Enzyme-inducing Anti-seizure Medications Research Articles

Direct-Acting Oral Anticoagulants and Antiseizure Medications for Atrial Fibrillation and Epilepsy and Risk of Thromboembolic Events.

Direct-acting oral anticoagulants (DOACs) are commonly prescribed with antiseizure medications (ASMs) due to concurrency of and the association between atrial fibrillation (AF) and epilepsy. However, enzyme-inducing (EI) ASMs may reduce absorption and accelerate metabolism of DOACs, potentially lowering DOAC levels and elevating thromboembolism risk. To assess the rates of thromboembolic and major bleeding events in adults with AF and epilepsy dispensed DOACs and EI ASMs vs DOACs with non-EI ASMs. This active-comparator, new-user cohort study included US health care data from the Clinformatics Data Mart database from October 2010 to September 2021 for a nationally representative population of adults with AF and epilepsy. Evaluations included episodes of contiguous coadministration of DOACs for AF with EI ASMs (exposed) or non-EI ASMs (referent) for epilepsy. Thromboembolic events (primary outcome) and major bleeding events (secondary outcome) were identified based on a series of validated, diagnosis-based coding algorithms. Data-adaptive, high-dimensional propensity score matching was used to control for observed confounders and proxies for unobserved confounders. Adjusted hazard ratios (AHRs) were estimated using Cox proportional hazards regression models with robust variance estimators to account for clustering within matched pairs. This study included 14 078 episodes (median age, 74 [IQR, 67-81]; 52.4% female) and 14 158 episodes (median age, 74 [IQR, 67-81]; 52.4% female) of incident DOAC and ASM use that met eligibility criteria for assessment of thromboembolic and major bleeding outcomes, respectively. Incidence was 88.5 per 1000 person-years for thromboembolic events and 68.3 per 1000 person-years for bleeding events. Compared with use of non-EI ASMs, use of EI ASMs with DOACs was not associated with a difference in risk of thromboembolic events (AHR, 1.10; 95% CI, 0.82-1.46) but was associated with a reduction in risk of major bleeding events (AHR, 0.63; 95% CI, 0.44-0.89). In this cohort study, EI ASMs were not associated with alteration in DOAC efficacy. Further research is needed on the reduction in bleeding risk associated with EI ASMs, as this may suggest that pharmacokinetic interactions are associated with lowering DOAC levels without negating therapeutic effects.

Thinking Three-Dimensionally: A Self- and Externally-Controlled Approach to Screening for Drug-Drug-Drug Interactions Among High-Risk Populations.

The global rise in polypharmacy has increased both the necessity and complexity of drug-drug interaction (DDI) assessments, given the growing potential for interactions involving more than two drugs. Leveraging large-scale healthcare claims data, we piloted a semi-automated, high-throughput case-crossover-based approach for drug-drug-drug interaction (3DI) screening. Cases were direct-acting oral anticoagulant (DOAC) users with either a major bleeding event during ongoing dispensings for potentially interacting, enzyme-inhibiting antihypertensive drugs (AHDs) (Study 1), or a thromboembolic event during ongoing dispensings for potentially interacting, enzyme-inducing antiseizure medications (ASMs) (Study 2). 3DI detection was based on screening for additional drug exposures that served as acute outcome triggers. To mitigate direct effects and confounding by concomitant drugs, self-controlled estimates were adjusted using negative cases (external "control" DOAC users with the same outcomes but co-dispensings for non-interacting AHDs or ASMs). Signal thresholds were set based on P-values and false discovery rate q-values to address multiple comparisons. Study 1: 285 drugs were examined among 3,306 episodes. Self-controlled assessments with q-value thresholds yielded 9 3DI signals (cases) and 40 DDI signals (negative cases). External adjustment generated 10 3DI signals from the P-value threshold and no signals from the q-value threshold. Study 2: 126 drugs were examined among 604 episodes. Assessments with P-value thresholds yielded 3 3DI and 26 DDI signals following self-control, as well as 4 3DI signals following adjustment. No 3DI signals met the q-value threshold. The presented self- and externally-controlled approach aimed to advance paradigms for real-world higher order drug interaction screening among high-susceptibility populations with pre-existent DDI risk.

Depot medroxyprogesterone acetate concentrations in patients with and without the use of antiseizure medications

ObjectivesTo measure plasma concentrations of medroxyprogesterone acetate (MPA) in users with epilepsy treated with anti-seizure medications and compare these to MPA concentrations in those without epilepsy. MethodsFor this multi-site cross-sectional study, we obtained a single blood sample from those with epilepsy treated with various anti-seizure medications (n=18) within the week before their next depot medroxyprogesterone (DMPA) injection. Among the participants without epilepsy (n=20), 10 similarly were scheduled within the week prior to the next injection, and 10 were scheduled at earlier intervals to attempt to balance the time intervals between groups. MPA concentrations were determined by a validated assay. ResultsMPA concentrations were similar among those with epilepsy and controls, and between groups with and without use of enzyme-inducing medications. The lowest MPA concentrations, under 0.07 ng/mL, were observed among two of eight using enzyme-inducing anti-seizure medications; one of 10 using non-inducing medications, and one of 19 controls had concentrations below 0.2 ng/mL. ConclusionsIn this exploratory study, lower MPA concentrations in some participants using enzyme-inducing anti-seizure medications suggest a potential interaction that could reduce DMPA efficacy.

Patterns and predictors of sexual dysfunction in women with epilepsy

ObjectivesAvailable data about sexual-related problems among Egyptian women with epilepsy (WWE) are scarce. Hence, this work aimed to study the pattern and predictors of sexual dysfunction in a sample of Egyptian WWE. MethodsIn this cross-sectional study, sexually active WWE and age and years of marriage-matched healthy controls were included. The Female Sexual Function Index questionnaire (FSFI) was used to assess sexual function in both groups. ResultsIn the patient group (n = 142), the median age was 33 (28–39), whereas the median age of the control group (n = 142) was 33.5 (28–36). Women with epilepsy had significantly lower desire, arousal, pain, and FSFI-total scores than the control group (P = 0.001, 0.001, 0.023, 0.008, respectively). There was a significant difference between the FSFI-total score of women on polytherapy and those on monotherapy (P = 0.042), as well as between those on enzyme-inducing ASMs and those on ASMs that did not affect P450 (P = 0.032). Seizure frequency in the last three months was negatively correlated with scores of desire, arousal, lubrication, orgasm, and satisfaction (P 0.047, 0.02, 0.009, 0.013, 0.046, respectively). By multiple backward linear regression models, age, and seizure frequency were the significant predictors of the FSFI-total score (B −0.219, −0.33, respectively). ConclusionThe pattern of sexual dysfunction among Egyptian WWE is characterized by reduced sexual desire, arousal deficits, and sexual-related pain. Seizure frequency, epilepsy duration, enzyme-inducing medications, and multiple anti-seizure medications (ASMs) may adversely affect WWE's sexual health. The only factor that could predict higher sexual dysfunction in WWE was higher seizure frequency.

Independent Associations of Incident Epilepsy and Enzyme-Inducing and Non–Enzyme-Inducing Antiseizure Medications With the Development of Osteoporosis

Both epilepsy and enzyme-inducing antiseizure medications (eiASMs) having varying reports of an association with increased risks for osteoporosis. To quantify and model the independent hazards for osteoporosis associated with incident epilepsy and eiASMS and non-eiASMs. This open cohort study covered the years 1998 to 2019, with a median (IQR) follow-up of 5 (1.7-11.1) years. Data were collected for 6275 patients enrolled in the Clinical Practice Research Datalink and from hospital electronic health records. No patients who met inclusion criteria (Clinical Practice Research Datalink-acceptable data, aged 18 years or older, follow-up after the Hospital Episode Statistics patient care linkage date of 1998, and free of osteoporosis at baseline) were excluded or declined. Incident adult-onset epilepsy using a 5-year washout and receipt of 4 consecutive ASMs. The outcome was incident osteoporosis as determined through Cox proportional hazards or accelerated failure time models where appropriate. Incident epilepsy was treated as a time-varying covariate. Analyses controlled for age, sex, socioeconomic status, cancer, 1 or more years of corticosteroid use, body mass index, bariatric surgery, eating disorders, hyperthyroidism, inflammatory bowel disease, rheumatoid arthritis, smoking status, falls, fragility fractures, and osteoporosis screening tests. Subsequent analyses (1) excluded body mass index, which was missing in 30% of patients; (2) applied propensity score matching for receipt of an eiASM; (3) restricted analyses to only those with incident onset epilepsy; and (4) restricted analyses to patients who developed epilepsy at age 65 years or older. Analyses were performed between July 1 and October 31, 2022, and in February 2023 for revisions. Of 8 095 441 adults identified, 6275 had incident adult-onset epilepsy (3220 female [51%] and 3055 male [49%]; incidence rate, 62 per 100 000 person-years) with a median (IQR) age of 56 (38-73) years. When controlling for osteoporosis risk factors, incident epilepsy was independently associated with a 41% faster time to incident osteoporosis (time ratio [TR], 0.59; 95% CI, 0.52-0.67; P < .001). Both eiASMs (TR, 0.91; 95% CI, 0.87-0.95; P < .001) and non-eiASMs (TR, 0.77; 95% CI, 0.76-0.78; P < .001) were also associated with significant increased risks independent of epilepsy, accounting for 9% and 23% faster times to development of osteoporosis, respectively. The independent associations among epilepsy, eiASMs, and non-eiASMs remained consistent in propensity score-matched analyses, cohorts restricted to adult-onset epilepsy, and cohorts restricted to late-onset epilepsy. These findings suggest that epilepsy is independently associated with a clinically meaningful increase in the risk for osteoporosis, as are both eiASMs and non-eiASMs. Routine screening and prophylaxis should be considered in all people with epilepsy.

Effects of low-dose titration on the tolerability and safety of perampanel

PurposeTo evaluate the effects of low-dose titration on the tolerability and safety of perampanel. MethodsWe retrospectively reviewed the records of 1065 patients who started perampanel therapy and compared the incidence of adverse events after standard titration (Group A: starting dose, 2 mg/day; titration speed, 2 mg/2 weeks or longer) and low-dose titration (Group B: starting dose, < 1 mg/day; titration speed, < 1 mg/2 weeks or longer). ResultsAdverse events were reported in 158 patients (14.8%) within the initial first 90 days of starting perampanel (mean concentration, 331 ng/mL). At 90 days, the cumulative incidence of adverse events was significantly higher in Group A than in Group B (24.5% vs. 16.3%, respectively; log-rank test p < 0.001). A Cox proportional hazards model also showed that low-dose titration decreased the incidence risk of adverse events (adjusted hazard ratio, 0.49; 95% confidence interval, 0.35–0.69). When the groups were stratified by use of enzyme-inducing antiseizure medications (inducers), Group A patients without inducers had a significantly higher cumulative incidence of adverse events than the other three subgroups (26.7%, p < 0.001). In patients taking 2 mg of perampanel, median concentrations in patients with or without inducers were 43 ng/mL and 204 ng/mL, respectively. ConclusionPerampanel is generally initiated at 2 mg, but serum perampanel concentrations show substantial interindividual variation. Our study suggests that care must be taken when setting the starting dose of perampanel. In particular, low-dose titration is recommended in patients not taking inducers.

Interactions Between Direct Oral Anticoagulants (DOACs) and Antiseizure Medications: Potential Implications on DOAC Treatment.

The use of direct oral anticoagulants (DOACs) is increasing because of their superior efficacy and safety compared with vitamin K antagonists. Pharmacokinetic drug interactions, particularly those involving cytochrome P450- mediated metabolism andP-glycoprotein transport, significantly affect the efficacy and safety of DOACs. In this article, we assess the effects of cytochrome P450- and P-glycoprotein-inducing antiseizure medications on DOAC pharmacokinetics in comparison to rifampicin. Rifampicin decreases to a varying extent the plasma exposure (area under the concentration-time curve) and peak concentration of each DOAC, consistent with its specific absorption and elimination pathways. For apixaban and rivaroxaban, rifampicin had a greater effect on the area under the concentration-time curve than on peak concentration. Therefore, using peak concentration to monitor DOAC concentrations may underestimate the effect of rifampicin on DOAC exposure. Antiseizure medications that are cytochrome P450 and P-glycoprotein inducers are commonly used with DOACs. Several studies have observed a correlation between the concomitant use of DOACs and enzyme-inducing antiseizure medications and DOAC treatment failure, for example, ischemic and thrombotic events. The European Society of Cardiology recommends avoiding this combination, as well as the combination of DOACs with levetiracetam and valproic acid, owing to a risk of low DOAC concentrations. However, levetiracetam and valproic acid are not cytochrome P450 or P-glycoprotein inducers, and the implications of their use with DOACs remain to be elucidated. Our comparative analysis suggests DOAC plasma concentration monitoring as a possible strategy to guide dosing owing to the predictable correlation between DOACs' plasma concentration and effect. Patients taking concomitant enzyme-inducing antiseizure medications are at risk for low DOAC concentrations and subsequently, treatment failure and thus can benefit from DOAC concentration monitoring to prophylactically identify this risk.

Therapeutic Drug Monitoring of Lacosamide in Chinese Pediatric Patients with Epilepsy: Efficacy and Factors Influencing the Plasma Concentration.

The impact of individual patient variables on drug metabolism is particularly important for antiseizure medication, and lacosamide has not been studied in Chinese pediatric patients with epilepsy. This study evaluated the effects of dose, age, sex, medication time, seizure type, and concomitant enzyme-inducing antiseizure medications (EIASMs) on the plasma concentration of lacosamide. A total of 500 pediatric patients from two hospitals in China were enrolled in this study. Lacosamide plasma concentration was processed using an ultra-performance liquid chromatography assay. Efficacy was evaluated based on the four-grade therapeutic effect criteria developed by the first National Epilepsy Academic Conference of the Chinese Medical Association. The responder rate to lacosamide therapy was 72.2% (361/500). There was a weaker relationship between the lacosamide daily dose and lacosamide plasma concentration (r=0.238). Lacosamide plasma concentrations of patients ranged from 1.5 to 19.7µg/mL, with a mean of 6.9±3.2µg/mL. The study results showed a significant contribution of age, body mass index, epilepsy duration, medication time, and EIASMs to the lacosamide plasma concentration (p<0.05). Patients taking concomitant EIASMs with lacosamide had a significantly lower mean lacosamide plasma concentration (5.9±2.6µg/mL) than patients taking concomitant non-EIASMs (7.5±3.5µg/mL, p<0.001). To ensure the clinical efficacy and safety of lacosamide therapy in pediatric patients, it is necessary to monitor the plasma concentration.

Identification of factors associated with new-onset vascular disease in patients admitted for video-EEG monitoring: A longitudinal cohort study

ObjectivePeople with epilepsy are at a higher risk of developing vascular disease. Understanding the risk factors in observational studies is hampered by the challenge in separating epilepsy-related risk and treatment-related risk, and uncertainty in the epilepsy diagnosis. This study aimed to identify factors associated with risk of subsequent vascular disease in patients with video-EEG monitoring (VEM) confirmed epilepsy. MethodsWe included patients with a diagnosis of epilepsy and nonepileptic disorders between January 1, 1995, and December 31, 2015. Incident cardiovascular, cerebrovascular, and peripheral vascular disease was determined by linkage to a state-wide hospital admissions database between 1st July 1994 and 28th February 2018. Incidence was compared with the general population. Results1728 patients (59.7% female, median age 35 years) underwent VEM, and were followed up for a median of 9.2 years (range 2.2–22.9 years). Eight-hundred and thirty -two were diagnosed with epilepsy and 896 nonepileptic disorders. The incidence of cerebrovascular disease was higher in both patients with epilepsy (incidence rate ratio [IRR] 1.78, p = 0.001) and with nonepileptic disorders (IRR 1.61, p < 0.001) than in the general population. Patients who took valproic acid (VPA) were at a lower risk of vascular disease than those taking enzyme-inducing antiseizure medications (EIASM, subdistribution hazard ratio [SHR] 0.42, p = 0.013), and those taking neither VPA nor EIASM (SHR 0.47, p = 0.03). There was no difference in the incidence of vascular disease between patients with epilepsy and those without epilepsy (SHR 0.94, p = 0.766). Factors associated with increased risk included age (SHR 1.04, p < 0.001), male sex (SHR 1.50, p = 0.017), and smoking (SHR 1.68, p = 0.017). SignificanceIn this study, both patients with epilepsy and without epilepsy had increased vascular risk. This suggests that the increased risk may be in part due to factors not directly related to epilepsy, such as EIASM use and vascular risk factors.

Epilepsy Care in Transgender Patients.

The goal of this review is to outline the main considerations when treating transgender patients with epilepsy. Points to be addressed include the gender affirming hormone therapy regimens and how they interact with anti-seizure medications and seizure control, as well as common co-morbidities in the transgender epilepsy population. Gender affirming hormone therapy (GAHT) may affect seizure control directly, due to proconvulsant or anticonvulsant properties. GAHT may interact with anti-seizure medications; most notably, estrogen will decrease serum concentration of lamotrigine. Enzyme-inducing anti-seizure medications may decrease hormone levels, potentially interfering with goals of GAHT. Transgender epilepsy patients are at risk for co-morbidities such as decreased bone mineral density and depression. There are minimal direct studies on treatment or outcomes in the transgender epilepsy population. Providers must be knowledgeable about the bi-directional interactions between gender affirming hormone therapy and anti-seizure medications, as well as direct hormonal influences on seizure control. Future research should directly evaluate outcomes in transgender epilepsy patients with regard to seizure control, success of hormone therapy, and management of co-morbidities, to further educate providers and patients how to best manage their healthcare.

Using nirmatrelvir/ritonavir in patients with epilepsy: An update from the Israeli chapter of the International League Against Epilepsy.

Presented herein are recommendations for use of nirmatrelvir/ritonavir in patients with epilepsy, as issued by the Steering Committee of the Israeli chapter of the International League Against Epilepsy. The recommendations suggest that patients on moderate‐to‐strong enzyme‐inducing antiseizure medications (ASMs) and everolimus should not be treated with nirmatrelvir/ritonavir; rectal diazepam may be used as an alternative to buccal midazolam; doses of ASMs that are cytochrome P450 (CYP3A4) substrates might be adjusted; and patients treated with combinations of nirmatrelvir/ritonavir and ASMs that are CYP3A4 substrates or lamotrigine should be monitored for drug efficacy and adverse drug reactions.

Interactions between antiseizure medications and contraception: A study about the knowledge of patients and their specialist physicians

Planning pregnancy is very important for women with epilepsy (WWE), because of the potential teratogenic effects and neurodevelopmental disorders of different antiseizure medications (ASMs). Nevertheless, contraception in WWE can be challenging due to the existence of drug interactions between ASMs and hormonal contraception. The aim of this study was to assess women’s knowledge of potential interactions between their ASMs and contraceptive options. The second objective was to assess neurologist’s knowledge of the potential interactions between ASMs and contraceptive methods.An anonymous online survey was proposed to reproductive-age WWE during consultation with their neurologist. Another online survey was proposed to neurologists. These surveys were performed through a French regional medical network.A total of 79 patients agreed to respond to the survey. Forty-nine women used lamotrigine alone or in combination, 15 used an enzyme-inducing ASM alone or in combination, 13 used non-enzyme-inducing ASM and 2 used both lamotrigine and an enzyme-inducing ASM. Half of the WWE had mistaken beliefs about interactions between their ASM and contraception. Among them, 35% of the women treated with an enzyme-inducing ASM were unaware of a potential decreased efficacy of hormonal contraception. Moreover, 51% of the women who were taking lamotrigine did not know that combined hormonal contraception might decrease the efficacy of their ASM. On the other hand, 64.5% of WWE without an enzyme-inducing ASM wrongly thought that their ASM can decrease their hormonal contraceptive efficacy. A total of 20 neurologists answered the online survey. It revealed specific gaps concerning interactions between ASM and contraceptives; in fact, 35% of answers concerning the identification of specific enzyme-inducing ASMs were wrong.This study therefore highlights the need for educational efforts for both WWE and their physicians regarding drug interactions between ASMs and hormonal contraceptives.

Sustained seizure freedom with adjunctive perampanel in patients with convulsive seizures: Post hoc analysis of open-label extension studies 307 and 332

ObjectiveSince increased mortality rates have been associated with convulsive seizures, it is important to achieve seizure control in these patients. Here, we report post hoc analyses to assess long-term seizure-freedom rates with adjunctive perampanel in patients (aged ≥ 12 years) with refractory focal to bilateral tonic-clonic seizures (FBTCS) or generalized tonic-clonic seizures (GTCS) who participated in open-label extension (OLEx) studies. MethodsPatients with focal-onset seizures, with/without FBTCS, who completed double-blind, Phase III Studies 304, 305, or 306 could enter OLEx Study 307 (16-week blinded Conversion; 256-week Maintenance). Patients with GTCS who completed the double-blind phase of Study 332 could enter the OLEx Phase (6-week blinded Conversion; 136-week Maintenance). Maximum perampanel dose: 12 mg/day. Seizure-freedom rates for up to 24 months were assessed in perampanel-treated patients who achieved seizure freedom during the double-blind studies to determine if their seizure-free status was maintained during the OLEx. In addition, to ensure any patients who only achieved seizure freedom during the OLEx were captured, seizure-freedom rates were also assessed in all patients who achieved and maintained a seizure-free status for a period of at least six consecutive months at any time during the double-blind and/or OLEx studies; some of these patients may have received placebo during the double-blind study but only their time on perampanel is included in the seizure-free analysis. Univariate and multivariate analyses were used to identify predictive factors for achieving seizure freedom for at least 6 months. Treatment-emergent adverse events (TEAEs) were assessed. ResultsOverall, 53.8% (n = 42/78) of patients who received perampanel and were FBTCS free during the double-blind studies remained seizure free for up to 24 months during Study 307, and 31.6% (n = 6/19) of patients who were GTCS free during the double-blind phase of Study 332 remained seizure free for up to 24 months during the OLEx Phase. Over 40% (FBTCS, 41.5% [n = 197/475]; GTCS, 52.9% [n = 73/138]) of patients were seizure free for a period of at least six consecutive months. Multivariate analysis showed that the best predictors of achieving seizure freedom from FBTCS for at least 6 months were lower baseline seizure frequency (p = 0.0014) and absence of enzyme-inducing anti-seizure medications at baseline (p = 0.0056); multivariate analysis was not conducted for GTCS since only one variable was identified as a significant predictor of seizure freedom in the univariate analysis (lower baseline seizure frequency).Perampanel was generally well tolerated with no new safety signals identified. The most common TEAE was dizziness. For both seizure types, 10% or fewer seizure-free patients discontinued perampanel due to TEAEs. ConclusionsThese results suggest that adjunctive perampanel may be a suitable long-term treatment option for patients (aged ≥ 12 years) with convulsive seizures to achieve and maintain seizure freedom.

Stroke and Ischemic Heart Disease With Enzyme-inducing Antiseizure Medications: Time to Change Prescribing Habits.

Importance: Enzyme-inducing antiseizure medications (eiASMs) have been hypothesized to be associated with long-term risks of cardiovascular disease.Objective: To quantify and model the putative hazard of cardiovascular disease secondary to eiASM use.Design, Setting, and Participants: This cohort study covered January 1990 to March 2019 (median [IQR] follow-up, 9 [4–15], years). The study linked primary care and hospital electronic health records at National Health Service hospitals in England. People aged 18 years or older diagnosed as having epilepsy after January 1, 1990, were included. All eligible patients were included with a waiver of consent. No patients were approached who withdrew consent. Analysis began January 2021 and ended August 2021.Exposures: Receipt of 4 consecutive EI ASMs (carbamazepine, eslicarbazepine, oxcarbazepine, phenobarbital, phenytoin, primidone, rufinamide, or topiramate) following an adult-onset (age >/=18 years) epilepsy diagnosis or repeated exposure in a weighted cumulative exposure model.Main Outcomes and Measures: Three cohorts were isolated, 1 of which comprised all adults meeting a case definition for epilepsy diagnosed after 1990, 1 comprised incident cases diagnosed after 1998 (hospital linkage date), and 1 was limited to adults diagnosed with epilepsy at 65 years or older. Outcome was incident cardiovascular disease (ischemic heart disease or ischemic or hemorrhagic stroke). Hazard of incident cardiovascular disease was evaluated using adjusted propensity-matched survival analyses and weighted cumulative exposure models.Results: Of 10,916,166 adults, 50,888 (.6%) were identified as having period-prevalent cases (median [IQR] age, 32 [19–50] years; 16 584 [53%] female), of whom 31,479 (62%) were diagnosed on or after 1990 and were free of cardiovascular disease at baseline. In a propensity-matched Cox proportional hazards model adjusted for age, sex, baseline socioeconomic status, and cardiovascular risk factors, the hazard ratio for incident cardiovascular disease was 1.21 (95% CI, 1.06–1.39) for those receiving eiASMs. The absolute difference in cumulative hazard diverges by more than 1% and greater after 10 years. For those with persistent exposure beyond 4 prescriptions, the median hazard ratio increased from a median (IQR) of 1.54 (1.28–1.79) when taking a relative defined daily dose of an eiASM of 1 to 2.38 (1.52–3.56) with a relative defined daily dose of 2 throughout a maximum of 25 years' follow-up compared with those not receiving an eiASM. The hazard was elevated but attenuated when restricting analyses to incident cases or those diagnosed when older than 65 years.Conclusions and Relevance: The hazard of incident cardiovascular disease is higher in those receiving eiASMs. The association is dose dependent and the absolute difference in hazard seems to reach clinical significance by approximately 10 years from first exposure.

Impact of carbamazepine on vitamin D levels: A meta-analysis

PurposeThere are longstanding concerns about the impact of enzyme-inducing anti-seizure medications (ASMs) on vitamin D, an important molecule in both bone metabolism and inflammation pathways. The relationship between chronic use of carbamazepine and vitamin D levels has been studied, but no comprehensive review to inform practitioners and policymakers is currently available. We performed a meta-analysis on studies that measured 25-hydroxyvitamin D (25OHD) levels in persons taking carbamazepine to determine whether this drug significantly reduces circulating 25OHD. Principal resultsFrom a literature search of the terms “carbamazepine” and “vitamin D”, we identified 12 studies that measured 25OHD levels in persons on carbamazepine monotherapy groups and controls. Persons taking carbamazepine had significantly lower 25OHD levels than persons not taking carbamazepine. The average 25OHD levels of carbamazepine-treated patients across all studies was 21.8 ng/mL (IQR 15.4,26.0) whereas 25OHD levels of control subjects was 28.0 ng/mL (IQR 20.8,30.4). The weighted difference of means was 4.00 ng/mL of 25OHD. Neither age nor sex nor duration of carbamazepine therapy had a significant impact on this finding. The effect was similar irrespective of whether the comparator group consisted of healthy controls or epilepsy patients taking non-inducing medications. Major conclusionsCarbamazepine use is associated with a reduction of 25OHD levels. In combination with other literature establishing the problematic metabolic effects of carbamazepine, this meta-analysis provides additional evidence in favor of the use of alternative ASMs as first-line agents. At minimum, vitamin D supplementation should be strongly considered for patients prescribed carbamazepine.

Association of Enzyme-Inducing Antiseizure Drug Use With Long-term Cardiovascular Disease

Enzyme-inducing antiseizure medications (eiASMs) have been hypothesized to be associated with long-term risks of cardiovascular disease. To quantify and model the putative hazard of cardiovascular disease secondary to eiASM use. This cohort study covered January 1990 to March 2019 (median [IQR] follow-up, 9 [4-15], years). The study linked primary care and hospital electronic health records at National Health Service hospitals in England. People aged 18 years or older diagnosed as having epilepsy after January 1, 1990, were included. All eligible patients were included with a waiver of consent. No patients were approached who withdrew consent. Analysis began January 2021 and ended August 2021. Receipt of 4 consecutive eiASMs (carbamazepine, eslicarbazepine, oxcarbazepine, phenobarbital, phenytoin, primidone, rufinamide, or topiramate) following an adult-onset (age ≥18 years) epilepsy diagnosis or repeated exposure in a weighted cumulative exposure model. Three cohorts were isolated, 1 of which comprised all adults meeting a case definition for epilepsy diagnosed after 1990, 1 comprised incident cases diagnosed after 1998 (hospital linkage date), and 1 was limited to adults diagnosed with epilepsy at 65 years or older. Outcome was incident cardiovascular disease (ischemic heart disease or ischemic or hemorrhagic stroke). Hazard of incident cardiovascular disease was evaluated using adjusted propensity-matched survival analyses and weighted cumulative exposure models. Of 10 916 166 adults, 50 888 (0.6%) were identified as having period-prevalent cases (median [IQR] age, 32 [19-50] years; 16 584 [53%] female), of whom 31 479 (62%) were diagnosed on or after 1990 and were free of cardiovascular disease at baseline. In a propensity-matched Cox proportional hazards model adjusted for age, sex, baseline socioeconomic status, and cardiovascular risk factors, the hazard ratio for incident cardiovascular disease was 1.21 (95% CI, 1.06-1.39) for those receiving eiASMs. The absolute difference in cumulative hazard diverges by more than 1% and greater after 10 years. For those with persistent exposure beyond 4 prescriptions, the median hazard ratio increased from amedian (IQR) of 1.54 (1.28-1.79) when taking a relative defined daily dose of an eiASM of 1 to 2.38 (1.52-3.56) with a relative defined daily dose of 2 throughout a maximum of 25 years' follow-up compared with those not receiving an eiASM. The hazard was elevated but attenuated when restricting analyses to incident cases or those diagnosed when older than 65 years. The hazard of incident cardiovascular disease is higher in those receiving eiASMs. The association is dose dependent and the absolute difference in hazard seems to reach clinical significance by approximately 10 years from first exposure.

Adjunctive Brivaracetam in Focal Epilepsy: Real-World Evidence from the BRIVAracetam add-on First Italian netwoRk STudy (BRIVAFIRST)

BackgroundIn randomized controlled trials, add-on brivaracetam (BRV) reduced seizure frequency in patients with drug-resistant focal epilepsy. Studies performed in a naturalistic setting are a useful complement to characterize the drug profile.ObjectiveThis multicentre study assessed the effectiveness and tolerability of adjunctive BRV in a large population of patients with focal epilepsy in the context of real-world clinical practice.MethodsThe BRIVAFIRST (BRIVAracetam add-on First Italian netwoRk STudy) was a retrospective, multicentre study including adult patients prescribed adjunctive BRV. Patients with focal epilepsy and 12-month follow-up were considered. Main outcomes included the rates of seizure‐freedom, seizure response (≥ 50% reduction in baseline seizure frequency), and treatment discontinuation. The incidence of adverse events (AEs) was also considered. Analyses by levetiracetam (LEV) status and concomitant use of strong enzyme-inducing antiseizure medications (EiASMs) and sodium channel blockers (SCBs) were performed.ResultsA total of 1029 patients with a median age of 45 years (33–56) was included. At 12 months, 169 (16.4%) patients were seizure-free and 383 (37.2%) were seizure responders. The rate of seizure freedom was 22.3% in LEV-naive patients, 7.1% in patients with prior LEV use and discontinuation due to insufficient efficacy, and 31.2% in patients with prior LEV use and discontinuation due to AEs (p < 0.001); the corresponding values for ≥ 50% seizure frequency reduction were 47.9%, 29.7%, and 42.8% (p < 0.001). There were no statistically significant differences in seizure freedom and seizure response rates by use of strong EiASMs. The rates of seizure freedom (20.0% vs. 16.6%; p = 0.341) and seizure response (39.7% vs. 26.9%; p = 0.006) were higher in patients receiving SCBs than those not receiving SCBs; 265 (25.8%) patients discontinued BRV. AEs were reported by 30.1% of patients, and were less common in patients treated with BRV and concomitant SCBs than those not treated with SCBs (28.9% vs. 39.8%; p = 0.017).ConclusionThe BRIVAFIRST provided real-world evidence on the effectiveness of BRV in patients with focal epilepsy irrespective of LEV history and concomitant ASMs, and suggested favourable therapeutic combinations.

Evaluation of two anti-seizure medication strategies in refractory epilepsy patients from a tertiary center with complementary insights from data visualization

ObjectiveTo evaluate the healthcare resources in a tertiary center related to exclusive use of non-enzyme inducing anti-seizure medications relative to concomitant use of enzyme-inducing anti-seizure medications in patients with refractory epilepsy. MethodsIn this retrospective case-time-control study, we compared the effects of two anti-seizure medication strategies: exclusively non-inducing anti-seizure medications (NIND) or a combination of NIND and inducing anti-seizure medications (IND+). The primary outcome parameter was the number of consultations with relevant healthcare professionals in our tertiary center, assessed with a negative binomial regression model, adjusting for several covariates like blood drug level and time interval (TI). Results from statistical models were visualized to explore the contribution of all covariates on the outcome in the total population and in subgroups. ResultsFrom the 21538 patients with refractory epilepsy referred to our center 1648 patients met the inclusion criteria. The regression model showed that the IND + strategy was significantly associated with fewer consultations compared to the NIND strategy (p < 0.001), reflected in an incidence risk ratio (IRR) of 0.844 (0.799−0.890). Visualization of subgroups, defined by anti-seizure medications strategy, revealed patterns in contribution of blood drug level measurements on the outcome. Although sex was not included as a covariate in the regression model, as it was eliminated by the backward-elimination approach, visualization of this subgroup showed differences in effects of blood drug level and TI. ConclusionFor patients with refractory epilepsy in our tertiary center, treatment following the IND + strategy is associated with fewer consultations with healthcare professionals compared to the NIND strategy. Comprehensive visualization of the results facilitated the exploration of effects of covariates across subgroups.

Enzyme-Inducing Antiseizure Drug Use Is Associated with Long-Term Cardiovascular Disease in a Dose Dependent Fashion in Adults with Epilepsy

Background: Enzyme-inducing antiseizure medications (eiASMs) have been associated with long-term risks of cardiovascular disease. The objective of this study was to quantify and model this putative hazard. Methods: We used the population-based the CALIBER © resource with linked primary and hospital data to isolate three cohorts, one comprising all adults meeting a case definition for epilepsy diagnosed after 1990, one comprising incident cases diagnosed after 1998 (hospital linkage date), and one limited to adults diagnosed with epilepsy at age ≥65. Exposure was receipt of four consecutive eiASMs following an epilepsy diagnosis and the outcome was incident cardiovascular disease (ischaemic heart disease or ischaemic or haemorrhagic stroke). The hazard of incident cardiovascular disease was evaluated using adjusted propensity matched survival analyses and weighted cumulative exposure models. Findings: Of 10,916,166 adults, we identified 50,888 (0.6%) period prevalent cases, of whom 31,466 (62%) were diagnosed on or after 1990 and were free of cardiovascular disease at baseline. In a propensity matched Cox proportional hazards model adjusted for age, sex, baseline socioeconomic status, and cardiovascular risk factors, the hazard of incident cardiovascular disease was 1.21 (95% confidence interval 1.06-1.39) for those receiving eiASMs. The absolute difference in cumulative hazard appeared to diverge significantly after 8-10 years. Median hazard ratio increased from 1.54 when taking a relative defined daily dose (rDDD) of an eiASM of 1 to 2.38 with a rDDD of 2 over a maximum of 25 years follow-up compared to those not receiving an eiASM. The hazard was elevated but attenuated when restricting analyses to incident cases or those diagnosed after age 65. Conclusions and relevance: There is a clinically meaningful hazard of incident cardiovascular disease in those receiving eiASMs. The effect is dose dependent and the absolute difference in hazard seems to reach clinical significance by approximately 10 years from first exposure. Funding Statement: This analysis was in part funded by the Canadian Frailty Network which is supported by the Government of Canada through the Networks Centres of Excellence (NCE) program, as well as through the University of Calgary. Declaration of Interests: All authors declare that they have no conflicts of interest. Ethics Approval Statement: The study was approved by the MHRA (UK) Independent Scientific Advisory Committee [17_064RA3], under Section 251 (NHS Social Care Act 2006).

The impact of medications and medical comorbidities on sexual function in people with epilepsy

ObjectivePeople with epilepsy experience increased rates of sexual dysfunction, often affecting quality of life. Sexual dysfunction may result from the underlying disorder, antiseizure or other medications, or comorbid psychosocial factors. This study evaluated the incidence and clinical associations of sexual dysfunction in adult epilepsy patients. Methods89 epilepsy patients 18 years and older admitted to the New York University Comprehensive Epilepsy Center epilepsy monitoring unit between 2016 and 2018 completed a survey on sexual functioning. The survey included demographic, clinical, and sexual functioning information with a validated measure of sexual function (the Arizona Sexual Experiences Scale (ASEX). ResultsOf 89 surveys completed, 15 (16.9 %) patients had discussed sexual functioning with a medical professional and 20 (22.5 %) reported sexual dysfunction. For the group, the mean ASEX score was 13.6 (SD 4.8). 59 (66.3 %) participants reported not being asked about sexual health by their doctor or nurse practitioner in the last year. The two independent predictors of sexual dysfunction were self-identifying as overweight/obese (OR 6.1, CI 1.4−26.5, P = 0.02) or taking strong enzyme-inducing antiseizure medications (OR 7.8, CI 1.4−44.9, P = 0.02). Other factors such as age, relationship status, duration of epilepsy, the presence of depression or anxiety, cardiovascular risk factors, and opioid/stimulant use, did not predict sexual dysfunction. SignificanceOur study showed that sexual dysfunction is common in epilepsy patients but infrequently discussed by medical professionals. Two modifiable risk factors, being overweight or taking strong enzyme-inducing antiseizure medications, were independently associated with sexual dysfunction, suggesting interventions to potentially improve sexual health.