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Fallik N, Trakhtenbroit I, Fahoum F, Goldstein L. Therapeutic drug monitoring in pregnancy: Levetiracetam. Epilepsia. 2024 May;65(5):1285-1293. Epub 2024 Feb 24. PMID: 38400747. doi:10.1111/epi.17925. Objective: Levetiracetam (LEV) is an antiseizure medication that is mainly excreted by the kidneys. Due to its low teratogenic risk, LEV is frequently prescribed for women with epilepsy (WWE). Physiological changes during gestation affect the pharmacokinetic characteristics of LEV. The goal of our study was to characterize the changes in LEV clearance during pregnancy and the postpartum period, to better plan an LEV dosing paradigm for pregnant women. Methods: This retrospective observational study incorporated a cohort of women who were followed up at the epilepsy in pregnancy clinic at Tel Aviv Sourasky Medical Center during the years 2020–2023. Individualized target concentrations of LEV and an empirical postpartum taper were used for seizure control and to reduce toxicity likelihood. Patient visits took place every 1–2 months and included a review of medication dosage, trough LEV blood levels, week of gestation and LEV dose at the time of level measurement, and seizure diaries. Total LEV concentration/dose was calculated based on LEV levels and dose as an estimation of LEV clearance. Results: A total of 263 samples were collected from 38 pregnant patients. We observed a decrease in LEV concentration/dose (C/D) as the pregnancy progressed, followed by an abrupt postpartum increase. Compared to the third trimester, the most significant C/D decrease was observed at the first trimester (slope =.85), with no significant change in the second trimester (slope =.11). A significant increase in C/D occurred postpartum (slope = 5.23). LEV dose was gradually increased by 75% during pregnancy compared to preconception. Average serum levels (μg/mL) decreased during pregnancy. During the postpartum period, serum levels increased, whereas the LEV dose was decreased by 24%, compared to the third trimester. Significance: LEV serum level monitoring is essential for WWE prior to and during pregnancy as well as postpartum. Our data contribute to determining a rational treatment and dosing paradigm for LEV use during both pregnancy and the postpartum period. Perucca P, Bourikas D, Voinescu PE, Vadlamudi L, Chellun D, Kumke T, Werhahn KJ, Schmitz B. Lacosamide and pregnancy: data from spontaneous and solicited reports. Epilepsia. 2024 May;65(5):1275-1284. Epub 2024 Feb 27. PMID: 38411300. doi:10.1111/epi.17924. Objective: In pregnancy, it is important to balance the risks of uncontrolled epileptic seizures to the mother and fetus against the potential teratogenic effects of antiseizure medications. Data are limited on pregnancy outcomes among patients taking lacosamide (LCM), particularly when taken as monotherapy. The objective of this analysis was to evaluate the pregnancy outcomes of LCM-exposed pregnancies. Methods: This analysis included all reports in the UCB Pharma pharmacovigilance database of exposure to LCM during pregnancy from spontaneous sources (routine clinical settings) or solicited reports from interventional clinical studies and noninterventional postmarketing studies. Prospective and retrospective reports were analyzed separately. Results: At the data cutoff (August 31, 2021), there were 202 prospective pregnancy cases with maternal exposure to LCM and known outcomes. Among these cases, 44 (21.8%) patients received LCM monotherapy and 158 (78.2%) received LCM polytherapy. Most patients received LCM during the first trimester (LCM monotherapy: 39 [88.6%]; LCM polytherapy: 143 [90.5%]). From the prospective pregnancy cases with maternal LCM exposure, there were 204 reported outcomes (two twin pregnancies occurred in the polytherapy group). The proportion of live births was 84.1% (37/44) in patients who received LCM as monotherapy, and 76.3% (122/160) for LCM polytherapy. The overall proportion of abortions (for any reason) was 15.9% (7/44) with LCM monotherapy, and 22.5% (36/160) with LCM polytherapy. Congenital malformations were reported in 2.3% (1/44) of known pregnancy outcomes with maternal exposure to LCM monotherapy, and 6.9% (11/160) with polytherapy. Significance: Our preliminary data do not raise major concerns on the use of LCM during pregnancy. Most pregnancies with LCM exposure resulted in healthy live births, and no new safety issues were identified. These findings should be interpreted with caution, as additional data are needed to fully evaluate the safety profile of LCM in pregnancy. [ABSTRACT FROM AUTHOR]

Safety and Efficacy of Prophylactic Levetiracetam for Prevention of Epileptic Seizures in the Acute Phase of Intracerebral Haemorrhage (PEACH): A Randomised, Double-Blind, Placebo-Controlled, Phase 3 Trial Peter-Derex L, Philippeau F, Garnier P, André-Obadia N, Boulogne S, Catenoix H, Convers P, Mazzola L, Gouttard M, Esteban M, Fontaine J, Mechtouff L, Ong E, Cho T-H, Nighoghossian N, Perreton N, Termoz A, Haesebaert J, Schott A-M, Rabilloud M, Pivot C, Dhelens C, Filip A, Berthezène Y, Rheims S, Boutitie F, Derex L. Lancet Neurol. 2022;21(9):781-791. doi:10.1016/S1474-4422(22)00235-6 Background: The incidence of early seizures (occurring within 7 days of stroke onset) after intracerebral haemorrhage reaches 30% when subclinical seizures are diagnosed by continuous EEG. Early seizures might be associated with haematoma expansion and worse neurological outcomes. Current guidelines do not recommend prophylactic antiseizure treatment in this setting. We aimed to assess whether prophylactic levetiracetam would reduce the risk of acute seizures in patients with intracerebral haemorrhage. Methods: The double-blind, randomised, placebo-controlled, phase 3 PEACH trial was conducted at three stroke units in France. Patients (aged 18 years or older) who presented with a non-traumatic intracerebral haemorrhage within 24 h after onset were randomly assigned (1:1) to levetiracetam (intravenous 500 mg every 12 h) or matching placebo. Randomisation was done with a web-based system and stratified by centre and National Institutes of Health Stroke Scale (NIHSS) score at baseline. Treatment was continued for 6 weeks. Continuous EEG was started within 24 h after inclusion and recorded over 48 h. The primary endpoint was the occurrence of at least one clinical seizure within 72 h of inclusion or at least one electrographic seizure recorded on continuous EEG, analysed in the modified intention-to-treat population, which comprised all patients who were randomly assigned to treatment and who had a continuous EEG performed. This trial was registered at ClinicalTrials.gov, NCT02631759, and is now closed. Recruitment was prematurely stopped after 48% of the recruitment target was reached due to a low recruitment rate and cessation of funding. Findings Between June 1, 2017, and April 14, 2020, 50 patients with mild-to-moderate severity intracerebral haemorrhage were included: 24 were assigned to levetiracetam and 26 to placebo. During the first 72 h, a clinical or electrographic seizure was observed in three (16%) of 19 patients in the levetiracetam group versus ten (43%) of 23 patients in the placebo group (odds ratio 0.16, 95% CI 0.03–0.94, p = 0.043). All seizures in the first 72 h were electrographic seizures only. No difference in depression or anxiety reporting was observed between the groups at 1 month or 3 months. Depression was recorded in three (13%) patients who received levetiracetam versus four (15%) patients who received placebo, and anxiety was reported for two (8%) patients versus one (4%) patient. The most common treatment-emergent adverse events in the levetiracetam group versus the placebo group were headache (nine [39%] vs six [24%]), pain (three [13%] vs ten [40%]), and falls (seven [30%] vs four [16%]). The most frequent serious adverse events were neurological deterioration due to the intracerebral haemorrhage (one [4%] vs four [16%]) and severe pneumonia (two [9%] vs two [8%]). No treatment-related death was reported in either group. Interpretation: Levetiracetam might be effective in preventing acute seizures in intracerebral haemorrhage. Larger studies are needed to determine whether seizure prophylaxis improves functional outcome in patients with intracerebral haemorrhage. [ABSTRACT FROM AUTHOR]

Safety, Efficacy, and Tolerability of Modified Atkins Diet in Persons With Drug-Resistant Epilepsy: A Randomized Controlled Trial Manral M, Dwivedi R, Gulati S, Kaur K, Nehra A, Pandey RM, Upadhyay AD, Sapra S, Tripathi M. Neurology. 2023. doi:10.1212/WNL.0000000000206776 Background and objectives: Modified Atkins Diet (MAD) has emerged as an adjuvant therapy in drug-resistant epilepsy (DRE). Most studies are in children, there is limited evidence for DRE in adults. The present study aimed to investigate if MAD along with standard drug therapy (SDT) was indeed more effective than SDT alone in reducing seizure frequency and improving psychological outcomes at 6 months in adolescents and adults with DRE (non-surgical). Methods: A prospective randomized controlled trial was conducted at tertiary care referral centre, in India. Persons with DRE aged 10-55 years attending outpatient epilepsy clinics between August 2015 and April 2019, who had more than two seizures/month despite using at least three appropriate anti-seizure medications (ASMs) at their maximum tolerated doses and had not been on any form of diet therapy for the past one year, were enrolled. Patients were assessed for the eligibility and randomly assigned to receive SDT plus MAD (intervention arm) or SDT alone (control arm). The primary outcome was >50% reduction in seizure-frequency, and the secondary outcomes were quality of life (QOL), behaviour, adverse events and rate of withdrawal at six months. Intention to treat analysis was performed. Results: 243 patients were screened for eligibility; 160 patients (80 adults and 80 adolescents) were randomized to either intervention or Control arm. Demographic and clinical characteristics in both groups were comparable at baseline. At six months >50% seizure reduction was seen in 26.2% in the intervention group versus 2.5% in the control group (95% CI 13.5-33.9; p < 0.001). Improvement in QOL was 52.1 ± 17.6 in the intervention group versus 42.5 ± 16.4 in the control group (mean difference, 9.6; 95%CI 4.3 to 14.9, p < 0.001). However, behaviour scores could be performed in 49 patients and improvement was seen in intervention versus control group (65.6 ± 7.9 versus 71.4 ± 8.1, p = 0.015) at the end of the study. One patient had weight loss; two patients had iarrhoea. Discussion: MAD group demonstrated improvement in all aspects (reduction in seizure-frequency, and behavioural problems) compared to control group at the end of the study. MAD is an effective modality in controlling seizures, further research is required to assess its efficacy in terms of biomarkers along with descriptive metabolomics studies. [ABSTRACT FROM AUTHOR]

Sex-Specific Disease Modifiers in Juvenile Myoclonic Epilepsy Shakeshaft A, Panjwani N, Collingwood A, Crudgington H, Hall A, Andrade DM, Beier CP, Fong CY, Gardella E, Gesche J, Greenberg DA, Hamandi K, Koht J, Lim KS, Moller RS, Ng CC, Orsini A, Rees MI, Rubboli G, Selmer KK, Striano P, Syvertsen M, Thomas RH, Zarubova J, Richardson MP, Strug LJ, Pal DK. Sci Rep. 2022;12(1):2785. doi:10.1038/s41598-022-06324-2. PubMed PMID: 35190554; PMCID: PMC8861057 Juvenile myoclonic epilepsy (JME) is a common idiopathic generalised epilepsy with variable seizure prognosis and sex differences in disease presentation. Here, we investigate the combined epidemiology of sex, seizure types and precipitants, and their influence on prognosis in JME, through cross-sectional data collected by The Biology of Juvenile Myoclonic Epilepsy (BIOJUME) consortium. 765 individuals met strict inclusion criteria for JME (female: male, 1.8:1). 59% of females and 50% of males reported triggered seizures, and in females only, this was associated with experiencing absence seizures (OR = 2.0, p < 0.001). Absence seizures significantly predicted drug resistance in both males (OR = 3.0, p = 0.001) and females (OR = 3.0, p < 0.001) in univariate analysis. In multivariable analysis in females, catamenial seizures (OR = 14.7, p = 0.001), absence seizures (OR = 6.0, p < 0.001) and stress-precipitated seizures (OR = 5.3, p = 0.02) were associated with drug resistance, while a photoparoxysmal response predicted seizure freedom (OR = 0.47, p = 0.03). Females with both absence seizures and stress-related precipitants constitute the prognostic subgroup in JME with the highest prevalence of drug resistance (49%) compared to females with neither (15%) and males (29%), highlighting the unmet need for effective, targeted interventions for this subgroup. We propose a new prognostic stratification for JME and suggest a role for circuit-based risk of seizure control as an avenue for further investigation. [ABSTRACT FROM AUTHOR]

Introduction: Aicardi syndrome is a rare neurodevelopmental disorder associated with epilepsy in females. Ketogenic diet therapy represents a possible nonpharmacologic treatment in Aicardi syndrome patients. Methods: All patients with Aicardi syndrome seen at Johns Hopkins Hospital (Baltimore, MD) and Johns Hopkins All Children's Hospital (St Petersburg, FL) treated with ketogenic diet therapy since 1994 were evaluated retrospectively. Results: Fifteen patients, ages 4 months to 34 years, were identified. Ten (67%) patients experienced a ≥50% seizure reduction after 3 months, with 3 (20%) having a ≥90% reduction. Only 1 patient was seizure-free for a short period of time. The number of drugs tried prior to ketogenic diet therapy initiation was correlated with ≥50% seizure reduction at 3 months, 5.8 vs 2.6 in responders versus nonresponders (P =.01). In addition, the mean number of drugs actively received also correlated, 3.0 vs 1.2, P =.005. Ketogenic diet therapy was slightly more successful in those without infantile spasms, 78% vs 50%, P =.33. Conclusion: Ketogenic diet therapy was helpful in Aicardi syndrome, although seizure freedom was rare. It was especially helpful for those who were more drug-resistant and did not have infantile spasms at ketogenic diet therapy onset. [ABSTRACT FROM AUTHOR]

The goal of this study was to determine the value of a certified child life specialist (CCLS) on the patient and staff experiences in an epilepsy monitoring unit (EMU). We integrated a CCLS into the EMU for all children as well as adults with intellectual disability. We surveyed families to determine the impact of child life services on their stay. EMU staff completed questionnaires to determine perceived impact to their job performance from the integration of the CCLS. All of the families (pediatric and adult patients) who responded to the survey reported the presence of the CCLS improved their hospital experience. Staff reported that the CCLS improved their daily work by allowing them to focus on their assigned medical duties. This preliminary pilot study suggests that CCLS can have a strong impact on the experience of patients and staff in an EMU. [ABSTRACT FROM AUTHOR]

The outcome for patients attempting dietary therapy for epilepsy a second time is unknown. Twenty-six subjects treated with the ketogenic diet as children who then began either the ketogenic diet or a Modified Atkins Diet (MAD) at least 6 months later were evaluated. The mean age at the first diet trial was 5.6 years and at the second diet trial was 11.5 years. Most restarted dietary therapy because of persistent seizures (65%) or recurrence after seizure freedom (19%). Overall, 77% had a ≥50% seizure reduction with the first diet, and 50% with the second diet, P = .04. Individual subject responses were largely similar, with 14 (54%) having identical seizure reduction both times, 9 worse (35%) with the second attempt, and 3 (16%) improved. The second diet trial was more likely to lead to >50% seizure reduction if the first trial was started at a later age (7.4 vs 3.9 years, P = .04). [ABSTRACT FROM AUTHOR]

During the 3rd International Symposium on Dietary Therapies held in Chicago, Illinois, there was a first-ever, half-day session devoted to the management of adults with epilepsy and other disorders with dietary treatments. Speakers from 3 different continents shared their successes, challenges, and future directions in their management of these patients. Diets used to treat adults included the classic ketogenic diet, the modified Atkins diet, and a low glycemic index treatment. The utility of dietary therapies was demonstrated not only in patients with epilepsy but also patients with propriospinal myoclonus, astrocytoma, type 2 diabetes, obesity, hyperlipidemia, and metabolic disorder. The session provided evidence that dietary therapies are safe and effective in adults. [ABSTRACT FROM AUTHOR]