P < .002).SignificanceA high short‐term mortality, stable over time, was observed in SE despite resolution of seizures, especially in SE with nonconvulsive semiology. Comparative AED efficacy showed no significant differences except for higher resolution rate for valproate versus levetiracetam in NCSE.