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Symptomatology of carbamazepine- and oxcarbazepine-induced hyponatremia in people with epilepsy.
Berghuis, B, Hulst, J, Sonsma, A, McCormack, M, de Haan, GJ, Sander, JW, Lindhout, D, Koeleman, BPC
Epilepsia. 2021;(3):778-784
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OBJECTIVE To ascertain whether adverse effects experienced by people taking carbamazepine or oxcarbazepine could be attributed to carbamazepine- or oxcarbazepine-induced hyponatremia (COIH). METHODS We performed an observational study, collecting data between 2017 and 2019 on serum sodium levels and adverse effects retrospectively in people with epilepsy while receiving treatment with either carbamazepine (CBZ) or oxcarbazepine (OXC). We defined hyponatremia as sodium level ≤134 mEq/L and severe hyponatremia as sodium level ≤128 mEq/L. Adverse effects experienced were compared between groups of individuals with and without hyponatremia. RESULTS A total of 1370 people using CBZ or OXC were identified, of whom 410 had at least one episode of hyponatremia. We checked for symptoms related to the use of CBZ and OXC in 710 people (410 with and 300 without hyponatremia) and found relevant information in 688. Adverse effects occurred in 65% of people with hyponatremia compared to 21% with normal sodium levels (odds ratio [OR] 7.5, P ≤ .001) and in 83% of people with severe hyponatremia compared to 55% in those with mild hyponatremia (P ≤ .001). Significant predictors of adverse effects were the drug (OXC vs CBZ), and the number of concomitant anti-seizure medications. Dizziness (28% vs 6%), tiredness (22% vs 7%), instability (19% vs 3%), and diplopia (16% vs 4%) were reported more often in the hyponatremia group than in patients with normal levels. SIGNIFICANCE People with COIH had a 7-fold increased risk of developing adverse effects during treatment. Clinicians should consider ascertainment of sodium levels in patients taking CBZ and OXC and act upon findings.
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Fetal loss and malformations in the MONEAD study of pregnant women with epilepsy.
Meador, KJ, Pennell, PB, May, RC, Van Marter, L, McElrath, TF, Brown, C, Gerard, E, Kalayjian, L, Gedzelman, E, Penovich, P, et al
Neurology. 2020;(14):e1502-e1511
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OBJECTIVE To examine occurrence of severe adverse fetal outcomes (SAO), including fetal loss and major congenital malformations (MCMs), in pregnant women with epilepsy (PWWE) vs healthy pregnant women (HPW). METHODS The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study is an NIH-funded, prospective, observational, multicenter investigation of pregnancy outcomes for both mother and child, which enrolled women December 2012 through January 2016. RESULTS The 351 PWWE had 365 conceptions, and 105 HPW had 109 conceptions. SAOs occurred more often in PWWE (7.9%) vs HPW (1.9%) (p = 0.025) with odds ratio (OR) 4.45 (95% confidence intervals [CI] 1.04-19.01). There were no significant differences for fetal loss (2.8% vs 0%, p = 0.126) or MCMs (5.2% vs 1.9%, p = 0.185; OR 2.86, 95% CI 0.65-12.53) individually. No fetal losses in PWWE appeared to be related to acute seizures. Outcomes were not affected by periconceptional folate, unplanned/unwanted pregnancies, prior maternal pregnancy history, or antiepileptic drug (AED) blood levels, except for an AED level effect for fetal loss that appeared to be due to polytherapy. Combined maternal or paternal family history of MCM was marginally associated with increased SAOs (p = 0.046). CONCLUSIONS The findings provide additional information on risks of SAOs in PWWE, assessing effects of both AED levels and periconceptional folate. Group differences in average enrollment gestational age could have affected fetal loss results. Analyses are limited by small sample sizes as the MONEAD study was not powered for these secondary outcomes. The large majority of pregnancies in women with epilepsy do not have SOAs.
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Effects of periconceptional folate on cognition in children of women with epilepsy: NEAD study.
Meador, KJ, Pennell, PB, May, RC, Brown, CA, Baker, G, Bromley, R, Loring, DW, Cohen, MJ, ,
Neurology. 2020;(7):e729-e740
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OBJECTIVE Emerging evidence suggests potential positive neuropsychological effects of periconceptional folate in both healthy children and children exposed in utero to antiseizure medications (ASMs). In this report, we test the hypothesis that periconceptional folate improves neurodevelopment in children of women with epilepsy by re-examining data from the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study. METHODS The NEAD study was an NIH-funded, prospective, observational, multicenter investigation of pregnancy outcomes in 311 children of 305 women with epilepsy treated with ASM monotherapy. Missing data points were imputed with Markov chain Monte Carlo methods. Multivariate analyses adjusted for multiple factors (e.g., maternal IQ, ASM type, standardized ASM dose, and gestational birth age) were performed to assess the effects of periconceptional folate on cognitive outcomes (i.e., Full Scale Intelligence Quotient [FSIQ], Verbal and Nonverbal indexes, and Expressive and Receptive Language indexes at 3 and 6 years of age, and executive function and memory function at 6 years of age). RESULTS Periconceptional folate was associated with higher FSIQ at both 3 and 6 years of age. Significant effects for other measures included Nonverbal Index, Expressive Language Index, and Developmental Neuropsychological Assessment Executive Function at 6 years of age, and Verbal Index and Receptive Language Index at 3 years of age. Nonsignificant effects included Verbal Index, Receptive Index, Behavior Rating Inventory of Executive Function-Parent Questionnaire Executive Function, and General Memory Index at 6 years of age, and Nonverbal Index and Expressive Index at 3 years of age. CONCLUSIONS Use of periconceptional folate in pregnant women with epilepsy taking ASMs is associated with better cognitive development. CLINICALTRIALSGOV IDENTIFIER NCT00021866.
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MONOZEB: Long-term observational study of eslicarbazepine acetate monotherapy.
Villanueva, V, Bermejo, P, Montoya, J, Massot-Tarrús, A, Galiano, ML, Toledo, M, Rodriguez-Uranga, JJ, Bertol, V, Mauri, JÁ, Poza, JJ, et al
Epilepsy & behavior : E&B. 2019;:51-59
Abstract
AIM: The aim of the study was to evaluate the effectiveness and tolerability of eslicarbazepine acetate (ESL) when used as monotherapy for 1 year or more in routine clinical use in patients with focal seizures in epilepsy clinics in Spain. METHODS This is a retrospective, observational, noninterventional study. Eligible patients were aged ≥18 years, had focal seizures, and started on ESL ≥1 year before database closure. Primary endpoint was the following: proportion seizure-free for ≥6 months at 1 and 2 years. Secondary endpoints included retention on ESL monotherapy at 1 and 2 years, seizure frequency change, seizure worsening, and side effects. Other analyses included seizure freedom from baseline to 1 and 2 years and outcomes in special populations. RESULTS Four hundred thirty-five patients were included (127 on first-line monotherapy and 308 converting to ESL monotherapy): median daily dose was 800 mg at all time points; 63.2% were seizure-free at 1 year, 65.1% at 2 years, and 50.3% for the entire follow-up. Mean duration of ESL monotherapy was 66.7 months; retention was 88.0% at 1 year and 81.9% at 2 years. Mean reduction in seizure frequency was 75.5% at last visit. Over the entire follow-up, seizure worsening was seen in 22 patients (5.1%), side effects in 28.0%, considered severe in 1.8%, and leading to discontinuation in 5.7%. Dizziness, hyponatremia (sodium <135 mEq/l), and somnolence were the most frequent side effects. Outcomes in special populations (patients aged ≥65 years and those with psychiatric history or learning difficulty) were consistent with the overall population. CONCLUSIONS Patients with focal seizures taking ESL monotherapy had excellent retention, high seizure-free rates, and good tolerability up to 2 years.
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Co-occurrence and Severity of Neurodevelopmental Burden (Cognitive Impairment, Cerebral Palsy, Autism Spectrum Disorder, and Epilepsy) at Age Ten Years in Children Born Extremely Preterm.
Hirschberger, RG, Kuban, KCK, O'Shea, TM, Joseph, RM, Heeren, T, Douglass, LM, Stafstrom, CE, Jara, H, Frazier, JA, Hirtz, D, et al
Pediatric neurology. 2018;:45-52
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BACKGROUND This study aims to determine the prevalence of neurodevelopmental impairments at age ten years among children born extremely preterm (less than 28 weeks gestational age) and to offer a framework for categorizing neurological limitations. METHODS A multicenter, prospective cohort follow-up study recruited 889 ten-year-old children born from 2002 to 2004. We assessed prevalence of cognitive impairment, measured by intelligent quotient and tests of executive function, cerebral palsy (CP), autism spectrum disorder (ASD), and epilepsy singly and in combination. The three levels of impairment severity were: category I-no major neurodevelopmental impairment; category II-normal cognitive ability with CP, ASD, and/or epilepsy; and category III-children with cognitive impairment. RESULTS A total 214 of 873 children (25%) had cognitive impairment, 93 of 849 children (11%) had CP, 61 of 857 children (7%) had ASD, and 66 of 888 children (7%) had epilepsy. Further, 19% of all children had one diagnosis, 10% had two diagnoses, and 3% had three diagnoses. Decreasing gestational age was associated with increasing number of impairments (P < 0.001). Half the children with cognitive impairment and one third of children with CP, ASD, or epilepsy had a single impairment. Six hundred one (68% [95% CI, 64.5%-70.7%]) children were in category I, 74 (8% [95% CI, 6.6%-10.3%]) were in category II, and 214 (24% [95% CI 21.7%-27.4%]) were in category III. CONCLUSIONS Three quarters of children had normal intellect at age ten years; nearly 70% were free of neurodevelopmental impairment. Forty percent of children with impairments had multiple diagnoses.
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Epilepsy as a risk factor for hepatic encephalopathy in patients with cirrhosis: a cohort study.
Jepsen, P, Christensen, J, Weissenborn, K, Watson, H, Vilstrup, H
BMC gastroenterology. 2016;(1):77
Abstract
BACKGROUND Epilepsy is associated with an increased mortality among cirrhosis patients, but the reasons are unknown. We aimed to determine whether epilepsy is a risk factor for developing hepatic encephalopathy (HE), which is a strong predictor of mortality. METHODS We used data from three randomized 1-year trials of satavaptan in cirrhosis patients with ascites. With Cox regression, we compared the hazard rates of HE grade 1-4 between those cirrhosis patients who did or did not have epilepsy. We adjusted for confounding by gender, age, cirrhosis etiology, diabetes, history of HE, Model for Endstage Liver Disease (MELD) score, serum sodium, albumin, lactulose use, rifaximin use, and benzodiazepine/barbiturate sedation. In a supplementary analysis we examined the association between epilepsy and the hazard rate of HE grade 2-4. RESULTS Of the 1120 cirrhosis patients with ascites, 21 (1.9 %) were diagnosed with epilepsy. These patients had better liver function at inclusion than the patients without epilepsy (median MELD score 7.9 vs. 11.4), and only one died during the trials. Nevertheless, seven patients with epilepsy had an HE episode during the follow-up, and the adjusted hazard ratio of HE grade 1-4 for patients with epilepsy vs. controls was 2.12 (95 % CI 0.99-4.55). The corresponding hazard ratio of HE grade 2-4 was 3.83 (95 % CI 1.65-8.87). CONCLUSIONS Our findings suggest that epilepsy is associated with an increased risk of HE in patients with cirrhosis.
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Intravenous lacosamide in clinical practice-Results from an independent registry.
Lang, N, Lange, M, Schmitt, FC, Bös, M, Weber, Y, Evers, S, Burghaus, L, Kellinghaus, C, Schubert-Bast, S, Bösel, J, et al
Seizure. 2016;:5-9
Abstract
PURPOSE This non-interventional study was conducted to evaluate the efficacy and tolerability of intravenous lacosamide (LCM-iv) under routine conditions in daily clinical practice as a prospective registry. METHODS Patients with any type of seizure or epilepsy syndrome were recruited in 16 neurological and neuropediatric centers in Germany if the treating physician decided to administer LCM-iv for any reason. Observation time per patient was 10 days with daily documentation of LCM-iv administration, type and frequency of seizures, currently used drugs and doses, and adverse events. Treatment efficacy, tolerability, and handling of LCM-iv were assessed using a five-step scale. RESULTS In 119 patients treating physicians classified epilepsies as focal in 66.1% and generalized in 17.4% (16.5% unclassifiable). Most common etiologies of seizures were tumors (36.1%) and cerebrovascular diseases (21.8%). Reasons for LCM-iv treatment included preparation for surgery (25.2%), convulsive (24.4%) and non-convulsive (18.5%) status epilepticus (SE), series of seizures (16.0%), gastrointestinal causes (5.9%), and acute seizures (4.2%). The median dose of LCM-iv was 300mg per day. In 45 of 64 patients (70.3%) with SE or series of seizures, epileptic activity ceased during observation time. Five patients showed abnormalities in ECG prior to the infusion and one patient afterwards, but during infusion no abnormalities were reported. Treating physicians rated efficacy and tolerability as very good or good in 77.6% and 93.1% of patients, respectively. CONCLUSIONS This large and independent multicenter registry on the use of LCM-iv in clinical practice demonstrates that LCM-iv is well-tolerated and highly efficacious when given in emergency situations, including patients experiencing SE. It is advisable to perform an electrocardiogram prior to LCM-iv administration.
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A prospective study of adverse drug reactions to antiepileptic drugs in children.
Anderson, M, Egunsola, O, Cherrill, J, Millward, C, Fakis, A, Choonara, I
BMJ open. 2015;(6):e008298
Abstract
OBJECTIVES To prospectively determine the nature and rate of adverse drug reactions (ADRs) in children on antiepileptic drugs (AEDs) and to prospectively evaluate the effect of AEDs on behaviour. SETTING A single centre prospective observational study. PARTICIPANTS Children (<18 years old) receiving one or more AEDs for epilepsy, at each clinically determined follow-up visit. PRIMARY AND SECONDARY OUTCOMES Primary outcome was adverse reactions of AEDs. Behavioural and cognitive functions were secondary outcomes. RESULTS 180 children were recruited. Sodium valproate and carbamazepine were the most frequently used AEDs. A total of 114 ADRs were recorded in 56 of these children (31%). 135 children (75%) were on monotherapy. 27 of the 45 children (60%) on polytherapy had ADRs; while 29 (21%) of those on monotherapy had ADRs. The risk of ADRs was significantly lower in patients receiving monotherapy than polytherapy (RR: 0.61, 95% CI 0.47 to 0.79, p<0.0001). Behavioural problems and somnolence were the most common ADRs. 23 children had to discontinue their AED due to an ADR. CONCLUSIONS Behavioural problems and somnolence were the most common ADRs. Polytherapy significantly increases the likelihood of ADRs in children. TRAIL REGISTRATION NUMBER EudraCT (2007-000565-37).
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Breastfeeding in children of women taking antiepileptic drugs: cognitive outcomes at age 6 years.
Meador, KJ, Baker, GA, Browning, N, Cohen, MJ, Bromley, RL, Clayton-Smith, J, Kalayjian, LA, Kanner, A, Liporace, JD, Pennell, PB, et al
JAMA pediatrics. 2014;(8):729-36
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IMPORTANCE Breastfeeding is known to have beneficial effects, but concern exists that breastfeeding during maternal antiepileptic drug (AED) therapy may be harmful. We previously noted no adverse effects of breastfeeding associated with AED use on IQ at age 3 years, but IQ at age 6 years is more predictive of school performance and adult abilities. OBJECTIVES To examine the effects of AED exposure via breastfeeding on cognitive functions at age 6 years. DESIGN, SETTING, AND PARTICIPANTS Prospective observational multicenter study of long-term neurodevelopmental effects of AED use. Pregnant women with epilepsy receiving monotherapy (ie, carbamazepine, lamotrigine, phenytoin, or valproate) were enrolled from October 14, 1999, through April 14, 2004, in the United States and the United Kingdom. At age 6 years, 181 children were assessed for whom we had both breastfeeding and IQ data. All mothers in this analysis continued taking the drug after delivery. MAIN OUTCOMES AND MEASURES Differential Ability Scales IQ was the primary outcome. Secondary measures included measures of verbal, nonverbal, memory, and executive functions. For our primary analysis, we used a linear regression model with IQ at age 6 years as the dependent variable, comparing children who breastfed with those who did not. Similar secondary analyses were performed for the other cognitive measures. RESULTS In total, 42.9% of children were breastfed a mean of 7.2 months. Breastfeeding rates and duration did not differ across drug groups. The IQ at age 6 years was related to drug group (P < .001 [adjusted IQ worse by 7-13 IQ points for valproate compared to other drugs]), drug dosage (regression coefficient, -0.1; 95% CI, -0.2 to 0.0; P = .01 [higher dosage worse]), maternal IQ (regression coefficient, 0.2; 95% CI, 0.0 to 0.4; P = .01 [higher child IQ with higher maternal IQ]), periconception folate use (adjusted IQ 6 [95% CI, 2-10] points higher for folate, P = .005), and breastfeeding (adjusted IQ 4 [95% CI, 0-8] points higher for breastfeeding, P = .045). For the other cognitive domains, only verbal abilities differed between the breastfed and nonbreastfed groups (adjusted verbal index 4 [95% CI, 0-7] points higher for breastfed children, P = .03). CONCLUSIONS AND RELEVANCE No adverse effects of AED exposure via breast milk were observed at age 6 years, consistent with another recent study at age 3 years. In our study, breastfed children exhibited higher IQ and enhanced verbal abilities. Additional studies are needed to fully delineate the effects of all AEDs. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00021866.