Dose Adjustment of Concomitant Antiseizure Medications During Cenobamate Treatment: Expert Opinion Consensus Recommendations.

INTRODUCTION: Our objective was to provide expert consensus recommendations to improve treatment tolerability through dose adjustments of concomitant antiseizure medications (ASMs) during addition of cenobamate to existing ASM therapy in adult patients with uncontrolled focal seizures. METHODS: A panel of seven epileptologists experienced in the use of ASMs, including cenobamate, used a modified Delphi process to reach consensus. The panelists discussed tolerability issues with concomitant ASMs during cenobamate titration and practical strategies for dose adjustments that may prevent or mitigate adverse effects. The resulting recommendations consider concomitant ASM dose level and specify proactive (prior to report of an adverse effect) and reactive (in response to report of an adverse effect) dose adjustment suggestions based on concomitant ASM pharmacokinetic and pharmacodynamic interactions with cenobamate. Specific dose adjustment recommendations are provided. RESULTS: We recommend proactively lowering the dose of clobazam, phenytoin, and phenobarbital due to their known drug-drug interactions with cenobamate, and lacosamide due to a pharmacodynamic interaction with cenobamate, to prevent adverse effects during cenobamate titration. Reactive lowering of a concomitant ASM dose is sufficient for other ASMs at standard dosing owing to quick resolution of adverse effects. For carbamazepine and lamotrigine doses exceeding the upper end of standard dosing (e.g., carbamazepine, greater than 1200 mg/day; lamotrigine, greater than 500 mg/day), we encourage consideration of proactive dose reduction at cenobamate 200 mg/day to prevent potential adverse effects. All dose reductions for adverse effects can be repeated every 2 weeks as dictated by the adverse effects. At cenobamate 200 mg/day, we recommend that patients be evaluated for marked improvement of seizures and further dose reductions be considered to reduce potentially unnecessary polypharmacy. CONCLUSION: The primary goal of the recommended dose reductions of concomitant ASMs is to prevent or resolve adverse effects, thereby allowing cenobamate to reach the optimal dose to achieve the maximal potential of improving seizure control.

Some people with epilepsy need to take more than one seizure medicine as part of their treatment. Taking more than one seizure medicine, however, can increase the risk of unwanted side effects. One approach to preventing side effects when adding a new seizure medicine is to lower the amount (dose) of existing seizure medicines. Cenobamate is a newer seizure medicine available in the USA for adults with focal seizures (also referred to as partial-onset seizures). Cenobamate, like many seizure medicines, must be titrated over time to a target dose. A group of epilepsy specialists met and developed recommendations for when and how to change the doses of existing seizure medicines when adding cenobamate. The goal of these recommendations is to prevent or reduce side effects like sleepiness or dizziness. The authors recommend that the dose of specific seizure medicines, including clobazam, lacosamide, phenytoin, and phenobarbital, be lowered as cenobamate is started or as cenobamate's dose is being increased (but before side effects occur). Regular doses of other seizure medicines can be lowered if a side effect occurs because reducing the dose of the other seizure medications can often stop the side effect. These recommendations may help patients successfully reach their optimal dose of cenobamate with fewer side effects, potentially improving their seizure control. Video Abstract: Dose Adjustment of Concomitant Antiseizure Medications During Cenobamate Treatment: Expert Opinion Consensus Recommendations.

Efficacy of cenobamate for uncontrolled focal seizures in patients with previous epilepsy-related surgery: Post hoc analysis of a phase 3, multicenter, open-label study.

OBJECTIVE: This post hoc analysis of 10 US study sites from a long-term open-label phase 3 study of adjunctive cenobamate evaluated the efficacy of cenobamate in patients with prior epilepsy-related surgery. METHODS: Patients with uncontrolled focal seizures despite taking stable doses of 1-3 concomitant antiseizure medications (ASMs) received increasing doses of cenobamate (12.5, 25, 50, 100, 150, 200 mg/day) at 2-week intervals over 12 weeks (target dose, 200 mg/day). Further increases up to 400 mg/day using biweekly 50-mg/day increments were allowed during the maintenance phase. Dose adjustments of cenobamate and concomitant ASMs were allowed. Data were assessed until the last clinic visit on or after September 1, 2019. RESULTS: Of the 240 eligible patients, 85 had prior epilepsy-related surgery and 155 were nonsurgical patients. Baseline focal seizure frequency per 28 days was numerically higher among prior surgery (mean=25.9/median=4.1/range=0.3-562.3) versus nonsurgical (mean=13.8/median=2.4/range=0.2-534.2) patients. Among all patients, 100 % seizure reduction ≥ 12 months at any consecutive month interval occurred in 30.6 % (26/85) prior surgery and 39.4 % (61/155; p > 0.05) nonsurgical patients (cenobamate treatment median duration=32.9 months). Among the 177 patients still receiving cenobamate at the data cutoff, 29.2 % (19/65) of prior surgery and 36.6 % (41/112; p > 0.05) of nonsurgical patients had 100 % seizure reduction ≥ 12 months at the data cutoff. Cenobamate was well tolerated. CONCLUSIONS: This post hoc analysis supports the efficacy of cenobamate in patients with refractory focal seizures despite prior surgery. These findings suggest cenobamate may be considered early in the treatment regimen, including, in some patients, before surgery is considered.

Antiepileptic drug withdrawal and seizure severity in the epilepsy monitoring unit.

OBJECTIVE: The goal of this study was to identify a strategy for antiepileptic drug (AED) reduction to allow efficient recording of focal seizures (FS) in patients undergoing video-electroencephalography (EEG) in an epilepsy monitoring unit (EMU) while avoiding the risk of complications associated with more severe seizure types. METHODS: We retrospectively reviewed consecutive patients admitted to our institution's EMU from July 1, 2016 to December 31, 2017. We included 114 presurgical patients who had AEDs reduced and at least one seizure during the admission. We compared AED dosages at which FS versus focal to bilateral tonic-clonic seizures (f-BTCS), seizure clusters, and lorazepam administration occurred. We also examined rate of AED reduction and seizure types. We used a receiver-operating characteristic (ROC) curve to identify a dose maximizing FS and minimizing other seizure types. RESULTS: Antiepileptic drug withdrawal rates ranged from 0 to 100% in the first 24 h (mean: 20%, standard deviation: 20%). Focal to bilateral tonic-clonic seizures and lorazepam administration occurred at a lower median AED dose than did FS (0%, 7.2%, and 43.8%, respectively, expressed as a percentage of the patient's outpatient daily AED dose; p < 0.001). A daily EMU-administered dose of one-third of the patient's outpatient AED dose allowed 55.0% of FS to occur while avoiding 82.0% of more severe seizure types. The seizure types had no difference in rate of AED withdrawal in the first 24 h of EMU stay. CONCLUSIONS: Focal seizures occurred at a higher AED dose than did f-BTCS. This may imply that a low minimally effective dose of AED could allow FS to be recorded while providing protection against f-BTCS. This strategy could improve efficacy and safety in the EMU.

Association between white matter hyperintensities, cortical volumes, and late-onset epilepsy.

OBJECTIVE: To identify the association between brain vascular changes and cortical volumes on MRI and late-onset epilepsy. METHODS: In 1993-1995, 1,920 participants (median age 62.7, 59.9% female) in the community-based Atherosclerosis Risk in Communities (ARIC) Study underwent MRI, and white matter hyperintensities were measured. In addition, in 2011-2013, 1,964 ARIC participants (median age 72.4, 61.1% female) underwent MRI, and cortical volumes and white matter hyperintensities were measured. We identified cases of late-onset epilepsy (starting at age 60 or later) from ARIC hospitalization records and Medicare claims data. Using the 1993-1995 MRI, we evaluated the association between white matter hyperintensities and subsequent epilepsy using survival analysis. We used the 2011-2013 MRI to conduct cross-sectional logistic regression to examine the association of cortical volumes and white matter hyperintensities with late-onset epilepsy. All models were adjusted for demographics, hypertension, diabetes, smoking, and APOE ε4 allele status. RESULTS: Ninety-seven ARIC participants developed epilepsy after having an MRI in 1993-1995 (incidence 3.34 per 1,000 person-years). The degree of white matter hyperintensities measured at ages 49-72 years was associated with the risk of late-onset epilepsy (hazard ratio 1.27 per age-adjusted SD, 95% confidence interval [CI] 1.06-1.54). Lower cortical volume scores were associated cross-sectionally with higher odds of late-onset epilepsy (odds ratio 1.87, 95% CI 1.16-3.02) per age-adjusted SD. CONCLUSIONS: This study demonstrates associations between earlier-life white matter hyperintensities on MRI and later-life incident epilepsy, and between cortical volumes measured later in life and late-onset epilepsy. These findings may help illuminate the causes of late-onset epilepsy.

Association Between Midlife Risk Factors and Late-Onset Epilepsy: Results From the Atherosclerosis Risk in Communities Study.

Importance: The incidence of epilepsy is higher in older age than at any other period of life. Stroke, dementia, and hypertension are associated with late-onset epilepsy; however, the role of other vascular and lifestyle factors remains unclear. Objective: To identify midlife vascular and lifestyle risk factors for late-onset epilepsy. Design, Setting, and Participants: The Atherosclerosis Risk in Communities (ARIC) study is a prospective cohort study of 15 792 participants followed up since 1987 to 1989 with in-person visits, telephone calls, and surveillance of hospitalizations (10 974 invited without completing enrollment). The ARIC is a multicenter study with participants selected from 4 US communities. This study included 10 420 black or white participants from ARIC with at least 2 years of Medicare fee-for-service coverage and without missing baseline data. Data were analyzed betweeen April 2017 and May 2018. Exposures: Demographic, vascular, lifestyle, and other possible epilepsy risk factors measured at baseline (age 45-64 years) were evaluated in multivariable survival models including demographics, vascular risk factors, and lifestyle risk factors. Main Outcomes and Measures: Time to development of late-onset epilepsy (2 or more International Classification of Diseases, Ninth Revision codes for epilepsy or seizures starting at 60 years or older in any claim [hospitalization or outpatient Medicare through 2013]), with first code for seizures after at least 2 years without code for seizures. Results: Of the 10 420 total participants (5878 women [56.4%] and 2794 black participants [26.8%]; median age 55 years at first visit), 596 participants developed late-onset epilepsy (3.33 per 1000 person-years). The incidence was higher in black than in white participants (4.71; 95% CI, 4.12-5.40 vs 2.88; 95% CI, 2.60-3.18 per 1000 person-years). In multivariable analysis, baseline hypertension (hazard ratio [HR], 1.30; 95% CI, 1.09-1.55), diabetes (HR, 1.45; 95% CI, 1.17-1.80), smoking (HR, 1.09; 95% CI, 1.01-1.17), apolipoprotein E ε4 genotype (1 allele HR, 1.22; 95% CI, 1.02-1.45; 2 alleles HR, 1.95; 95% CI, 1.35-2.81), and incident stroke (HR, 3.38; 95% CI, 2.78-4.10) and dementia (HR, 2.56; 95% CI, 2.11-3.12) were associated with an increased risk of late-onset epilepsy, while higher levels of physical activity (HR, 0.90; 95% CI, 0.83-0.98) and moderate alcohol intake (HR, 0.72; 95% CI, 0.57-0.90) were associated with a lower risk. Results were similar after censoring individuals with stroke or dementia. Conclusions and Relevance: Potentially modifiable risk factors in midlife and the APOE ε4 genotype were positively associated with risk of developing late-onset epilepsy. Although stroke and dementia were both associated with late-onset epilepsy, vascular and lifestyle risk factors were significant even in the absence of stroke or dementia.

Effects of marketed antiepileptic drugs and placebo in the human photosensitivity screening protocol.

A study of epilepsy patients with a reproducible range of photoparoxysmal responses (PPR) (epileptiform discharges evoked by flashing lights) has been used as a "proof-of-concept" trial to determine if novel potential antiepileptic drugs (AEDs) should proceed in development. The standard design for this trial requires a 3-day inpatient stay and is single-blind. We evaluated two marketed and effective AEDs-one narrow-spectrum [carbamazepine (CBZ)], and one broad-spectrum [levetiracetam (LEV)]-using a novel double-blinded, cross-over outpatient version of the trial to detect acute drug effects of the two marketed AEDs on photosensitivity. We tested 6 patients with a known stable photosensitivity response, using single oral doses of CBZ 400 mg and LEV 1000 mg, compared to 2 test days with single placebo doses. Patients who received LEV had the lowest mean PPR (compared with placebo and CBZ). The mixed effect model showed a significant effect of LEV in all eye closure conditions (p < 0.001). There was no evidence of a significant change in PPR after CBZ or placebo treatment. In conclusion, LEV 1000 mg, but not CBZ 400 mg, was effective in suppressing photosensitivity within a 6-h period compared with placebo showing the ability of our novel photosensitivity trial design to demonstrate effects of broad-spectrum AEDs. We cannot confirm the ability of the photosensitivity trial to detect the narrow-spectrum AED CBZ in our design. The novel outpatient study design is feasible and is expected to reduce costs compared with previous methodology.

Variation of seizure frequency with ovulatory status of menstrual cycles.

PURPOSE: To determine if seizure frequency differs between anovulatory and ovulatory cycles. METHODS: The data came from the 3-month baseline phase of an investigation of progesterone therapy for intractable focal onset seizures. Of 462 women who enrolled, 281 completed the 3-month baseline phase and 92 had both anovulatory and ovulatory cycles during the baseline phase. Midluteal progesterone levels ≥5 ng/ml were used to designate cycles as ovulatory. Among the 92 women, average daily seizure frequency (ADSF) for all seizures combined and each type of seizure considered separately (secondary generalized tonic-clonic seizures - 2°GTCS, complex partial seizures - CPS, simple partial seizures - SPS) were compared between anovulatory and ovulatory cycles using paired t-tests. A relationship between the proportional differences in ADSF and estradiol/progesterone (EP) serum level ratios between anovulatory and ovulatory cycles was determined using bivariate correlational analysis. KEY FINDINGS: ADSF was 29.5% greater for 2°GTCS during anovulatory than during ovulatory cycles. ADSF did not differ significantly for CPS or SPS or for all seizures combined. Proportional differences in anovulatory/ovulatory 2°GTCS ADSF ratios correlated significantly with differences in anovulatory/ovulatory EP ratios. Among the 281 women, the three seizure types did not differ in ovulatory rates, but EP ratios were greater for cycles with 2°GTCS than partial seizures only. SIGNIFICANCE: Seizure frequency is significantly greater for 2°GTCS, but not CPS or SPS, during anovulatory cycles than ovulatory cycles. Because the proportional increases in 2°GTCS frequency during anovulatory cycles correlate with the proportional increases in EP level ratios, these findings support a possible role for reproductive steroids in 2°GTCS occurrence.

Treating patients with medically resistant epilepsy.

Recent evidence suggests that medically resistant epilepsy can be identified if seizures persist despite adequate doses of 2 appropriate first-line antiepileptic drugs (AEDs). Patients with medically resistant epilepsy should have their seizures carefully characterized in order to confirm their diagnosis, select treatment, and assist in determining prognosis. Patients should be counseled about factors that aggravate epilepsy and the importance of adhering to treatments. Physicians should carefully inquire about side effects and alter therapy to eliminate or minimize these symptoms. Uncontrolled seizures cause injuries, disability, and increased mortality, so surgery should be considered as soon as seizures are proven to be medically resistant. Patients with incomplete response to AEDs and who are not surgical candidates may benefit from additional medication trials or from palliative nonmedical therapies, such as vagal nerve stimulation.