Elevated Mortality Rate in Patients With Functional Seizures After Diagnosis and Referral.

Background and Objectives: To evaluate the standardized mortality ratio (SMR) of patients in the United States referred to a multidisciplinary clinic for treatment of functional seizures. Methods: We identified patients who had or had not died based on automated retrospective review of electronic health records from a registry of patients referred to a single-center multidisciplinary functional seizures treatment clinic. We calculated an SMR by comparing the number of observed deaths with the expected number of deaths in an age-matched, sex-matched, and race-matched population within the same state, and year records were available. Results: A total of 700 patients with functional seizures (mean age 37 years, 78% female) were followed up for 1,329 patient-years for a median of 15 months per patient (interquartile range 6-37 months). We observed 11 deaths, corresponding to a mortality rate of 8.2 per 1,000 patient-years and an SMR of 2.4 (95% confidence interval: 1.17-4.22). Five of 9 patients with identified circumstances around their death were in hospice care when they passed. None of the identified causes of death were related to seizures directly. Discussion: These data provide further evidence of elevated mortality in functional seizures soon after diagnosis and referral to treatment. These data from the decentralized health care system of the United States build on the findings from other countries with large-scale health registries.

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.

Machine Learning and Artificial Intelligence Applications to Epilepsy: a Review for the Practicing Epileptologist.

PURPOSE OF REVIEW: Machine Learning (ML) and Artificial Intelligence (AI) are data-driven techniques to translate raw data into applicable and interpretable insights that can assist in clinical decision making. Some of these tools have extremely promising initial results, earning both great excitement and creating hype. This non-technical article reviews recent developments in ML/AI in epilepsy to assist the current practicing epileptologist in understanding both the benefits and limitations of integrating ML/AI tools into their clinical practice. RECENT FINDINGS: ML/AI tools have been developed to assist clinicians in almost every clinical decision including (1) predicting future epilepsy in people at risk, (2) detecting and monitoring for seizures, (3) differentiating epilepsy from mimics, (4) using data to improve neuroanatomic localization and lateralization, and (5) tracking and predicting response to medical and surgical treatments. We also discuss practical, ethical, and equity considerations in the development and application of ML/AI tools including chatbots based on Large Language Models (e.g., ChatGPT). ML/AI tools will change how clinical medicine is practiced, but, with rare exceptions, the transferability to other centers, effectiveness, and safety of these approaches have not yet been established rigorously. In the future, ML/AI will not replace epileptologists, but epileptologists with ML/AI will replace epileptologists without ML/AI.

Using Verbally-Reported and Video-Observed Semiology to Identify Functional Seizures.

Diagnosis of functional seizures, also known as psychogenic nonepileptic seizures, starts with a clinical interview and description of the seizures. A targeted approach to this evaluation can provide valuable information to gauge the likelihood of functional seizures as compared with other similar conditions including but not limited to epileptic seizures. This review focuses on the use of patient and witness descriptions and seizure videos to identify patients with probable functional seizures. Particular emphasis is given to recognizing the limitations of the available data and the influence of health-care provider expertise on diagnostic accuracy.

Functional Seizure Clinics: A Proposed Financially Viable Solution to the Neurologist Supply and Demand Mismatch.

Background and Objectives: Projections from recent studies suggest that by 2025, there will not be enough neurologists to meet the demand in 41 states. In this study, we investigate the financial impact and improved access to care for persons with epilepsy that is possible by implementing a multidisciplinary treatment clinic for persons with functional seizures (FS), previously referred to as psychogenic nonepileptic seizures, thus separating those patients out of an epilepsy clinic. Methods: This observational retrospective study used real-time data of 156 patients referred to an FS clinic integrated into a tertiary care epilepsy center to simulate its effect on epilepsy division access and finances. Access was measured using simulations of the number of return patient visits (RPVs) and new patient visits (NPVs) of patients with FS to a dedicated epilepsy clinic, based on survey results inquiring about the standard of care without the FS clinic. Finances were simulated using the resultant access multiplied by respective wRVU and reimbursement per CPT code. Results: Treatment of 156 patients with FS in a multidisciplinary FS clinic resulted in 343 newly opened NPVs, reimbursement of $102,000, and 1,200 wRVUs in our dedicated epilepsy clinic. There were 686 RPVs, $103,000 in reimbursement, and 1,320 wRVUs. Relative to the total number of NPVs with epilepsy clinic epileptologists, 343 NPVs represent a biennial 15.5% increase in available new patient visit slots. Discussion: Our findings describe the financial viability of integrating a treatment clinic for persons with FS by directing them to FS-specialized treatment and thereby increasing access for patients with probable epilepsy to the dedicated epilepsy clinic. This study provides a potential solution to the national mismatch in the supply and demand of neurologists and an initial framework to use for those who wish to establish or integrate FS services in their institution.

Increasing challenges to trial recruitment and conduct over time.

OBJECTIVE: This study was undertaken to evaluate how the challenges in the recruitment and retention of participants in clinical trials for focal onset epilepsy have changed over time. METHODS: In this systematic analysis of randomized clinical trials of adjunct antiseizure medications for medication-resistant focal onset epilepsy, we evaluated how the numbers of participants, sites, and countries have changed since the first such trial in 1990. We also evaluated the proportion of participants who completed each trial phase and their reasons for early trial exit. We analyzed these trends using mixed effects generalized linear models accounting for the influence of the number of trial sites and trial-specific variability. RESULTS: The number of participants per site has steadily decreased over decades, with recent trials recruiting fewer than five participants per site (reduction by .16 participants/site/year, p < .0001). Fewer participants also progressed from recruitment to randomization over time (odds ratio = .94/year, p = .014). Concurrently, there has been an increase in the placebo response over time (increase in median percent reduction of .4%/year, p = .02; odds ratio of increase in 50% responder rate of 1.03/year, p = .02), which was not directly associated with the number of sites per trial (p > .20). SIGNIFICANCE: This historical analysis highlights the increasing challenges with participant recruitment and retention, as well as increasing placebo response. It serves as a call to action to change clinical trial design to address these challenges.

Sustainability of seizure reduction and seizure control with adjunctive cenobamate: Post hoc analysis of a phase 3, open-label study.

OBJECTIVE: In this post hoc analysis of a subset of patients from a long-term, open-label phase 3 study, we assessed ≥50%, ≥75%, ≥90%, and 100% seizure reduction and sustainability of these responses with cenobamate using a time-to-event analytical approach. METHODS: Of 240 patients with uncontrolled focal seizures who had adequate seizure data available, 214 completed the 12-week titration phase and received ≥1 dose of cenobamate in the maintenance phase (max dose 400 mg/day) and were included in this post hoc analysis. Among patients who met an initial given seizure-reduction level (≥50%, ≥75%, ≥90%, or 100%), sustainability of that response was measured using a time-to-event methodology. An event was defined as the occurrence of a study visit at which the seizure frequency during the interval since the prior study visit exceeded the initially attained reduction level. Study visits during the maintenance phase occurred at 3-month intervals. RESULTS: Of the 214 patients analyzed, 188 (88%), 177 (83%), 160 (75%), and 145 (68%) met ≥50%, ≥75%, ≥90%, and 100% seizure-reduction responses, respectively, for at least one study visit interval during the maintenance phase. The median (95% confidence interval [CI]) time to first visit without a ≥50% seizure reduction was not reached by 30 months of follow-up (53% of patients maintained their initial ≥50% seizure reduction). Median (95% CI) time to first visit without sustaining the initial ≥75%, ≥90%, or 100% seizure reduction was 13.0 (7.5-21.9) months, 7.5 (5.4-11.6) months, and 7.0 (5.3-10.4) months, respectively. Among the 145 patients who had 100% seizure reduction during at least one study visit, 22% remained seizure-free for at least 30 months and 63% had ≤3 study visits with seizures. SIGNIFICANCE: Adjunctive treatment with cenobamate led to sustained seizure reductions during the maintenance phase of the phase 3 safety study.

Amygdala subfield and prefrontal cortex abnormalities in patients with functional seizures.

BACKGROUND: Functional seizures (FS) are paroxysmal episodes, resembling epileptic seizures, but without underlying epileptic abnormality. The aetiology and neuroanatomic associations are incompletely understood. Recent brain imaging data indicate cerebral changes, however, without clarifying possible pathophysiology. In the present study, we specifically investigated the neuroanatomic changes in subregions of the amygdala and hippocampus in FS. METHODS: T1 MRI scans of 37 female patients with FS and 37 age-matched female seizure naïve controls (SNC) were analyzed retrospectively in FreeSurfer version 7.1. Seizure naïve controls included patients with depression and anxiety disorders. The analysis included whole-brain cortical thickness, subcortical volumes, and subfields of the amygdala and hippocampus. Group comparisons were carried out using multivariable linear models. RESULTS: The FS and SNC groups did not differ in the whole hippocampus and amygdala volumes. However, patients had a significant reduction of the right lateral amygdala volume (p = 0.00041), an increase of the right central amygdala, (p = 0.037), and thinning of the left superior frontal gyrus (p = 0.024). Additional findings in patients were increased volumes of the right medial amygdala (p = 0.031), left anterior amygdala (p = 0.017), and left dentate gyrus of the hippocampus (p = 0.035). CONCLUSIONS: The observations from the amygdala and hippocampus segmentation affirm that there are neuroanatomic associations of FS. The pattern of these changes aligned with some of the cerebral changes described in chronic stress conditions and depression. The pattern of detected changes further study, and may, after validation, provide biomarkers for diagnosis and treatment.

Sudden unexpected death in epilepsy during cenobamate clinical development.

OBJECTIVE: We assessed mortality, sudden unexpected death in epilepsy (SUDEP), and standardized mortality ratio (SMR) among adults treated with cenobamate during the cenobamate clinical development program. METHODS: We retrospectively analyzed deaths among all adults with uncontrolled focal (focal to bilateral tonic-clonic [FBTC], focal impaired awareness, focal aware) or primary generalized tonic-clonic (PGTC) seizures who received ≥1 dose of adjunctive cenobamate in completed and ongoing phase 2 and 3 clinical studies. In patients with focal seizures from completed studies, median baseline seizure frequencies ranged from 2.8 to 11 seizures per 28 days and median epilepsy duration ranged from 20 to 24 years. Total person-years included all days that a patient received cenobamate during completed studies or up to June 1, 2022, for ongoing studies. All deaths were evaluated by two epileptologists. All-cause mortality and SUDEP rates were expressed per 1000 person-years. RESULTS: A total of 2132 patients (n = 2018 focal epilepsy; n = 114 idiopathic generalized epilepsy) were exposed to cenobamate for 5693 person-years. Approximately 60% of patients with focal seizures and all patients in the PGTC study had tonic-clonic seizures. A total of 23 deaths occurred (all in patients with focal epilepsy), for an all-cause mortality rate of 4.0 per 1000 person-years. Five cases of definite or probable SUDEP were identified, for a rate of .88 per 1000 person-years. Of the 23 overall deaths, 22 patients (96%) had FBTC seizures, and all 5 of the SUDEP patients had a history of FBTC seizures. The duration of exposure to cenobamate for patients with SUDEP ranged from 130 to 620 days. The SMR among cenobamate-treated patients in completed studies (5515 person-years of follow-up) was 1.32 (95% confidence interval [CI] .84-2.0), which was not significantly different from the general population. SIGNIFICANCE: These data suggest that effective long-term medical treatment with cenobamate may reduce excess mortality associated with epilepsy.

Time-to-event clinical trial designs: Existing evidence and remaining concerns.

Well-designed placebo-controlled clinical trials are critical to the development of novel treatments for epilepsy, but their design has not changed for decades. Patients, clinicians, regulators, and innovators all have concerns that recruiting for trials is challenging, in part, due to the static design of maintaining participants for long periods on add-on placebo when there are an increasing number of options for therapy. A traditional trial maintains participants on blinded treatment for a static period (e.g., 12 weeks of maintenance), during which participants on placebo have an elevated risk of sudden unexpected death in epilepsy compared to patients on an active treatment. Time-to-event trials observe participants on blinded treatment until a key event occurs (e.g., post-randomization seizure count matches pre-randomization monthly seizure count). In this article, we review the evidence for these designs based on re-analysis of prior trials, one published trial that used a time-to-second seizure design, and experience from an ongoing blinded trial. We also discuss remaining concerns regarding time-to-event trials. We conclude that, despite potential limitations, time-to-event trials are a potential promising mechanism to make trials more patient friendly and reduce placebo exposure, which are urgent needs to improve safety and increase recruitment to trials.

Reasons for ineligibility for clinical trials of patients with medication-resistant epilepsy.

Selection criteria for clinical trials for medication-resistant epilepsy are used to limit variability and to ensure safety. However, it has become more challenging to recruit subjects for trials. This study investigated the impact of each inclusion and exclusion criterion on medication-resistant epilepsy clinical trial recruitment at a large academic epilepsy center. We retrospectively identified all patients with medication-resistant focal or generalized onset epilepsy who attended an outpatient clinic over a consecutive 3-month period. We assessed each patient's eligibility for trials with commonly required inclusion and exclusion criteria to evaluate the proportion of eligible patients and the most common reasons for exclusion. Among 212 patients with medication-resistant epilepsy, 144 and 28 patients met the criteria for focal or generalized onset epilepsy, respectively. Overall, 9.4% (n = 20) patients were eligible for trials (19 focal onset and one generalized onset). Most patients were excluded from the study due to insufficient seizure frequency (58% of focal onset, 55% of generalized onset). A small proportion of patients with medication-resistant epilepsy were eligible for trials based on common selection criteria. These eligible patients may not be representative of the general population of patients with medication-resistant epilepsy. Insufficient seizure frequency was the most common reason for exclusion.

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.

Are brain MRI abnormalities associated with the semiology of functional seizures?

PURPOSE: To investigate whether radiologically apparent brain magnetic resonance imaging (MRI) abnormalities are associated with the functional seizure (FS) semiology. METHODS: All patients with a diagnosis of FS at the epilepsy centers at Shiraz University of Medical Sciences, Iran; Aichi Medical University Hospital, Japan; University of Michigan, USA; University of California, Los Angeles, USA; Emory University School of Medicine, USA; and Hospital el Cruce, Argentina, were studied. RESULTS: One hundred patients were included; 77 (77%) had motor functional seizures. Lobar location of brain abnormality did not have an association with the semiology (p = .83). There was no significant difference between ictal behaviors in patients with frontal or parietal lesions compared to those with temporal or occipital lesions. CONCLUSION: There were no associations between functional seizure ictal behaviors and locations of the radiologically apparent brain MRI abnormalities. Further studies are needed to evaluate the underpinnings of varying behaviors in FS.

Self-Reported Severity and Causes of Traumatic Brain Injury in Patients With Epileptic or Functional Seizures.

Background and Objectives: Although moderate and severe traumatic brain injury (TBI) can cause posttraumatic epilepsy (PTE), many patients with functional seizures (FS) also report a history of mild TBI. To determine whether features of TBI history differ between patients with epileptic seizures (ES) and FS, we compared patient reports of TBI severity, symptoms, and causes of injury. Methods: We recruited patients undergoing video-EEG evaluation for the diagnosis of ES, FS, mixed ES and FS, or physiologic seizure-like events at an academic, tertiary referral center. Patients and their caregivers were interviewed before final video-EEG diagnosis regarding their TBI histories, including concussive symptoms and causes of injury. Results: Of 506 patients, a greater percentage of patients with FS reported a history of TBI than patients with ES (70% vs 59%, aOR = 1.75 [95% CI: 1.00-3.05], p = 0.047). TBI with loss of consciousness (LOC) lasting less than 30 minutes was more frequently reported among patients with FS than with ES (27% vs 13%, aOR = 2.38 [1.26-4.47], p < 0.01). The proportion of patients reporting other neurologic symptoms immediately after TBI was not significantly different between FS and ES (40% vs 29%, p = 0.08). Causes of TBI were found to differ, with TBIs caused by falls from a height (17% vs 10%, aOR = 2.24 [1.06-4.70], p = 0.03) or motor vehicle collisions (27% vs 11%, aOR = 2.96 [1.54-5.67], p < 0.01) reported more frequently in FS than ES. Discussion: Our findings further the association of mild TBI with FS and prompt reconsideration of typical assumptions regarding the significance of a reported TBI history in patients with previously undifferentiated seizures. Although common in both groups, TBI with LOC less than 30 minutes and causes of injury that are commonly believed to be more severe were reported more frequently in FS than ES. This suggests that a patient or caregiver reporting of these features does not imply that PTE is a more probable diagnosis than FS. Although a history of TBI with LOC and presumed high-risk causes of injury intuitively raises suspicion for PTE, clinicians should be cautioned that these historical factors also were a frequent finding in patients with FS.

Incidence of and predictors for antiseizure medication gaps in Medicare beneficiaries with epilepsy: a retrospective cohort study.

BACKGROUND: For the two-thirds of patients with epilepsy who achieve seizure remission on antiseizure medications (ASMs), patients and clinicians must weigh the pros and cons of long-term ASM treatment. However, little work has evaluated how often ASM discontinuation occurs in practice. We describe the incidence of and predictors for sustained ASM fill gaps to measure discontinuation in individuals potentially eligible for ASM withdrawal. METHODS: This was a retrospective cohort of Medicare beneficiaries. We included patients with epilepsy by requiring International Classification of Diseases codes for epilepsy/convulsions plus at least one ASM prescription each year 2014-2016, and no acute visit for epilepsy 2014-2015 (i.e., potentially eligible for ASM discontinuation). The main outcome was the first day of a gap in ASM supply (30, 90, 180, or 360 days with no pills) in 2016-2018. We displayed cumulative incidence functions and identified predictors using Cox regressions. RESULTS: Among 21,819 beneficiaries, 5191 (24%) had a 30-day gap, 1753 (8%) had a 90-day gap, 803 (4%) had a 180-day gap, and 381 (2%) had a 360-day gap. Predictors increasing the chance of a 180-day gap included number of unique medications in 2015 (hazard ratio [HR] 1.03 per medication, 95% confidence interval [CI] 1.01-1.05) and epileptologist prescribing physician (≥25% of that physician's visits for epilepsy; HR 2.37, 95% CI 1.39-4.03). Predictors decreasing the chance of a 180-day gap included Medicaid dual eligibility (HR 0.75, 95% CI 0.60-0.95), number of unique ASMs in 2015 (e.g., 2 versus 1: HR 0.37, 95% CI 0.30-0.45), and greater baseline adherence (> 80% versus ≤80% of days in 2015 with ASM pill supply: HR 0.38, 95% CI 0.32-0.44). CONCLUSIONS: Sustained ASM gaps were rarer than current guidelines may suggest. Future work should further explore barriers and enablers of ASM discontinuation to understand the optimal discontinuation rate.

Time to exceed pre-randomization monthly seizure count for perampanel in participants with primary generalized tonic-clonic seizures: A potential clinical end point.

OBJECTIVE: To evaluate the exploratory time to exceed pre-randomization seizure count (T-PSC) in the determination of efficacy of adjunctive perampanel in participants with primary generalized tonic-clonic (PGTC) seizures in generalized-onset epilepsy. METHODS: In this multicenter, double-blind study (ClinicalTrials.gov identifier: NCT01393743), participants ≥12 years of age with treatment-resistant idiopathic generalized epilepsy were randomized to receive placebo or adjunctive perampanel (≤8 mg/day) across a 17-week double-blind treatment phase (4-week titration; 13-week maintenance). We evaluated the pre-planned exploratory end point of the T-PSC using a Kaplan-Meier analysis. We also re-evaluated the correspondence of the primary end points of median percent seizure frequency change (MPC) and 50% responder rate (50RR) calculated at T-PSC and at the end of the trial. RESULTS: The exploratory end point of median T-PSC on placebo was 43 days and >120 days on perampanel (log-rank p < .001). The primary end points calculated at T-PSC did not differ significantly from the end points at the end of the trial (MPC -31% vs -42% at T-PSC; 50RR 32% vs 51% at T-PSC). After T-PSC was reached, participants had a median (interquartile range) of 5 (3-13) additional seizures on placebo and 5 (2-10) on perampanel. SIGNIFICANCE: The exploratory end point of T-PSC demonstrated the effectiveness of perampanel despite a shorter duration of monitoring. The seizures that occurred after T-PSC did not influence the conclusions of the trial; therefore, T-PSC may be a viable alternative to traditional trial end points that reduces the risk to participants.

Clinical MRI morphological analysis of functional seizures compared to seizure-naïve and psychiatric controls.

PURPOSE: Functional seizures (FS), also known as psychogenic nonepileptic seizures (PNES), are physical manifestations of acute or chronic psychological distress. Functional and structural neuroimaging have identified objective signs of this disorder. We evaluated whether magnetic resonance imaging (MRI) morphometry differed between patients with FS and clinically relevant comparison populations. METHODS: Quality-screened clinical-grade MRIs were acquired from 666 patients from 2006 to 2020. Morphometric features were quantified with FreeSurfer v6. Mixed-effects linear regression compared the volume, thickness, and surface area within 201 regions-of-interest for 90 patients with FS, compared to seizure-naïve patients with depression (n = 243), anxiety (n = 68), and obsessive-compulsive disorder (OCD, n = 41), respectively, and to other seizure-naïve controls with similar quality MRIs, accounting for the influence of multiple confounds including depression and anxiety based on chart review. These comparison populations were obtained through review of clinical records plus research studies obtained on similar scanners. RESULTS: After Bonferroni-Holm correction, patients with FS compared with seizure-naïve controls exhibited thinner bilateral superior temporal cortex (left 0.053 mm, p = 0.014; right 0.071 mm, p = 0.00006), thicker left lateral occipital cortex (0.052 mm, p = 0.0035), and greater left cerebellar white-matter volume (1085 mm3, p = 0.0065). These findings were not accounted for by lower MRI quality in patients with FS. CONCLUSIONS: These results reinforce prior indications of structural neuroimaging correlates of FS and, in particular, distinguish brain morphology in FS from that in depression, anxiety, and OCD. Future work may entail comparisons with other psychiatric disorders including bipolar and schizophrenia, as well as exploration of brain structural heterogeneity within FS.

Changes in the Use of Brand Name and Generic Medications and Total Prescription Cost Among Medicare Beneficiaries With Epilepsy.

OBJECTIVE: To characterize trends in antiseizure medication (ASM) fills and total prescription costs in people with epilepsy. METHODS: This was a retrospective cohort study of beneficiaries with epilepsy (ASM, plus International Classification of Diseases codes) in a 20% random Medicare sample, with continuous Fee-For-Service coverage (Parts A, B, and D) in 2008-2018. We summed the number of pill days and costs (adjusted to 2018 dollars) per person-year for each ASM. ASMs were categorized into brand versus generic, first- versus newer-generation, and enzyme-inducers versus non-inducers. RESULTS: There were 77,000-133,000 beneficiaries with epilepsy per year. The most common ASM was phenytoin in 2008, which shifted to levetiracetam in 2018 (2008: phenytoin 25%, levetiracetam 14%; 2018: phenytoin 9%, levetiracetam 27%). Brand name (2008: 56%; 2018: 14%), first-generation (2008: 55%; 2018: 32%), and enzyme-inducing ASMs (2008: 44%; 2018: 24%) each decreased over time as a proportion of pill days. The number of brand pill days per person-year initially decreased (e.g. 2008: 250; 2009: 121; 2010: 96), but then plateaued (2013-2018: between 66-69) given a notable increase in lacosamide pill days per person (2008: 0; 2018: 20). Total brand name costs per year initially decreased 2008-2010 (2008: $150 million; 2010: $72 million) but then increased after 2010 (2018: $256 million). In 2018 brand name ASMs represented 79% of costs despite representing only 14% of pill days, a one-year pill supply became 277% more expensive for brand name but 42% less expensive for generic medications over time (2008: brand ∼$2,800 versus generic ∼$800; 2018: brand ∼$10,700 versus generic ∼$460), and many common brand name ASMs cost approximately ten-fold more per pill day than their generic equivalents. CONCLUSIONS: First-generation and enzyme-inducing ASMs waned from 2008 to 2018. While brand name ASMs initially waned translating into lower costs and potentially higher value care, after 2010 brand name costs markedly increased due to increasing use of lacosamide plus a 277% increase in per-pill cost of brand name ASMs. Brand name ASMs represented a small minority of prescriptions, but the large majority of costs.

Reappraisal of the Medical Research Council Antiepileptic Drug Withdrawal Study: Contamination-adjusted and dose-response re-analysis.

OBJECTIVE: The 1991 Medical Research Council (MRC) Study compared seizure relapse for seizure-free patients randomized to withdraw vs continue of antiseizure medications (ASMs). We re-analyzed this trial to account for crossover between arms using contamination-adjusted intention to treat (CA ITT) methods, to explore dose-response curves, and to validate predictions against external data. ITT assesses the effect of being randomized to withdraw, as-treated analysis assesses the confounded effect of withdrawing, but CA ITT assesses the unconfounded effect of actually withdrawing. METHODS: CA ITT involves two stages. First, we used randomized arm to predict whether patients withdrew their ASM (logistic) or total daily ASM dose (linear). Second, we used those values to predict seizure occurrence (logistic). RESULTS: The trial randomized 503 patients to withdraw and 501 patients to continue ASMs. We found that 316 of 376 patients (88%) who were randomized to withdraw decreased their dose at every pre-seizure visit, compared with 35 of 424 (8%) who were randomized to continue (p < .01). Adjusted odds ratios of a 2-year seizure for those who withdrew vs those who did not was 1.3 (95% confidence interval [CI] 0.9-1.9) in the as-treated analysis, 2.5 (95% CI 1.9-3.4) comparing those randomized to withdraw vs continue for ITT, and 3.1 (95% CI 2.1-4.5) for CA ITT. Probabilities (withdrawal vs continue) were 28% vs 24% (as-treated), 40% vs 22% (ITT), and 43% vs 21% (CA ITT). Differences between ITT and CA ITT were greater when varying the predictor (reaching zero ASMs) or outcome (1-year seizures). As-treated dose-response curves demonstrated little to no effects, but larger effects in CA ITT analysis. MRC data overpredicted risk in Lossius data, with moderate discrimination (areas under the curve ~0.70). SIGNIFICANCE: CA ITT results (the effect of actually withdrawing ASMs on seizures) were slightly greater than ITT effects (the effect of recommend withdrawing ASMs on seizures). How these findings affect clinical practice must be individualized.