Exit Strategy: Balancing the Risks and Rewards of Antiseizure Medication Withdrawal.

The majority of people with epilepsy achieves long-term seizure-freedom and may consider withdrawal of their anti-seizure medications (ASMs). Withdrawal of ASMs can yield substantial benefits but may be associated with potential risks. This review critically examines the existing literature on ASM withdrawal, emphasizing evidence-based recommendations, where available. Our focus encompasses deprescribing strategies for individuals who have attained seizure freedom through medical treatment, those who have undergone successful epilepsy surgery, and individuals initiated on ASMs following acute symptomatic seizures. We explore state-of-the-art prognostic models in these scenarios that could guide the decision-making process. The review underscores the importance of a collaborative shared-decision approach between patients, caregivers, and physicians. We describe the subjective and objective factors influencing these decisions and illustrate how trade-offs may be effectively managed in practice.

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.

Hospital variation of outcomes in status epilepticus.

OBJECTIVE: Understanding factors driving variation in status epilepticus outcomes would be critical to improve care. We evaluated the degree to which patient and hospital characteristics explained hospital-to-hospital variability in intubation and postacute outcomes. METHODS: This was a retrospective cohort study of Medicare beneficiaries admitted with status epilepticus between 2009 and 2019. Outcomes included intubation, discharge to a facility, and 30- and 90-day readmissions and mortality. Multilevel models calculated percent variation in each outcome due to hospital-to-hospital differences. RESULTS: We included 29 150 beneficiaries. The median age was 68 years (interquartile range [IQR] = 57-78), and 18 084 (62%) were eligible for Medicare due to disability. The median (IQR) percentages of each outcome across hospitals were: 30-day mortality 25% (0%-38%), any 30-day readmission 14% (0%-25%), 30-day status epilepticus readmission 0% (0%-3%), 30-day facility stay 40% (25%-53%), and intubation 46% (20%-61%). However, after accounting for many hospitals with small sample size, hospital-to-hospital differences accounted for 2%-6% of variation in all unadjusted outcomes, and approximately 1%-5% (maximally 8% for 30-day readmission for status epilepticus) after adjusting for patient, hospitalization, and/or hospital characteristics. Although many characteristics significantly predicted outcomes, the largest effect size was cardiac arrest predicting death (odds ratio = 10.1, 95% confidence interval = 8.8-11.7), whereas hospital characteristics (e.g., staffing, accreditation, volume, setting, services) all had lesser effects. SIGNIFICANCE: Hospital-to-hospital variation explained little variation in studied outcomes. Rather, certain patient characteristics (e.g., cardiac arrest) had greater effects. Interventions to improve outcomes after status epilepticus may be better focused on individual or prehospital factors, rather than at the inpatient systems level.

Variation in seizure risk increases from antiseizure medication withdrawal among patients with well-controlled epilepsy: A pooled analysis.

OBJECTIVE: Guidelines suggest considering antiseizure medication (ASM) discontinuation in seizure-free patients with epilepsy. Past work has poorly explored how discontinuation effects vary between patients. We evaluated (1) what factors modify the influence of discontinuation on seizure risk; and (2) the range of seizure risk increase due to discontinuation across low- versus high-risk patients. METHODS: We pooled three datasets including seizure-free patients who did and did not discontinue ASMs. We conducted time-to-first-seizure analyses. First, we evaluated what individual patient factors modified the relative effect of ASM discontinuation on seizure risk via interaction terms. Then, we assessed the distribution of 2-year risk increase as predicted by our adjusted logistic regressions. RESULTS: We included 1626 patients, of whom 678 (42%) planned to discontinue all ASMs. The mean predicted 2-year seizure risk was 43% [95% confidence interval (CI) 39%-46%] for discontinuation versus 21% (95% CI 19%-24%) for continuation. The mean 2-year absolute seizure risk increase was 21% (95% CI 18%-26%). No individual interaction term was significant after correcting for multiple comparisons. The median [interquartile range (IQR)] risk increase across patients was 19% (IQR 14%-24%; range 7%-37%). Results were unchanged when restricting analyses to only the two RCTs. SIGNIFICANCE: No single patient factor significantly modified the influence of discontinuation on seizure risk, although we captured how absolute risk increases change for patients that are at low versus high risk. Patients should likely continue ASMs if even a 7% 2-year increase in the chance of any more seizures would be too much and should likely discontinue ASMs if even a 37% risk increase would be too little. In between these extremes, individualized risk calculation and a careful understanding of patient preferences are critical. Future work will further develop a two-armed individualized seizure risk calculator and contextualize seizure risk thresholds below which to consider discontinuation. PLAIN LANGUAGE SUMMARY: Understanding how much antiseizure medications (ASMs) decrease seizure risk is an important part of determining which patients with epilepsy should be treated, especially for patients who have not had a seizure in a while. We found that there was a wide range in the amount that ASM discontinuation increases seizure risk-between 7% and 37%. We found that no single patient factor modified that amount. Understanding what a patient's seizure risk might be if they discontinued versus continued ASM treatment is critical to making informed decisions about whether the benefit of treatment outweighs the downsides.

Deprescribing medications among patients with multiple prescribers: A socioecological model.

Deprescribing is the intentional dose reduction or discontinuation of a medication. The development of deprescribing interventions should take into consideration important organizational, interprofessional, and patient-specific barriers that can be further complicated by the presence of multiple prescribers involved in a patient's care. Patients who receive care from an increasing number of prescribers may experience disruptions in the timely transfer of relevant healthcare information, increasing the risk of exposure to drug-drug interactions and other medication-related problems. Furthermore, the fragmentation of healthcare information across health systems can contribute to the refilling of discontinued medications, reducing the effectiveness of deprescribing interventions. Thus, deprescribing interventions must carefully consider the unique characteristics of patients and their prescribers to ensure interventions are successfully implemented. In this special article, an international working group of physicians, pharmacists, nurses, epidemiologists, and researchers from the United States Deprescribing Research Network (USDeN) developed a socioecological model to understand how multiple prescribers may influence the implementation of a deprescribing intervention at the individual, interpersonal, organizational, and societal level. This manuscript also includes a description of the concept of multiple prescribers and outlines a research agenda for future investigations to consider. The information contained in this manuscript should be used as a framework for future deprescribing interventions to carefully consider how multiple prescribers can influence the successful implementation of the service and ensure the intervention is as effective as possible.

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.

Lamotrigine and exogenous estrogen among females with epilepsy: A retrospective analysis of administrative claims data.

OBJECTIVE: Exogenous estrogen reduces lamotrigine serum concentrations. Little is known about whether providers adjust lamotrigine doses for addition of exogenous estrogen among people with epilepsy, despite expert recommendations. We determined the incidence of dose increases in lamotrigine following incident prescription of estrogen among females with epilepsy (FWE) in claims data. METHODS: We used Optum's de-identified Clinformatics® Data Mart Database to create a cohort of U.S. FWE prescribed lamotrigine at a stable dose, with a subsequent prescription for estrogen from 2011 to 2021. We calculated cumulative incidence functions of dose increases in lamotrigine following prescription of exogenous estrogen. We performed a Cox proportional hazards model for multiple candidate predictors of a lamotrigine dose increase. RESULTS: The cohort included 643 FWE, with median age of 31 (interquartile ratio [IQR] 20-42). The cumulative incidence of any lamotrigine increase was 28% (95% confidence interval [CI] 25%-32%). The median number of days after the first estrogen fill until the first lamotrigine adjustment was 118 (IQR 48-188). In unadjusted Cox models, older age, use of estrogen in hormone replacement therapy as opposed to contraception, and annual household income of $50,000-$99,999 (compared with <$50,000) were significant negative predictors of a dose adjustment in lamotrigine with hazard ratios (HRs) of 0.82 (95% CI 0.72-0.92), 0.63 (95% CI 0.42-0.95), and 0.62 (95% CI 0.40-0.95). In the adjusted Cox model, age and income remained significant predictors with HRs of 0.79 (95% CI 0.66-0.94) and 0.59 (95% CI 0.36-0.95). CONCLUSION: Dose increase of lamotrigine following addition of exogenous estrogen is rare among U.S. FWE, with potential disparities based on age and income level. More guidance may be needed for providers on this topic.

Secular Trends in Central Nervous System-Active Polypharmacy Among Serial Cross-Sections of US Adults, 2009-2020.

BACKGROUND: Data comprehensively examining trends in central nervous system (CNS)-active polypharmacy are limited. The objective of this cross-sectional study was to characterize the composition of and trends in CNS-active medication use in US adults. METHODS: We included all participants ≥ 18 years old in the National Health and Nutrition Examination Study (NHANES), 2009-2020. The primary outcome was the percent of adults with CNS-active polypharmacy. This was defined as ≥ 3 medications among antidepressants [tricyclic, selective and serotonin-norepinephrine reuptake inhibitors (SSRIs and SNRIs), opioids, antiepileptics, antipsychotics, benzodiazepines, and nonbenzodiazepine receptor agonists ("Z-drugs")]. Secondary outcomes included prevalence of any CNS-active medication and specific medications and classes over time, and their indications. Percentages were weighted according to NHANES's nationally representative sampling frame. log binomial regressions evaluated the relative risk (RR) for each outcome, comparing the last (2017-2020) versus the first (2010-2011) survey cycle. RESULTS: We included 34,189 adults (18.8% at least 65 years old) from five serial cross-sections (survey cycles). The prevalence of CNS-active polypharmacy was 2.1% in 2009-2010 and 2.6% in 2017-2020 [RR 1.18, 95% confidence interval (CI) 0.94-1.47]. The prevalence of CNS-active polypharmacy did not significantly change within any specific age group (e.g., age at least 65 years: RR 1.29, CI 0.74-2.24). The prevalence of any CNS-active medication was 21.0% in 2009 and 24.6% in 2017-2020 (RR] 1.12, 95% CI 1.02-1.25). A substantial increase occurred for antiepileptics (5.1-8.3%), specifically among participants aged 65 years and older (8.3-13.7%). This was largely driven by increasing gabapentin prevalence (1.4-3.6% overall; 3.3-7.9% age 65 years and older). Anticholinergic, SSRIs/SNRIs, antiepileptics, and benzodiazepines were elevated in most cycles for participants at least 65 years old compared with participants less than 65 years, and opioid use was increased in several cycles for older participants as well. Alprazolam was the most common benzodiazepine and third most common medication for anxiety/depression. Gabapentin was the most common CNS-active medication (3.6% of all participants in 2017-2020), followed by sertraline, citalopram, and acetaminophen-hydrocodone (each ~2%). The most common categories were antidepressants (13.7% in 2017-2020), followed by opioids (5.1% in 2017-2020). CONCLUSIONS: CNS-active medications are increasingly common, particularly gabapentin, and use of any CNS-active medication increased by 12%. Numerous CNS-active classes also increased in older adults throughout the years. Increasing suboptimal medication use highlight the need for further investigation into causes for potentially inappropriate prescribing, particularly for older adults.

Generalization of finetuned transformer language models to new clinical contexts.

Objective: We have previously developed a natural language processing pipeline using clinical notes written by epilepsy specialists to extract seizure freedom, seizure frequency text, and date of last seizure text for patients with epilepsy. It is important to understand how our methods generalize to new care contexts. Materials and methods: We evaluated our pipeline on unseen notes from nonepilepsy-specialist neurologists and non-neurologists without any additional algorithm training. We tested the pipeline out-of-institution using epilepsy specialist notes from an outside medical center with only minor preprocessing adaptations. We examined reasons for discrepancies in performance in new contexts by measuring physical and semantic similarities between documents. Results: Our ability to classify patient seizure freedom decreased by at least 0.12 agreement when moving from epilepsy specialists to nonspecialists or other institutions. On notes from our institution, textual overlap between the extracted outcomes and the gold standard annotations attained from manual chart review decreased by at least 0.11 F1 when an answer existed but did not change when no answer existed; here our models generalized on notes from the outside institution, losing at most 0.02 agreement. We analyzed textual differences and found that syntactic and semantic differences in both clinically relevant sentences and surrounding contexts significantly influenced model performance. Discussion and conclusion: Model generalization performance decreased on notes from nonspecialists; out-of-institution generalization on epilepsy specialist notes required small changes to preprocessing but was especially good for seizure frequency text and date of last seizure text, opening opportunities for multicenter collaborations using these outcomes.

Predictors of referral for long-term EEG monitoring for Medicare beneficiaries with drug-resistant epilepsy.

OBJECTIVE: For people with drug-resistant epilepsy, the use of epilepsy surgery is low despite favorable odds of seizure freedom. To better understand surgery utilization, we explored factors associated with inpatient long-term EEG monitoring (LTM), the first step of the presurgical pathway. METHODS: Using 2001-2018 Medicare files, we identified patients with incident drug-resistant epilepsy using validated criteria of ≥2 distinct antiseizure medication (ASM) prescriptions and ≥1 drug-resistant epilepsy encounter among patients with ≥2 years pre- and ≥1 year post-diagnosis Medicare enrollment. We used multilevel logistic regression to evaluate associations between LTM and patient, provider, and geographic factors. We then analyzed neurologist-diagnosed patients to further evaluate provider/environmental characteristics. RESULTS: Of 12 044 patients with incident drug-resistant epilepsy diagnosis identified, 2% underwent surgery. Most (68%) were diagnosed by a neurologist. In total, 19% underwent LTM near/after drug-resistant epilepsy diagnosis; another 4% only underwent LTM much prior to diagnosis. Patient factors most strongly predicting LTM were age <65 (adjusted odds ratio 1.5 [95% confidence interval 1.3-1.8]), focal epilepsy (1.6 [1.4-1.9]), psychogenic non-epileptic spells diagnosis (1.6 [1.1-2.5]) prior hospitalization (1.7, [1.5-2]), and epilepsy center proximity (1.6 [1.3-1.9]). Additional predictors included female gender, Medicare/Medicaid non-dual eligibility, certain comorbidities, physician specialties, regional neurologist density, and prior LTM. Among neurologist-diagnosed patients, neurologist <10 years from graduation, near an epilepsy center, or epilepsy-specialized increased LTM likelihood (1.5 [1.3-1.9], 2.1 [1.8-2.5], 2.6 [2.1-3.1], respectively). In this model, 37% of variation in LTM completion near/after diagnosis was explained by individual neurologist practice and/or environment rather than measurable patient factors (intraclass correlation coefficient 0.37). SIGNIFICANCE: A small proportion of Medicare beneficiaries with drug-resistant epilepsy completed LTM, a proxy for epilepsy surgery referral. While some patient factors and access measures predicted LTM, non-patient factors explained a sizable proportion of variance in LTM completion. To increase surgery utilization, these data suggest initiatives targeting better support of neurologist referral.

Antiseizure Medication Withdrawal Practice Patterns: A Survey Among Members of the American Academy of Neurology and EpiCARE.

Background and Objectives: To describe neurologist practice patterns, challenges, and decision support needs pertaining to withdrawal of antiseizure medications (ASMs) in patients with well-controlled epilepsy. Methods: We sent an electronic survey to (1) US and (2) European physician members of the American Academy of Neurology and (3) members of EpiCARE, a European Reference Network for rare and complex epilepsies. Analyses included frequencies and percentages, and we showed distributions through histograms and violin plots. Results: We sent the survey to 4,923 individuals; 463 consented, 411 passed eligibility questions, and 287 responded to at least 1 of these questions. Most respondents indicated that they might ever consider ASM withdrawal, with respondents treating mostly children being more likely ever to consider withdrawal (e.g., medical monotherapy: children 96% vs adults 81%; p < 0.05). The most important factors when making decisions included seizure probability (83%), consequences of seizures (73%), and driving (74%). The top challenges when making decisions included unclear seizure probability (81%), inadequate guidelines (50%), and difficulty communicating probabilities (45%). Respondents would consider withdrawal after a median of 2-year seizure freedom, but also responded that they would begin withdrawal on average only when the postwithdrawal seizure relapse risk in the coming 2 years was less than 15%-30%. Wide variation existed in the use of words or numbers in respondents' counsel methods, for example, percentages vs frequencies or probability of seizure freedom vs seizure. The most highly rated point-of-care methods to inform providers of calculated risk were Kaplan-Meier curves and showing percentages only, rather than pictographs or text recommendations alone. Discussion: Most surveyed neurologists would consider withdrawing ASMs in seizure-free individuals. Seizure probability was the largest factor driving decisions, yet estimating seizure probabilities was the greatest challenge. Respondents on average indicated that they may withdraw ASM after a minimum seizure-free duration of 2 years, yet also on average were willing to withdraw when seizure risk decreased below 15%-30%, which is lower than most patients' postwithdrawal risk at 2-year seizure freedom and lower than the equivalent even of a first seizure of life. These findings will inform future efforts at developing decision support tools aimed at optimizing ASM withdrawal decisions.

Best-worst scaling preferences among patients with well-controlled epilepsy: Pilot results.

Epilepsy is a common, serious condition. Fortunately, seizure risk decreases with increasing seizure-free time on antiseizure medications (ASMs). Eventually, patients may consider whether to stop ASMs, which requires weighing treatment benefit versus burden. We developed a questionnaire to quantify patient preferences relevant to ASM decision-making. Respondents rated how concerning they would finding relevant items (e.g., seizure risks, side effects, cost) on a Visual Analogue Scale (VAS, 0-100) and then repeatedly chose the most and least concerning item from subsets (best-worst scaling, BWS). We pretested with neurologists, then recruited adults with epilepsy who were seizure-free at least one year. Primary outcomes were recruitment rate, and qualitative and Likert-based feedback. Secondary outcomes included VAS ratings and best-minus-worst scores. Thirty-one of 60 (52%) contacted patients completed the study. Most patients felt VAS questions were clear (28; 90%), easy to use (27; 87%), and assessed preferences well (25; 83%). Corresponding results for BWS questions were 27 (87%), 29 (97%), and 23 (77%). Physicians suggested adding a 'warmup' question showing a completed example and simplifying terminology. Patients suggested ways to clarify instructions. Cost, inconvenience of taking medication, and laboratory monitoring were the least concerning items. Cognitive side effects and a 50% seizure risk in the next year were the most concerning items. Twelve (39%) of patients made at least one 'inconsistent choice' for example ranking a higher seizure risk as lower concern compared with a lower seizure risk, though 'inconsistent choices' represented only 3% of all question blocks. Our recruitment rate was favorable, most patients agreed the survey was clear, and we describe areas for improvement. 'Inconsistent' responses may lead us to collapse seizure probability items into a single 'seizure' category. Evidence regarding how patients weigh benefits and harms may inform care and guideline development.

Antiseizure medication withdrawal risk estimation and recommendations: A survey of American Academy of Neurology and EpiCARE members.

OBJECTIVE: Choosing candidates for antiseizure medication (ASM) withdrawal in well-controlled epilepsy is challenging. We evaluated (a) the correlation between neurologists' seizure risk estimation ("clinician predictions") vs calculated predictions, (b) how viewing calculated predictions influenced recommendations, and (c) barriers to using risk calculation. METHODS: We asked US and European neurologists to predict 2-year seizure risk after ASM withdrawal for hypothetical vignettes. We compared ASM withdrawal recommendations before vs after viewing calculated predictions, using generalized linear models. RESULTS: Three-hundred and forty-six neurologists responded. There was moderate correlation between clinician and calculated predictions (Spearman coefficient 0.42). Clinician predictions varied widely, for example, predictions ranged 5%-100% for a 2-year seizure-free adult without epileptiform abnormalities. Mean clinician predictions exceeded calculated predictions for vignettes with epileptiform abnormalities (eg, childhood absence epilepsy: clinician 65%, 95% confidence interval [CI] 57%-74%; calculated 46%) and surgical vignettes (eg, focal cortical dysplasia 6-month seizure-free mean clinician 56%, 95% CI 52%-60%; calculated 28%). Clinicians overestimated the influence of epileptiform EEG findings on withdrawal risk (26%, 95% CI 24%-28%) compared with calculators (14%, 95% 13%-14%). Viewing calculated predictions slightly reduced willingness to withdraw (-0.8/10 change, 95% CI -1.0 to -0.7), particularly for vignettes without epileptiform abnormalities. The greatest barrier to calculator use was doubting its accuracy (44%). SIGNIFICANCE: Clinicians overestimated the influence of abnormal EEGs particularly for low-risk patients and overestimated risk and the influence of seizure-free duration for surgical patients, compared with calculators. These data may question widespread ordering of EEGs or time-based seizure-free thresholds for surgical patients. Viewing calculated predictions reduced willingness to withdraw particularly without epileptiform abnormalities.

Frequency of and factors associated with antiseizure medication discontinuation discussions and decisions in patients with epilepsy: A multicenter retrospective chart review.

OBJECTIVE: Guidelines suggest considering antiseizure medication (ASM) discontinuation in patients with epilepsy who become seizure-free. Little is known about how discontinuation decisions are being made in practice. We measured the frequency of, and factors associated with, discussions and decisions surrounding ASM discontinuation. METHODS: We performed a multicenter retrospective cohort study at the University of Michigan (UM) and two Dutch centers: Wilhelmina Children's Hospital (WCH) and Stichting Epilepsie Instellingen Nederland (SEIN). We screened all children and adults with outpatient epilepsy visits in January 2015 and included those with at least one visit during the subsequent 2 years where they were seizure-free for at least one year. We recorded whether charts documented (1) a discussion with the patient about possible ASM discontinuation and (2) any planned attempt to discontinue at least one ASM. We conducted multilevel logistic regressions to determine factors associated with each outcome. RESULTS: We included 1058 visits from 463 patients. Of all patients who were seizure-free at least one year, 248/463 (53%) had documentation of any discussion and 98/463 (21%) planned to discontinue at least one ASM. Corresponding frequencies for patients who were seizure-free at least 2 years were 184/285 (65%) and 74/285 (26%). The probability of discussing or discontinuing increased with longer duration of seizure freedom. Still, even for patients who were 10 years seizure-free, our models predicated that in only 49% of visits was a discontinuation discussion documented, and in only 16% of visits was it decided to discontinue all ASMs. Provider-to-provider variation explained 18% of variation in whether patients discontinued any ASM. SIGNIFICANCE: Only approximately half of patients with prolonged seizure freedom had a documented discussion about ASM discontinuation. Discontinuation was fairly rare even among low-risk patients. Future work should further explore barriers to and facilitators of counseling and discontinuation attempts.