Antiseizure medication discontinuation: A mixed-methods exploration of factors considered by patients when approaching decision-making.

Anti-seizure medications (ASMs) are often prescribed using a trial-and-error approach with a similar sequence for many patients. Comparative effectiveness data beyond the first ASM prescription are limited. Artificial intelligence can automatically extract information from electronic health records (EHRs) and augment clinical trials. We conducted a retrospective cohort comparative effectiveness study of currently available ASMs using emulated clinical trials through a causal inference- and informatics-based framework. We extracted data from EHRs using natural language processing algorithms to collect epilepsy covariates and seizure outcomes. We compared ASMs using weighted Kaplan-Meier analyses and log-rank tests with Bonferroni corrections. We compared ASMs across seizure freedom over 2 years of follow-up, and drug retention rate over 5 years of follow-up. Emulated trials included 1596 patients (8379 patient-years) for seizure freedom as outcome and 2945 patients (14 238 patient-years) for retention as outcome. For all epilepsy types, among first-line ASMs, levetiracetam and lamotrigine were superior to oxcarbazepine for seizure freedom (P < 0.001), and levetiracetam was superior to lamotrigine and oxcarbazepine for retention (P < 0.001); among second-line ASMs, lacosamide had the best retention (P < 0.001) but lower seizure freedom rate than topiramate (P = 0.032); among third-line ASMs, cenobamate had longer retention than brivaracetam, but lower seizure freedom rate than clobazam and brivaracetam (P < 0.001). For focal epilepsies, first-line ASMs achieved similar rates of seizure freedom, but levetiracetam remained superior to lamotrigine and oxcarbazepine for retention (P < 0.001); among second-line ASMs, topiramate and lacosamide were both superior to zonisamide for seizure freedom (P < 0.001), while lacosamide remained superior to topiramate and zonisamide for retention (P < 0.002); among third-line ASMs, cenobamate, brivaracetam and clobazam achieved similar retention and seizure freedom. For generalized and unclassified epilepsies, first-line ASMs achieved similar seizure freedom, but levetiracetam remained superior to lamotrigine and oxcarbazepine for retention (P < 0.02); topiramate had the best seizure freedom among second-line ASMs (P < 0.001), while lacosamide again had better retention than zonisamide (P < 0.006); there were insufficient patients included in third-line ASM trials for this subgroup. In conclusion, emulated clinical trials provide a useful framework for studying the comparative effectiveness of anti-seizure medications using real-world observational data. Our findings of differences in seizure freedom and retention between ASMs help to generate hypotheses that should be tested in future prospective, randomized comparative effectiveness trials.

Network analysis of antiseizure medication use, efficacy, and safety in epilepsy: A retrospective cohort study in a tertiary care center

Antiseizure medications (ASMs) are standard treatment for epilepsy. Yet, because ASMs can have adverse effects, guidelines suggest considering ASM withdrawal after a period of seizure freedom. We explored patients' perceived seizure risk, seizure risk tolerance, and risk counseling techniques. We interviewed adults at least one-year seizure free, seen for epilepsy across 3 academic institutions. Participants rated their own perceived seizure risks (0 "definitely would not have another seizure" to 10 "definitely would") on vs off ASMs, discussed what minimal clinically important differences would be to justify ASM continuation, rated how likely they might be to withdraw ASMs (1 "not at all likely" to 7 "extremely likely") under different hypothetical seizure risks, and recalled their previous seizure risk counseling. The median age (N = 32) was 46 years (interquartile range [IQR] 33-56), with a median of 3 years since their last seizure (IQR 2-11). Participants rated their two-year chance of another seizure on ASMs as a median 1 (IQR 0 to 2) on a "0-10" scale, compared with a median 5 (IQR 4 to 7) off ASMs. Participants believed that their current ASMs have a median effectiveness of 9 (IQR 7-10) on a "0-10" scale. Participants believed that a median effectiveness of 6 (IQR 4 to 9) on a "0-10" scale would warrant remaining on ASMs, although 5 participants would continue their ASM if it extended the time until next seizure by any amount no matter how small. Regarding how likely they would be to withdraw ASMs under different hypothetical seizure risks, median responses on a "1-7" scale were 5 (IQR 1-6) when shown two-year seizure risks of 10% on vs 11% off ASMs, 1 (1-3) if 10% vs 20%, and 1 (1-2) if 25% vs 50%. No participant recalled having been presented with numerical seizure estimates regarding possible ASM withdrawal, yet 16 (50%) would like this information particularly in our presented graphical format. Participants believed that their ASMs were highly effective and were often reluctant to withdraw. Showing hypothetical seizure risks influenced decisions, and graphical risk communication tools were generally welcomed.

Despite strong evidence supporting timely surgical evaluation, many children with drug-resistant epilepsy undergo multiple antiseizure medication (ASM) trials before surgery. Because guidelines recommend evaluation after failure of 2 appropriate ASMs, evaluation after failure of >2 ASMs serves as a clinically relevant benchmark. The aim of this study was to identify factors associated with initiation of surgical evaluation after failure of >2 ASMs and evaluate its association with seizure freedom. We performed a retrospective analysis using the Pediatric Epilepsy Research Consortium Surgery Database, including 24 US pediatric epilepsy centers. Children aged 18 years and younger who initiated epilepsy surgery evaluation between January 2018 and February 2023 were included. Timing of evaluation was defined by the number of ASM failures before first phase I evaluation (≤2 vs >2). Unadjusted analyses and multivariable logistic regression were used to identify predictors of later evaluation and assess its association with seizure freedom, adjusting for etiology, seizure type, MRI findings, and surgical procedure. Among 1,767 patients, 802 (45.4%) initiated surgical evaluation after failing ≤2 ASMs and 965 (54.6%) after failing >2 ASMs, with a median age at seizure onset of 5.96 and 4.00 years, respectively. Factors independently associated with later initiation of surgical evaluation included genetic etiology (odds ratio [OR] 1.83, 95% CI 1.28-2.60), generalized seizures (OR 2.64, 95% CI 1.58-4.40), daily seizures (OR 1.69, 95% CI 1.33-2.14), multiple seizure types (OR 1.59, 95% CI 1.39-1.82), normal MRI (OR 1.82, 95% CI 1.52-2.18), and abnormal neurologic examination (OR 2.44, 95% CI 2.01-2.96). Surgical intervention rates were similar (∼50%) between groups. Patients who initiated surgical evaluation after failure of ≤2 ASMs had significantly higher seizure freedom rates (60.8% vs 39.3%, p < 0.001). On multivariable analysis, failure of >2 ASMs before surgical evaluation was independently associated with lower odds of seizure freedom (OR 0.66, 95% CI 0.45-0.96, p = 0.028). Initiation of surgical evaluation after failure of more than 2 ASMs is associated with more complex epilepsy phenotypes and lower rates of seizure freedom. However, 80% of these patients still experienced a >50% reduction in seizures, highlighting the therapeutic benefits of timely epilepsy surgery-even when seizure freedom is unlikely-regardless of epilepsy subtype.

IntroductionVagus nerve stimulation (VNS) is an effective, non-pharmacological therapy for epileptic seizures. Until now, favorable combinations of different groups of antiseizure medication (ASM) and VNS have not been sufficiently addressed. The aim of this study was to identify the synergistic effects between VNS and different ASMs.MethodsWe performed an observational study of patients with epilepsy who were implanted with VNS and had a stable ASM therapy during the first 2 years after the VNS implantation. Data were collected from the Mainz Epilepsy Registry. The efficacy of VNS depending on the concomitantly used ASM group/individual ASMs was assessed by quantifying the responder rate (≥ 50% seizure reduction compared to the time of VNS implantation) and seizure freedom (absence of seizures during the last 6 months of the observation period).ResultsOne hundred fifty one patients (mean age 45.2 ± 17.0 years, 78 females) were included in the study. Regardless of the used ASM, the responder rate in the whole cohort was 50.3% and the seizure freedom was 13.9%. Multiple regression analysis showed that combination of VNS with synaptic vesicle glycoprotein (SV2A) modulators (responder rate 64.0%, seizure freedom 19.8%) or slow sodium channel inhibitors (responder rate 61.8%, seizure freedom 19.7%) was associated with a statistically significant better responder rate and seizure freedom than combinations of VNS and ASM with other mechanism of action. Within these ASM groups, brivaracetam showed a more favorable effect than levetiracetam, whereas lacosamide and eslicarbazepine were comparable in their effects.ConclusionOur data suggest that the combination of VNS with ASMs belonging to either SV2A modulators or slow sodium channel inhibitors could be optimal to achieve a better seizure control following VNS. However, these preliminary data require further validation under controlled conditions.

IntroductionIn one third of all patients with epilepsy, seizure freedom is not achieved through anti-seizure medication (ASM). These patients have an increased risk of earlier death, poorer cognitive development, and reduced quality of life. Cenobamate (CNB) has recently been approved as a promising novel ASM drug for the treatment of adults with focal-onset epilepsy. However, there is little experience for its application in pediatric patients.MethodsIn a multicenter study we evaluated retrospectively the outcome of 16 pediatric patients treated “off label” with CNB.ResultsIn 16 patients with a mean age of 15.38 years, CNB was started at an age of 15.05 years due to DRE. Prior to initiation of therapy, an average of 10.56 (range 3–20) ASM were prescribed. At initiation, patients were taking 2.63 (range 1–4) ASM. CNB was increased by 0.47 ± 0.27mg/kg/d every 2 weeks with a mean maximum dosage of 3.1 mg/kg/d (range 0.89–7) and total daily dose of 182.81 mg (range 50–400 mg). Seizure freedom was achieved in 31.3% and a significant seizure reduction of >50% in 37.5%. Adverse events occurred in 10 patients with fatigue/somnolence as the most common. CNB is taken with high adherence in all but three patients with a median follow-up of 168.5 daysConclusionCenobamate is an effective ASM for pediatric patients suffering from drug-resistant epilepsy. In addition to excellent seizure reduction or freedom, it is well-tolerated. Cenobamate should be considered as a novel treatment for DRE in pediatric patients.

<h3>Objective:</h3> An online CME-certified activity was developed to educate neurologists on the importance of achieving seizure freedom and clinical data on seizure freedom for anti-seizure medications (ASMs), particularly among patients refractory to treatment. <h3>Background:</h3> The primary goals of epilepsy treatment are to achieve seizure freedom without side effects. However many patients with epilepsy continue to experience seizures and are not offered therapeutic options that may offer greater seizure control. <h3>Design/Methods:</h3> The online CME activity consisted of a 30-minute video discussion between three expert epileptologists. Educational effect was assessed by comparing neurologists’ pre- and post-activity responses to four questions. A paired-samples t-test was used to assess significant differences between pre- and post-assessment responses. Cohen’s <i>d</i> was used to calculate the effect size of the online education. Data were collected between April 6, 2022 and June 29, 2022. <h3>Results:</h3> Among neurologists who participated in the activity, a small educational effect was observed (n=133; <i>d</i>=.34, <i>P</i>&lt;.001). The following areas showed significant (<i>P</i> &lt;.05) pre- vs post-educational improvements: patient-related consequences of uncontrolled seizures and the seizure-freedom rate reported in a clinical trial of an ASM in patients with treatment refractory focal seizures. There was a non-significant pre-vs post educational improvement on a question asking about how to address dosing when a new ASM is added to an existing ASM. Participation in the activity resulted in 32% of neurologists reporting an increase in confidence regarding their ability to optimize the dosing of ASMs to maximize the chance of achieving seizure freedom. <h3>Conclusions:</h3> The results indicated that a CME-certified 30-minute video activity was effective at improving knowledge among neurologists’ regarding seizure freedom in patients with epilepsy. Given the lack of a significant educational effect on ASM dosing, future education should continue to address dosing in the setting of combination ASM therapy. <b>Disclosure:</b> Dr. Finnegan has nothing to disclose. Jovana Lubarda has nothing to disclose. The institution of Dr. Chung has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for ucb pharma. Dr. Chung has received personal compensation in the range of $500-$4,999 for serving as a Consultant for SK Life sciences. Dr. Chung has received personal compensation in the range of $500-$4,999 for serving as a Consultant for eisai. Dr. Chung has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for eisai. Dr. Chung has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for ucb. Dr. Chung has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for SK Life sciences. Dr. Chung has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for sunovion.

IntroductionEpilepsy is a serious neurological disease, ranking high in the top causes of disability. The main goal of its treatment is to achieve seizure freedom without intolerable adverse effects. However, approximately 40% of patients suffer from Drug-Resistant Epilepsy (DRE) despite the availability of the latest options called third-generation Anti-Seizure Medications(ASMs). Cenobamate is the first ASM approved in Spain for the adjunctive treatment of Focal-Onset Seizures (FOS) in adult patients with DRE. The introduction of a new drug increases the number of therapeutic options available, making it important to compare it with existing alternatives in terms of clinical benefit and efficiency. PurposeThis study aimed to compare the clinical benefit, in terms of the Number Needed to Treat (NNT), and the efficiency, in terms of Cost per NNT (CNT), associated with cenobamate versus third-generation ASMs used in Spain for the adjunctive treatment of FOS in patients with DRE. MethodsThe Number Needed to Treat data was calculated based on the ≥50% responder rate and seizure freedom endpoints (defined as the percentage of patients achieving 50% and 100% reduction in seizure frequency, respectively), obtained from pivotal clinical trials performed with cenobamate, brivaracetam, perampanel, lacosamide, and eslicarbazepine acetate. The NNT was established as the inverse of the treatment responder rate minus the placebo responder rate and was calculated based on the minimum, mid-range Daily Defined Dose (DDD), and maximum doses studied in the pivotal clinical trials of each ASM. CNT was calculated by multiplying the annual treatment cost by NNT values for each treatment option. ResultsIn terms of NNT, cenobamate was the ASM associated with the lowest values at all doses for both ≥50% responder rate and seizure freedom compared with the alternatives. In terms of CNT, for ≥50% responder rate, cenobamate was the ASM associated with the lowest CNT values at DDD and lacosamide and eslicarbazepine acetate at the minimum and maximum dose, respectively. For seizure freedom, cenobamate was associated with the lowest CNT value at DDD and the maximum dose and lacosamide at the minimum dose. ConclusionsCenobamate could represent the most effective ASM in all doses studied compared to the third-generation ASMs and the most efficient option at DDD for both ≥50% responder rate and seizure freedom. This study could represent an important contribution towards informed decision-making regarding the selection of the most appropriate therapy for FOS in adult patients with DRE from a clinical and economical perspective in Spain.

BackgroundMost patients with idiopathic generalized epilepsy have good seizure control on antiseizure medications. Although idiopathic generalized epilepsy subtypes such as juvenile absence epilepsy and juvenile myoclonic epilepsy have a high risk of relapse, childhood absence epilepsy may have seizure remission. After 2 years of seizure freedom in childhood absence epilepsy, typically antiseizure medications are discontinued, but follow-up protocols are unclear. This study aims to evaluate how often patients with idiopathic generalized epilepsy undergo electroencephalography (EEG) after antiseizure medication withdrawal, how often antiseizure medications are restarted based on EEG findings, and if this varies between physicians and advanced practice providers at our institution.MethodsThis was a retrospective chart review. Data were collected using electronic medical records of pediatric patients (<18 years) with idiopathic generalized epilepsy who were successfully weaned off antiseizure medications at Penn State Children's Hospital from 2010 to 2020.ResultsWe reviewed 1409 charts and found 52 patients meeting criteria. Seventeen of 52 patients (32%) had a repeat EEG within 6 months of antiseizure medication withdrawal following seizure freedom. Of those 17 patients, 3 (17.6%) had generalized epileptiform discharges on EEG. Of these 3 patients, 2 (66%) were restarted on antiseizure medications based on the abnormal EEG. None had seizure relapse.ConclusionObtaining a repeat EEG in patients after antiseizure medication withdrawal following seizure freedom is common. Patients with an abnormal EEG are often restarted on antiseizure medications, irrespective of clinical seizure relapse. Considering the high health care costs of EEGs and antiseizure medication side effects, we propose that if patients with idiopathic generalized epilepsy do well clinically following antiseizure medication withdrawal, EEGs may not be necessary.

Clinical factors associated with late seizure remission after failed epilepsy surgery

BACKGROUND Approximately 60% of patients with gliomas suffer from medically refractory brain tumor related epilepsy (BTRE), requiring two or more antiseizure medications (ASMs)(Seidel, 2022). Seizures, in addition to the use of multiple ASMs, are associated with lower quality of life in patients (Terman, 2020; Iannou 2022). Clobazam is an add-on therapy which can be effective in refractory BTRE (Van der Meer 2023, Brahmbhatt 2021). This study evaluates the response of patients with refractory BTRE to clobazam and the potential to reduce other ASMs. METHODS This single study retrospective analysis evaluates 48 patients from a single institution diagnosed with a glioma who received clobazam at some point in their treatment between June 2017- June 2024. Data was collected, including seizure type, frequency, and ASMs, at 6 months and last documented follow-up visit. RESULTS At 6 months on clobazam, 68.8% (33/48) of patients were seizure free, and at the final timepoint (average 26.8 months), 60.4% (29/48) were seizure free. At 6 months, 33.3% (16/48) of patients were able to decrease their total other ASMs while maintaing seizure freedom. Of those who did not decrease the number of other ASMs taken, 21.9% (7/32) were able to reduce the dosage of other ASMs. At the final timepoint, 50.0% (24/48) of patients decreased the number of other ASMs they were taking. CONCLUSIONS Despite failing other ASMs, the majority of patients who took clobazam became seizure free. While seizure freedom is the overall goal, reducing side effects is equally important for quality of life. After initiating clobazam, number and dosages of concurrent ASMs may also be reduced while maintaining seizure freedom or a reduced seizure frequency.

Perampanel effectiveness and tolerability in patients with epilepsy at long-term follow-up

Understanding the multi-faceted treatment outcomes of newly diagnosed epilepsy is critical for developing rational therapeutic strategies. A meta-analysis was conducted to derive pooled estimates of a range of seizure outcomes in children and adults with newly diagnosed epilepsy commenced on antiseizure medication treatment, and to identify factors associated with different outcomes. PubMed/EMBASE were screened for eligible articles between 1 January, 1995 and 1 May, 2021 to include unselected cohort studies with a ≥ 12-month follow-up of seizure outcomes. Proportions of patients seizure free at different follow-up timepoints and their characteristics at the study population level were extracted. The patients were group-wise aggregated using a random-effects model. Primary outcomes were proportions of patients with cumulative 1-year seizure freedom (C1YSF), and 1-year and 5-year terminal seizure freedom (T1YSF and T5YSF). Secondary outcomes included the proportions of patients with early sustained seizure freedom, drug-resistant epilepsy and seizure-free off antiseizure medication at the last follow-up (off antiseizure medications). A separate random-effects meta-analysis was performed for nine predictors of importance. In total, 39 cohorts (total n = 21,139) met eligibility criteria. They included 15 predominantly adult cohorts (n = 12,024), 19 children (n = 6569), and 5 of mixed-age groups (n = 2546). The pooled C1YSF was 79% (95% confidence interval [CI] 74-83). T1YSF was 68% (95% CI 63-72) and T5YSF was 69% (95% CI 62-75). Children had higher C1YSF (85% vs 68%, p < 0.001) and T1YSF than adult cohorts (74% vs 61%, p = 0.007). For secondary outcomes, 33% (95% CI 27-39) of patients achieved early sustained seizure freedom, 17% (95% CI 13-21) developed drug resistance, and 39% (95% CI 30-50) were off antiseizure medications at the last follow-up. Studies with a longer follow-up duration correlated with higher C1YSF (p < 0.001) and being off antiseizure medications (p = 0.045). Outcomes were not associated with study design (prospective vs retrospective), cohort size, publication year, or the earliest date of recruitment. Predictors of importance in newly diagnosed epilepsy include etiology, epilepsy type, abnormal diagnostics (neuroimaging, examination, and electroencephalogram findings), number of seizure types, and pre-treatment seizure burden. Seizure freedom is achieved with currently available antiseizure medications in most patients with newly diagnosed epilepsy, yet this is often not immediate, may not be sustainable, and has not improved over recent decades. Symptomatic etiology, abnormal neuro-diagnostics, and increased pre-treatment seizure burden and seizure types are important predictors for unfavorable outcomes in newly diagnosed epilepsy. The study findings may be used as a quantitative benchmark on the efficacy of future antiseizure medication therapy for this patient population.

To investigate the interaction among the efficacy, tolerability and overall effectiveness of the first antiseizure medication in patients 16years or older with newly diagnosed epilepsy. The study included 584 patients who were referred to the Tampere University Hospital between 1 January 1995 and 31 December 2005 and were diagnosed with epilepsy. All individuals were retrospectively followed up until 31 December 2006, until reaching at least one year of seizure freedom, or until death if before the cut-off date. Overall, after thorough validation of the epilepsy diagnosis 459 patients comprised the study cohort; among these patients, 73% of males and 60% of females became seizure-free for at least one year with the first antiseizure medication. The seizure freedom rate for focal epilepsy was 67%. There was no significant difference in focal epilepsy to achieve seizure freedom between oxcarbazepine, carbamazepine or valproic acid. The seizure freedom rate among patients above 60years of age was 67%. For patients with structural and unknown aetiology, seizure freedom rates were 61.5% and 75.3%, respectively. Additionally, epileptiform activity on EEG in patients with focal epilepsy decreased odds of seizure freedom in adjusted logistic regression models (OR 0.55, p=0.036). This study provides a more positive prediction of seizure freedom compared with previous studies with the onset of epilepsy at 16years or older with an overall estimation that two-thirds of patients with new-onset epilepsy obtain seizure freedom with the first antiseizure medication.

ObjectivesTo determine the clinical features and anti-seizure medication (ASM) strategies associated with an unanticipated substantial improvement in seizure control in patients with drug-resistant epilepsy (DRE). MethodsThis retrospective analysis of patients attending a tertiary care epilepsy clinic between 2008 and 2017 identified all patients with active DRE (at least 1 seizure per month for 6 months, despite treatment with 2 different ASMs). All treatment interventions were recorded from when DRE was first identified to the end of the study. The primary end points were seizure freedom or meaningful reduction in seizure frequency (greater than 75 %) sustained for at least 12 months after a treatment intervention. ResultsThree hundred and twenty-two patients were included in the analysis. Overall, 10 % became seizure free following ASM adjustment and an additional 10 % had a greater than 75 % improvement in seizure control (median follow-up, 4 years). An ASM introduction was ten times more likely than an ASM dose increase to improve seizure control. Combined focal and generalized epilepsy, intellectual disability and prior treatment with more than 5 ASMs were more frequently observed in those with continued pharmacoresistance. ASM responders were more likely to have primary generalized epilepsy. Rational polytherapy (combining ASMs with different mechanisms of action) was almost ubiquitous amongst ASMs responders (95 % taking at least 2 drugs with different mechanistic targets). Of the ASM additions that heralded improved seizure control, 85 % were maintained at submaximal doses. ConclusionsThis retrospective analysis of a large number of ‘real-world’ patients provides evidence to persist with ASM trials in DRE. Early rotation of ASMs if a clinical response is not observed at a substantial dose and rational ASM polytherapy may yield better clinical outcomes in patients with DRE, although a prospective study would need to be conducted to validate these findings.