Introduction Residents in NH are more likely to be diagnosed with epilepsy or seizures, which are associated with higher mortality and complicate care. This setting provides unique challenges in the treatment of seizures however, little is known about current management practices in NH. Most studies in the literature concentrate on the use of antiseizure medications (ASMs) but little is known about the management of the acute seizure and clinical guidance is needed to ensure the safety of this vulnerable population. The objective of this study was to survey current practices, identifying knowledge deficits and inform future educational endeavors, including acute seizure action plans (ASAPs). Methods A survey was developed pertaining to a broad spectrum of clinical aspects in the management of acute seizures in NH, distinguishing first time seizures from those in the setting of a known seizure disorder. It was sent to NH medical directors throughout the US and data was gathered from those who had at least one new case of new onset/epilepsy in the last 3 years. Results Ninety-one NH directors responded with 52 % having a seizure protocol. Nurses are responsible in the majority of cases for protocol activation. Regardless of the patient’s seizure history, rescue medications are given in the majority of cases, oral benzodiazepines, followed by intravenous and then rectal benzodiazepines. Newer intranasal and intramuscular formulations of benzodiazepines were less frequently prescribed. The most commonly prescribed ASM is levetiracetam, followed by lamotrigine, valproic acid and phenytoin. Staff training and in-service education occur infrequently. Respondents thought no-cost seizure education would be highly beneficial. Conclusions and implications Only approximately half of NH have protocols for the acute management of seizures. Rescue medications are given regardless of seizure history and often older ASMs are used for long-term management. Our study highlights areas of knowledge deficits and treatment areas for improvement, identifying the need and potential for ASAPs in NHs.

Purpose of review An increased interest in epilepsy in older adults has emerged as the global population ages. The purpose of this article is to review the literature regarding the pharmacological treatment of epilepsy in older adults, highlighting issues specifically pertinent to those living with comorbid neurodegenerative disorders. Recent findings Although new original research remains sparse, in the last 5 years, there has been a growing number of studies addressing the relationship between epilepsy and neurodegenerative disorders. Accurate diagnosis is incredibly challenging with electroencephalogram findings often requiring circumspect interpretation. Older individuals are often excluded from or under-represented in clinical trials, and there are sparse guidelines offered on the management of these patients, with even less available in reference to those with neurodegenerative comorbidities. Summary We propose that seizures occurring earlier in the neurodegenerative process should be treated aggressively, with the goal to inhibit neuro-excitotoxicity and the associated neuronal loss. By strategically choosing newer antiseizure medications with less adverse effects and a holistic approach to treatment, a patient's time living independently can be conserved. In addition, we advocate for original, multinational collaborative research efforts.

Objective: This study aimed to characterize the relationship between lacosamide pharmacokinetics and renal function in older adults with epilepsy. Background: Lacosamide is an anti-seizure medication (ASM) indicated for focal-onset seizures which is primarily excreted through the renal route. Changes in clearance with increased age could lead to pharmacokinetic changes in medications that are eliminated via the kidney; therefore, older adults, being more sensitive to these changes may need lower doses than younger adults. Design/Methods: Data on patients diagnosed with epilepsy according to ICD10 codes and having at least one steady-state lacosamide concentration measurement between January 2015 and July 2020 met inclusion. A linear mixed model was developed to characterize differences in lacosamide dose normalized concentrations (DNCs = blood concentration/total daily dose) with respect to creatinine clearance (CLCR). CLCR was calculated using the Cockcroft-Gault equation as indicated for lacosamide dosing (package insert), thus incorporating the effect of patient age and sex. The model was controlled for covariates including ethnicity, route of administration (oral/intravenous), aspartate aminotransferase concentration, alanine aminotransferase concentration, regime (monotherapy/polytherapy), presence of CYP450 inducers & inhibitors, and critically ill status as signified by prescription. Model significance was set to α≤0.05 (R software (version 4.1.2)). Results: 2291 lacosamide DNCs from 676 patients were included. The median[range] dose and DNC were 300 mg [50–1000 mg] and 23(ug/L)/mg [1–480(ug/L)/mg], respectively. For a given subject the mean DNC of lacosamide decreased by 6% (95% confidence interval: 3.5–8.9%, p<0.01) per unit increase in the CLCR. Route of administration (p=0.01) and presence of a CYP450 inducer (p<0.01) showed a statistically significant effect on DNCs. Conclusions: Creatinine clearance was a significant predictor of lacosamide DNCs in older patients with epilepsy. Thus, as CLCR changes are more pronounced as one ages, modification in dosing regimens may be required to maintain lacosamide concentrations in the tolerable and effective range. Disclosure: Miss Avachat has nothing to disclose. The institution of Dr. Reeder has received research support from American Epilepsy Society . Mr. Long has received personal compensation for serving as an employee of PharmaVelox. Dr. Leppik has nothing to disclose. The institution of Dr. Patel has received research support from Ucb. The institution of Dr. Birnbaum has received research support from National Institutes of Health. Dr. Birnbaum has received intellectual property interests from a discovery or technology relating to health care.

Background: Little is known about the distribution of cannabidiol (CBD) and Delta 9-tetrahydrocannabinol (THC) to patients participating in state medical cannabis programs. The Minnesota cannabis program requires third-party testing of products with limited formulations of cannabis for distribution to patients. Objective: To characterize the distribution of cannabis products, their CBD/THC content, and dosing among patients with qualifying conditions. Methods: This is a retrospective analysis of similar to 50% of registered users receiving medical cannabis in Minnesota (June 16, 2016, to November 15, 2019). Data included formulation, CBD/THC prescribed doses, and qualifying conditions. The primary end points were calculated using daily dose and duration of use. Comparisons were made for CBD and THC total daily dose dispensed, patient age, and approved product. Nonparametric statistical tests were used (significance was set at p < 0.05). Results: A total of 11,520 patients were listed with 1 qualifying condition. The most common condition was intractable pain (60.0%). Median dispensation duration varied from 53 days (cancer) to 322 days (muscle spasms). Most (>= 62.8%) patients across all qualifying conditions received both CBD and THC. Median THC dose was lower in older (>= 65 years) compared with younger adults with intractable pain (p < 0.0001) and cancer patients (p = 0.0152), and the same pattern was found CBD dose with seizure (p = 0.0498) patients. For commercial products with Food and Drug Administration indications, the median CBD total daily dose was 86.9% lower than the recommended doses for patients with seizures (Epidiolex: Jazz Pharmaceuticals, Palo Alto CA) and median THC total daily dose was 65.3% (Syndros: Benuvia Manufacturing, Round Rock, TX) or 79.3% lower (Marinol: Banner Pharmacaps, Inc., High Point, NC) for cancer patients. Conclusions: A majority of patients received products containing both CBD and THC. Dosages varied by age group and were lower than recommended for conditions with Food and Drug Administration-approved products. Complex pharmacokinetics of THC and CBD, possible age-related changes in physiology, unknown efficacy, and potential for drug interactions all increase the need for monitoring of patients receiving cannabis products. (c) 2023 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

BackgroundThe long-term efficacy and safety of adjunctive perampanel was evaluated in patients aged≥60 years with focal-onset seizures (FOS) with/without focal to bilateral tonic-clonic seizures (FBTCS) who participated in open-label extension Studies 307 (NCT00735397) and 335 (NCT01618695).MethodsPatients received perampanel 2–12 mg/day during Studies 307 (16-week blinded Conversion; 256-week Maintenance) and 335 (4-week Pre-conversion; 6-week Conversion; ≥46-week Maintenance). Assessments included median per cent reduction in seizure frequency/28 days vs pre-perampanel baseline, 50% responder rates and treatment-emergent adverse events (TEAEs).ResultsThe Safety Analysis Set included 71 patients (mean age, 64.0 years). Seizure frequency reductions during Years 1 and 2 were 31.7% (n=71) and 44.5% (n=38) (total FOS), and 95.5% (n=19) and 100.0% (n=9) (FBTCS), respectively. Seizure frequency reductions were observed during Years 3/4 (low patient numbers); over one-third of patients achieved a ≥50% seizure reduction each year. During Years 1, 2, 3 and 4, TEAE incidence was 87.3% (n=62/71), 60.4% (n=29/48), 47.4% (n=9/19) and 57.1% (n=8/14), respectively; most common were dizziness and fall during Years 1/2 and 3/4, respectively.ConclusionPerampanel was associated with reductions in seizure frequency over 4 years in elderly patients. The safety profile was consistent with the overall populations.FundingEisai Inc. stella_ngo@eisai.com33

Approximately 10% of nursing home (NH) residents are taking an anti-seizure medication (ASM), and 7.8% have an epilepsy/seizure indication. In one recent study, levetiracetam (LEV) and phenytoin (PHT) were the most commonly prescribed ASMs in US NH residents. There are major differences in pharmacokinetics (PK) among ASMs. PHT has complicated PK and its absorption is pH-dependent, and LEV is very water-soluble with few drug interactions. The side effect profiles also differ, with PHT being associated with ataxia and LEV with behavioral problems. This study was done to evaluate the intraindividual variability of (LEV) and phenytoin (PHT) plasma levels in nursing home (NH) residents, and characterize the association between blood concentrations and its variability, with the presence of falls and seizures.

Older adults represent a highly heterogeneous population, with multiple diverse subgroups. Therefore, an individualized approach to treatment is essential to meet the needs of each unique subgroup. Most comparative studies focusing on treatment of epilepsy in older adults have found that levetiracetam has the best chance of long-term seizure freedom. However, there is a lack of studies investigating other newer generation antiseizure medications (ASMs). Although a number of randomized clinical trials have been performed on older adults with epilepsy, the number of participants studied was generally small, and they only investigated short-term efficacy and tolerability. Quality of life as an outcome is often missing but is necessary to understand the effectiveness and possible side effects of treatment. Prognosis needs to move beyond the focus on seizure control to long-term patient-centered outcomes. Dosing studies with newer generation ASMs are needed to understand which treatments are the best in the older adults with different comorbidities. In particular, more high-level evidence is required for older adults with Alzheimer's disease with epilepsy and status epilepticus. Future treatment studies should use greater homogeneity in the inclusion criteria to allow for clearer findings that can be comparable with other studies to build the existing treatment evidence base.

To provide an overview of perampanel efficacy data in elderly patients (≥60 years) who participated in Phase III/IV Studies 307, 335 open-label extension (OLEx), 412, 342, and 506.

Objective: The point prevalence of epilepsy is high in nursing homes (NH), but the incidence of epilepsy after admission is unknown. This study was done to determine the incidence of epilepsy/seizure (epi/sz) comorbid with other conditions in older adult NH residents. Design: Retrospective evaluation of Minimum Data Set records to identify new onset epi/sz in NH residents. Setting and Participants: Five cross-sectional cohorts of all residents in any Medicare/Medicaid certified NH in the United States on July 15 of each year 2003-2007. Measures: Epi/sz was identified by International Classification of Diseases, Ninth Revision codes (345.xx or 780.39) or check box on the Minimum Data Set. Those with no such code on admission and with 1 to 3 plus years of follow-up (n = 3,609,422) were followed through 2007 or end of stay. Results: Overall incidence of epi/sz was 16.42/1000 patient years (PY). Incidence was highest in the first year after admission and declined thereafter. There were more women (n = 2,523,951) than men (n = 1,089,631), but men had a higher incidence (21.17/1000PY) compared with women (14.81/1000PY). Although the 65-74 years of age cohort included fewer residents (n = 594,722) compared with the age 85 years + cohort (n = 1,520,167), the younger residents had the highest incidence (28.53/1000 PY) compared with the oldest, 10.22/1000 PY for the age 85+ years cohort. The highest incidences were among those with brain tumor (122.55/1000PY), followed by head injury (45.66/1000PY). Overall, 714,340 had a diagnosis of stroke, and incidence was 27.52/1000PY. Those with none of selected risk factors had an overall incidence of 12.45/1000PY. Conclusions and Implications: The incidence of epi/sz in older individuals after admission to a NH is high. There is a need to develop practice approaches to best manage this large cohort. There does not appear to be a uniform approach to managing new onset epilepsy in NHs at this time. Studies to develop evidence for practice guidelines are needed. (C) 2022 AMDA - The Society for Post-Acute and Long-Term Care Medicine.

Allopregnanolone (ALLO) is a neurosteroid that modulates synaptic and extrasynaptic GABAA receptors. We hypothesize that ALLO may be useful as first-line treatment of status epilepticus (SE). Our objectives were to (1) characterize ALLO pharmacokinetics-pharmacodynamics PK-PD after intravenous (IV) and intramuscular (IM) administration and (2) compare IV and IM ALLO safety and tolerability. Three healthy dogs and two with a history of epilepsy were used. Single ALLO IV doses ranging from 1-6 mg/kg were infused over 5 minutes or injected IM. Blood samples, vital signs, and sedation assessment were collected up to 8 hours postdose. Intracranial EEG (iEEG) was continuously recorded in one dog. IV ALLO exhibited dose-proportional increases in exposure, which were associated with an increase in absolute power spectral density in all iEEG frequency bands. This relationship was best described by an indirect link PK-PD model where concentration-response was described by a sigmoidal maximum response (Emax) equation. Adverse events included site injection pain with higher IM volumes and ataxia and sedation associated with higher doses. IM administration exhibited incomplete absorption and volume-dependent bioavailability. Robust iEEG changes after IM administration were not observed. Based on PK-PD simulations, a 2 mg/kg dose infused over 5 minutes is predicted to achieve plasma concentrations above the EC50, but below those associated with heavy sedation. This study demonstrates that ALLO is safe and well tolerated when administered at 1-4 mg/kg IV and up to 2 mg/kg IM. The rapid onset of effect after IV infusion suggests that ALLO may be useful in the early treatment of SE. SIGNIFICANCE STATEMENT: The characterization of the pharmacokinetics and pharmacodynamics of allopregnanolone is essential in order to design clinical studies evaluating its effectiveness as an early treatment for status epilepticus in dogs and people. This study has proposed a target dose/therapeutic range for a clinical trial in canine status epilepticus.

Introduction Many commonly prescribed drugs cause cognitive deficits. We investigated whether parameters of the resting-state electroencephalogram (rsEEG) are related to the severity of cognitive impairments associated with administration of the antiseizure drug topiramate (TPM) and the benzodiazepine lorazepam (LZP). Methods We conducted a double-blind, randomized, placebo-controlled crossover study. After a baseline visit, subjects completed three sessions at which they received either a single dose of TPM, LZP, or placebo. Four-hours after drug administration and at baseline, subjects completed a working memory (WM) task after their rsEEG was recorded. After quantifying drug-related behavioral (WM accuracy (ACC)/reaction time (RT)) and electrophysiological (alpha, theta, beta (1,2), gamma power) change for each subject, we constructed drug-specific mixed effects models of change for each WM and EEG measure. Regression models were constructed to characterize the relationship between baseline rsEEG measures and drug-related performance changes. Results Linear mixed effects models showed theta power increases in response to TPM administration. The results of the regression models revealed a number of robust relationships between baseline rsEEG parameters and TPM-related, but not LZP-related, WM impairment. Conclusions We showed for the first time that parameters of the rsEEG are associated with the severity of TPM-related WM deficits; this suggests that rsEEG measures may have novel clinical applications in the future.

OBJECTIVES/GOALS: Allopregnanolone (ALLO), a modulator of GABAA receptors, may be useful as a treatment for human and canine benzodiazepine-refractory status epilepticus (SE). Our objective was to develop a phamacokinetic-pharmacodynamic (PKPD) model relating ALLO plasma concentrations to electroencephalographic (EEG) effects in dogs. METHODS/STUDY POPULATION: Four healthy dogs and one dog with epilepsy that had implanted intracranial electrodes were utilized. ALLO doses ranging from 1-6 mg/kg were administered IV over 5 min. EEG data were collected during four IM doses (1-2 mg/kg). Blood samples were collected up to 6 hr following dosing. ALLO concentrations were measured using HPLC-MS/MS. Power density was determined in EEG bands using a custom algorithm. A two-compartment link PKPD model was developed to describe the relation between ALLO plasma concentration and change in EEG power in the alpha, beta, delta and theta bands. RESULTS/ANTICIPATED RESULTS: ALLO caused a rapid increase in absolute power density in all EEG bands measured (1-4, >4 – 8, >8 – 12, >12 – 25, and >25 – 100 Hz). The onset of effect was rapid (1-3 min) and demonstrated by frequency band and dose analysis. Concentration-EEG data were best fit by a two-compartment PK model and sigmoidal Emax PD indirect link model. The beta frequency band was most sensitive, showing increases in power at the lowest ALLO concentrations. The EC50 concentration for the beta frequency was ~270 ng/mL. The EC50 values for effects on the other frequency bands were ~500-700 ng /mL. In conclusion, IV ALLO causes a rapid effect on EEG that can be used to determine minimal plasma concentrations associated with target engagement. DISCUSSION/SIGNIFICANCE OF IMPACT: Dose selection for future clinical trials will use the effective concentrations determined here in conjunction with studies in animal status epilepticus models. Studies are planned in client owned dogs with epilepsy to evaluate clinical efficacy in dogs and as nonclinical proof-of-concept evidence supporting translational studies in people. CONFLICT OF INTEREST DESCRIPTION: Michael Rogawski and Dorota Zolkowska are named as inventors on patent applications claiming use of neuroactive steroids including allopregnanolone and ganaxolone in the treatment of status epilepticus.

Drug side effects that impair cognition can lead to diminished quality of life and discontinuation of therapy. Topiramate is an antiepileptic drug that elicits cognitive deficits more frequently than other antiepileptic drugs, impairing multiple cognitive domains including language, attention, and memory. Although up to 40% of individuals taking topiramate may experience cognitive deficits, we are currently unable to predict which individuals will be most severely affected before administration. The objective of this study was to show the contributions of plasma concentration and working memory capacity in determining the severity of an individual's topiramate-related cognitive impairment. Subjects were enrolled in a double-blind, placebo-controlled crossover study during which they received a single dose of either 100, 150, or 200 mg topiramate. Working memory function was assessed using a modified Sternberg working memory task with 3 memory loads administered 4 hours after dosing. After adjustment for differences in working memory capacity, each 1 mu g/mL of topiramate plasma concentration was associated with a 3.6% decrease in accuracy for all memory loads. Placebo effects occurred as a function of working memory capacity, with individuals with high working memory capacity experiencing less severe placebo-related impairment compared with those with low working memory capacity. Our results demonstrate that severity of topiramate-related cognitive deficits occurs as a function of both drug exposure and baseline cognitive function. By identifying patient- and exposure-related characteristics that modulate the severity of cognitive side effects, topiramate dosing strategies may be individually tailored in the future to prevent unwanted cognitive impairment.

Background: A sensitive, robust method was developed and validated to quantitate 13 major natural cannabinoid parent and metabolite compounds in human plasma at or below 0.5 ng/mL. Methods: A liquid chromatography tandem mass spectrometry method was developed and validated to measure 13 cannabinoid compounds: cannabidiol (CBD), cannabidiolic acid, cannabidivarin, cannabinol, cannabigerol, cannabigerolic acid, cannabichromene, Δ9-tetrahydocannabinol (THC), Δ9-tetrahydrocannabinolic acid A (THCA), Δ9-tetrahydrocannabivarin (THCV), 11-hydroxy-Δ9-tetrahydrocannbinol (11-OH-THC), 11-nor-9-carboxy-Δ9-tetrahydrocannbinol (THC-COOH), and 11-nor-9-carboxy-Δ9-tetrahydrocannabinol glucuronide (THC-COOH-glu). Samples (200 µL) were extracted through protein precipitation and separated with a Kinetex EVO C18 column and a 65%–95% gradient of methanol and 0.2% ammonium hydroxide/H2O at a flow rate of 0.4 mL/min. Samples were obtained from patients with epilepsy receiving cannabis for the treatment of seizures. Results: The extracted lower limit of quantification was 0.05 ng/mL for CBD, cannabidivarin, cannabinol, and 11-OH-THC; 0.10 ng/mL for cannabidiolic acid, cannabigerol, cannabichromene, cannabigerolic acid, THC, THCA, and THCV; and 0.50 ng/mL for THC-COOH and THC-COOH-glu. Mean quality control intraday accuracy and precision for all analytes ranged 96.5%–104% and 2.7%–4.9%, respectively, whereas interday accuracy and precision ranged 98%–103.3% and 0.2%–3.6%, respectively. An absolute matrix effect was observed for some analytes, however, with minimal relative matrix effect. Lack of nonspecific drug binding to extraction glass and plasticware was verified. Patient CBD levels ranged from 0.135 to 11.13 ng/mL. Conclusions: The validated method met FDA guidelines for bioanalytical assays precision and accuracy criteria. The assay reliably confirmed the use of particular medical cannabis formulations in patient samples as well as reliably measured low CBD concentrations from single-dose CBD exposure.

OBJECTIVE:To evaluate the pharmacokinetics of a purified oral cannabidiol (CBD) capsule administered with and without food in adults with refractory epilepsy. METHODS:Adult patients who were prescribed CBD for seizures, had localization-related intractable epilepsy with ≥4 seizures per month, and qualified for Minnesota cannabis were enrolled. A single dose of 99% pure CBD capsules was taken under both fasting (no breakfast) and fed (high fat 840-860 calorie) conditions. Blood sampling for CBD plasma concentrations was performed under each condition between 0 and 72 hours post-dose and measured by a validated liquid chormatography-mass spectometry assay. CBD pharmacokinetic profiles including maximum concentration (Cmax ), area-under-the-curve from zero to infinity (AUC0-∞ ), and time-to-maximum concentration (Tmax ) were calculated. The confidence intervals (CIs) for log-transformed Cmax and AUC0-∞ ratios between fed and fasting states were calculated. Seizure and adverse events information was collected. RESULTS:Eight patients completed the study. On average Cmax was 14 times and AUC0-∞ 4 times higher in the fed state. The 90% CI for the ratio of fed versus fast conditions for Cmax and AUC0-∞ were 7.47-31.86 and 3.42-7.82, respectively. No sequence or period effect for Cmax and AUC0-∞ was observed. No adverse events were reported. SIGNIFICANCE:Administering CBD as a capsule rather than a liquid allows for more precise determination of pharmacokinetics parameters and is more representative of CBD swallowed products. The fat content of a meal can lead to significant increases in Cmax and AUC0-∞ and can account for variability in bioavailability and overall drug exposure within patients with oral products.