Symptomatology of carbamazepine- and oxcarbazepine-induced hyponatremia in people with epilepsy.

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.

Well-being of mothers with epilepsy with school-aged children.

PURPOSE: The purpose of the study was to examine different aspects of well-being in mothers with epilepsy with school-aged children. METHODS: In an observational study, mothers, identified from the European Registry of Antiepileptic Drugs and Pregnancy database in the Netherlands, completed questions on epilepsy, the impact of epilepsy on daily functioning, quality of life, behavioral problems, and parenting stress. Descriptive analyses were performed to examine the prevalence of behavioral problems and the impact of epilepsy on different aspects of the mother's daily functioning and family life. We subsequently investigated which factors contributed most to the impact of maternal epilepsy using regression analyses. RESULTS: One hundred fifty-six (46%) of the 342 invited mothers with epilepsy participated. The majority (89%) had low epilepsy severity, with well-controlled seizures. Internalizing problems within the borderline or clinical range were reported by 23% of the mothers. Behavioral problems were significantly correlated with epilepsy severity (r = 0.26, p = .002), impact of epilepsy on daily functioning (r = 0.32, p < .001), and quality of life (r = -0.52, p < 01). Quality of life was in general good (mean = 8, standard deviation [SD] = 1), with low impact of epilepsy. Epilepsy affected mostly maternal self-confidence, work, and general health. Mothers indicated to experience no to little impact of epilepsy on the relationship with their children, partner, or family. Regression analyses showed that epilepsy severity (1.0, 95% confidence interval [CI]: 0.4 to 1.6; p = .002) and quality of life (-1.3, CI: -2.3 to -0.4; p = .007) were significant contributors to the impact of epilepsy on daily functioning, while other factors (maternal education, family type, behavioral problems, and parenting stress) were nonsignificant. DISCUSSION: The current study shows that mothers with epilepsy generally fared well. Epilepsy negatively impacted the lives of some mothers, though. As maternal well-being is of importance for mother-child interaction and child development, clinicians should be aware of the impact of epilepsy on maternal psychosocial outcomes and family life of women with epilepsy.

Neurocognition after prenatal levetiracetam, lamotrigine, carbamazepine or valproate exposure.

OBJECTIVE: To examine neurocognitive functioning of children exposed prenatally to carbamazepine, lamotrigine, levetiracetam or valproate monotherapy. METHODS: In a prospective observational study, children aged 6 or 7 years, identified from the European Registry of Antiepileptic Drugs and Pregnancy database in The Netherlands, were assessed using the Wechsler Intelligence Scale for Children and the developmental neuropsychological assessment. Maternal IQ was measured using Wechsler Adult Intelligence Scale. Assessors were blinded to drug exposures. RESULTS: One hundred and sixty-one children (one set of twins and 21 sibling pairs) of 139 mothers were included. As a group, children achieved average scores on neurocognitive outcomes. Children exposed to valproate (n = 22) performed lower on all six neurocognitive domains, especially language, than those exposed to carbamazepine (n = 32), lamotrigine (n = 82) or levetiracetam (n = 25). After controlling for maternal IQ and drug dose, the verbal IQ of valproate-exposed children was on average 9.1 points lower than those exposed to carbamazepine (95% confidence interval [CI] 1.3-17.0; p = 0.023), 10.3 lower than lamotrigine-exposed children (CI 3.4-17.3; p = 0.004) and 13.4 lower than levetiracetam-exposed children (CI 5.2-21.6; p = 0.002). No significant dose-effect was found. Virtually no significant differences were found between lamotrigine and levetiracetam or lamotrigine and carbamazepine exposed children. CONCLUSIONS: Consistent with previous research, valproate-exposed children experienced more problems compared to three other common antiepileptic drugs, while children exposed to lamotrigine, carbamazepine or levetiracetam revealed little to no problems. This illustrates the need for systematic follow-up of prenatally exposed children, to support pre-pregnancy counseling and treatment decisions in women of reproductive age.

Declining malformation rates with changed antiepileptic drug prescribing: An observational study.

OBJECTIVE: Changes in prescribing patterns of antiepileptic drugs (AEDs) in pregnant women with epilepsy would be expected to affect the risk of major congenital malformations (MCMs). To test this hypothesis, we analyzed data from an international pregnancy registry (EURAP). METHODS: EURAP is an observational prospective cohort study designed to determine the risk of MCMs after prenatal exposure to AEDs. The Cochrane-Armitage linear trend analysis was used to assess changes in AED treatment, prevalence of MCMs, and occurrence of generalized tonic-clonic seizures (GTCs) over 3 time periods: 2000-2005 (n = 4,760), 2006-2009 (n = 3,599), and 2010-2013 (n = 2,949). RESULTS: There were pronounced changes in the use of specific AEDs over time, with a decrease in the use of valproic acid and carbamazepine and an increase in the use of lamotrigine and levetiracetam. The prevalence of MCMs with monotherapy exposure decreased from 6.0% in 2000-2005 to 4.4% in 2010-2013. The change over time in MCM frequency after monotherapy exposure showed a significant linear trend in the crude analysis (p = 0.0087), which was no longer present after adjustment for changes in AED treatment (p = 0.9923). There was no indication of an increase over time in occurrence of GTCs during pregnancy. CONCLUSIONS: There have been major changes in AED prescription patterns over the years covered by the study. In parallel, we observed a significant 27% decrease in the prevalence of MCMs. The results of adjusting the trend analysis for MCMs for changes in AED treatment suggest that changes in prescription patterns played a major role in the reduction of teratogenic events.

Behavioral problems in children of mothers with epilepsy prenatally exposed to valproate, carbamazepine, lamotrigine, or levetiracetam monotherapy.

OBJECTIVE: To examine the behavioral functioning of children prenatally exposed to carbamazepine (CBZ), lamotrigine (LTG), levetiracetam (LEV), or valproate (VPA) monotherapy. METHODS: In collaboration with the European Registry of Antiepileptic Drugs and Pregnancy (EURAP), the Dutch EURAP & Development study was designed, a prospective observational study. Between January 2015 and March 2018, the Child Behavior Checklist and the Social Emotional Questionnaire were used to examine the nature and severity of behavioral problems. VPA-exposed children were compared to children exposed to CBZ, LTG, or LEV, taking potential confounders into account. A direct comparison was also made between LTG and LEV, as these are first-choice treatments for many women with epilepsy of childbearing potential. RESULTS: Of the 405 invited, 181 children were included; 26 were exposed to VPA, 37 to CBZ, 88 to LTG, and 30 to LEV. For most children, both parents completed the behavioral questionnaires. Across all four antiepileptic drug (AED) exposure groups, high percentages of children with clinically relevant behavior problems were found, with behavioral problems occurring in 32% of VPA-exposed children, 14% of CBZ, 16% of LTG, and 14% of LEV. After controlling for potential confounders, VPA-exposed children had significantly more social problems than those exposed to LTG (-2.8, 95% confidence interval [CI] = -5.2 to -0.4; P = 0.022) or LEV (-3.2, CI: -6.1 to -0.3; P = 0.028), and significantly more attention problems than LEV-exposed children (-3.7, CI: -6.7 to -0.8; P = 0.013). LTG-exposed children had significantly more attention deficit (-9.2, CI: -17.3 to 1.1; P = 0.026), but significantly less anxious behavior when compared to LEV-exposed children (9.0, CI: 0.3-17.6; P = 0.042). SIGNIFICANCE: Compared to population norms, a high proportion of children of mothers with epilepsy exposed prenatally to monotherapy with four common AEDs had clinical behavioral problems reported by parents. Different patterns were seen, with some but not all subscales raised for all AED exposure groups. It is important that prenatally AED-exposed children are regularly screened for behavioral problems so that appropriate help can be provided.

Fetal methotrexate syndrome: A systematic review of case reports.

Methotrexate is a folic acid antagonist known to be teratogenic in humans. Several cases of congenital malformations after fetal exposure to methotrexate have been published, resulting in the establishment of the 'fetal methotrexate syndrome'. However, it is unclear which congenital anomalies can truly be attributed to methotrexate exposure. The objective of this review is to delineate a consistent phenotype of the fetal methotrexate syndrome. We performed a systematic review that yielded 29 cases of (congenital) anomalies after in utero exposure to methotrexate and compared their malformation pattern to that of children and fetuses with congenital anomalies in general. Statistically significant higher proportions of microcephaly, craniosynostosis, tetralogy of Fallot, pulmonary valve atresia, limb reduction defects and syndactyly were found in the methotrexate group, indicating that these congenital anomalies are truly part of the fetal methotrexate syndrome. These results aid clinicians with diagnosing fetal methotrexate syndrome.

Maternal epilepsy and behavioral development of the child: Family factors do matter.

PURPOSE: The purpose of the study was to examine whether mothers with epilepsy experience family problems and to investigate the possible mediating role of distinct family factors in the relationship between maternal epilepsy and child behavioral problems, in which it is also investigated whether more proximal family factors mediate the more distal family factors. METHODS: In an observational study, with children identified from the European Registry of Antiepileptic Drugs and Pregnancy database in the Netherlands (EURAP-NL), parents completed questionnaires on maternal epilepsy, family factors (proximal, distal, contextual, global), and child behavior. Hierarchical multilevel regression analyses were performed to examine the relative contribution of epilepsy-related and family factors on child internalizing and externalizing problems. RESULTS: Between January 2015 and March 2018, the questionnaires were completed for 175 children. Mothers with epilepsy showed significantly more parenting stress and problems with parenting than mothers from the general population. Family factors were significantly associated with child behavioral problems. For internalizing problems, maternal epilepsy, global, contextual, and distal family factors were each found to have significant added value. Distal family factors contributed most to internalizing problems and showed a mediating role for epilepsy-related factors and previous added family factors in the model. Global, contextual, distal, and proximal factors were all found to be significant contributors to externalizing problems, with the factor most proximal to the child (quality of parent-child interaction) showing the largest effect. DISCUSSION: Including family factors in research regarding children of mothers with epilepsy is important as they can have a contribution additional to the teratogenic risks of prenatal exposure to antiepileptic drugs (AEDs). Family factors, in particular distal and proximal family factors, can weaken or strengthen child development and may provide starting points for interventions.

A genome-wide association study of sodium levels and drug metabolism in an epilepsy cohort treated with carbamazepine and oxcarbazepine.

OBJECTIVE: To ascertain the clinical and genetic factors contributing to carbamazepine- and oxcarbazepine-induced hyponatremia (COIH), and to carbamazepine (CBZ) metabolism, in a retrospectively collected, cross-sectional cohort of people with epilepsy. METHODS: We collected data on serum sodium levels and antiepileptic drug levels in people with epilepsy attending a tertiary epilepsy center while on treatment with CBZ or OXC. We defined hyponatremia as Na+ ≤134 mEq/L. We estimated the CBZ metabolic ratio defined as the log transformation of the ratio of metabolite CBZ-diol to unchanged drug precursor substrate as measured in serum. RESULTS: Clinical and genetic data relating to carbamazepine and oxcarbazepine trials were collected in 1141 patients. We did not observe any genome-wide significant associations with sodium level in a linear trend or hyponatremia as a dichotomous trait. Age, sex, number of comedications, phenytoin use, phenobarbital use, and sodium valproate use were significant predictors of CBZ metabolic ratio. No genome-wide significant associations with CBZ metabolic ratio were found. SIGNIFICANCE: Although we did not detect a genetic predictor of hyponatremia or CBZ metabolism in our cohort, our findings suggest that the determinants of CBZ metabolism are multifactorial.

Exposure to antiepileptic drugs in pregnancy: The need for a family factor framework.

PURPOSE: Children exposed to antiepileptic drugs (AEDs) in utero are at risk for developmental problems. Maternal epilepsy, its impact on the family system, and other family factors may also contribute. We reviewed the possible associations between family factors and developmental outcome in children who had been exposed to AED during pregnancy. METHODS: We conducted a narrative review and searched MEDLINE, Embase, Google Scholar, and PsycINFO on the following terms: in utero exposure, pregnancy outcome, and AEDs. A family factor framework (the ABCX model) served as the basis to review distinct family factors in children who were exposed to AEDs in pregnancy. RESULTS: Few studies have investigated these factors. Mothers with epilepsy have problems caring for themselves and for the child and experience more parenting stress. There is a paucity of studies of the possible impact of family factors on the neurocognitive and behavioral development of children of mothers with epilepsy. DISCUSSION: Further work is required to ascertain which family factors are associated with child development in addition to the effects of AED exposure and their potential interaction. As epilepsy may have considerable impact on intrafamily factors and as children are especially vulnerable to such effects, study designs incorporating family factors should be encouraged.

Comparative risk of major congenital malformations with eight different antiepileptic drugs: a prospective cohort study of the EURAP registry.

BACKGROUND: Evidence for the comparative teratogenic risk of antiepileptic drugs is insufficient, particularly in relation to the dosage used. Therefore, we aimed to compare the occurrence of major congenital malformations following prenatal exposure to the eight most commonly used antiepileptic drugs in monotherapy. METHODS: We did a longitudinal, prospective cohort study based on the EURAP international registry. We included data from pregnancies in women who were exposed to antiepileptic drug monotherapy at conception, prospectively identified from 42 countries contributing to EURAP. Follow-up data were obtained after each trimester, at birth, and 1 year after birth. The primary objective was to compare the risk of major congenital malformations assessed at 1 year after birth in offspring exposed prenatally to one of eight commonly used antiepileptic drugs (carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, topiramate, and valproate) and, whenever a dose dependency was identified, to compare the risks at different dose ranges. Logistic regression was used to make direct comparisons between treatments after adjustment for potential confounders and prognostic factors. FINDINGS: Between June 20, 1999, and May 20, 2016, 7555 prospective pregnancies met the eligibility criteria. Of those eligible, 7355 pregnancies were exposed to one of the eight antiepileptic drugs for which the prevalence of major congenital malformations was 142 (10·3%) of 1381 pregnancies for valproate, 19 (6·5%) of 294 for phenobarbital, eight (6·4%) of 125 for phenytoin, 107 (5·5%) of 1957 for carbamazepine, six (3·9%) of 152 for topiramate, ten (3·0%) of 333 for oxcarbazepine, 74 (2·9%) of 2514 for lamotrigine, and 17 (2·8%) of 599 for levetiracetam. The prevalence of major congenital malformations increased with the dose at time of conception for carbamazepine (p=0·0140), lamotrigine (p=0·0145), phenobarbital (p=0·0390), and valproate (p<0·0001). After adjustment, multivariable analysis showed that the prevalence of major congenital malformations was significantly higher for all doses of carbamazepine and valproate as well as for phenobarbital at doses of more than 80 mg/day than for lamotrigine at doses of 325 mg/day or less. Valproate at doses of 650 mg/day or less was also associated with increased risk of major congenital malformations compared with levetiracetam at doses of 250-4000 mg/day (odds ratio [OR] 2·43, 95% CI 1·30-4·55; p=0·0069). Carbamazepine at doses of more than 700 mg/day was associated with increased risk of major congenital malformations compared with levetiracetam at doses of 250-4000 mg/day (OR 2·41, 95% CI 1·33-4·38; p=0·0055) and oxcarbazepine at doses of 75-4500 mg/day (2·37, 1·17-4·80; p=0·0169). INTERPRETATION: Different antiepileptic drugs and dosages have different teratogenic risks. Risks of major congenital malformation associated with lamotrigine, levetiracetam, and oxcarbazepine were within the range reported in the literature for offspring unexposed to antiepileptic drugs. These findings facilitate rational selection of these drugs, taking into account comparative risks associated with treatment alternatives. Data for topiramate and phenytoin should be interpreted cautiously because of the small number of exposures in this study. FUNDING: Bial, Eisai, GlaxoSmithKline, Janssen-Cilag, Novartis, Pfizer, Sanofi-Aventis, UCB, the Netherlands Epilepsy Foundation, and Stockholm County Council.

Maternal and fetal outcomes associated with vagus nerve stimulation during pregnancy.

OBJECTIVE: To access the effect of vagus nerve stimulation (VNS) on the outcome of pregnancy. METHODS: We used the International Registry of Antiepileptic Drugs and Pregnancy (EURAP) and its network to search for women receiving adjunctive VNS during pregnancy. Data on maternal and fetal outcomes were extracted from the registry databases and outcomes were evaluated. RESULTS: Twenty-six pregnancies were identified in 25 women. All women were exposed to a relative high VNS stimulation level (mean duty cycle 18%, range 5%-51%). Most women had seizures during pregnancy and almost 70% were on antiepileptic drug (AED) polytherapy. The proportion of women with obstetrical interventions was 53.9% (95% confidence interval [CI] 33.4%-73.4%) which was higher compared to the EURAP average (48.2%; 95% CI 47.2%-49.1%). One infant (3.9%; 95% CI 0.1%-19.6%) was born with a major malformation (unilateral congenital glaucoma), which is within the range expected among offspring of AED-treated women. CONCLUSION: Although the present series of VNS-exposed pregnancies is the largest reported to date, the sample size is insufficient to draw any firm conclusions on the safety of VNS in pregnancy but the findings suggest an increased rate of obstetrical interventions, and no clear signal of VNS-related teratogenicity.

Carbamazepine- and oxcarbazepine-induced hyponatremia in people with epilepsy.

OBJECTIVE: To ascertain possible determinants of carbamazepine (CBZ)- and oxcarbazepine (OXC)-induced hyponatremia in a large cohort of people with epilepsy. METHODS: We collected data on serum sodium levels in people with epilepsy who were attending a tertiary epilepsy center while on treatment with CBZ or OXC. We defined hyponatremia as Na+ ≤134 mEq/L and severe hyponatremia as Na+ ≤128 mEq/L. RESULTS: We identified 1,782 people who had used CBZ (n = 1,424) or OXC (n = 358), of whom 50 were treated with both drugs. Data on sodium level measurements were available in 1,132 on CBZ and in 289 on OXC. Hyponatremia occurred in 26% of those taking CBZ and 46% of those taking OXC. This was severe in 7% in the CBZ group and 22% in the OXC group. Hyponatremia was symptomatic in 48% and led to admissions in 3%. Age over 40 years, high serum levels of CBZ and OXC, and concomitant use of other antiepileptic drugs were the main risk factors for hyponatremia in both treatment groups. Female patients on OXC were at a higher risk than male patients of hyponatremia. The risk of hyponatremia on CBZ was significantly associated with the risk of hyponatremia on OXC within a subgroup that used both drugs consecutively. SIGNIFICANCE: Hyponatremia is a common problem in people taking CBZ or OXC. Regular ascertainment of sodium levels in those taking either drug is recommended and results should be acted on.

Withdrawal of valproic acid treatment during pregnancy and seizure outcome: Observations from EURAP.

Based on data from the EURAP observational International registry of antiepileptic drugs (AEDs) and pregnancy, we assessed changes in seizure control and subsequent AED changes in women who underwent attempts to withdraw valproic acid (VPA) during the first trimester of pregnancy. Applying Bayesian statistics, we compared seizure control in pregnancies where VPA was withdrawn (withdrawal group, n = 93), switched to another AED (switch group, n = 38), or maintained (maintained-therapy group, n = 1,588) during the first trimester. The probability of primarily or secondarily generalized tonic-clonic seizures (GTCS) was lower in the maintained-therapy group compared with the other two groups, both in the first trimester and for the entire duration of pregnancy. GTCS were twice as common during pregnancy in the withdrawal (33%) and switch groups (29%) compared with the maintained-treatment group (16%). Limitations in the data and study design do not allow to establish a cause-effect relationship between treatment changes and seizure outcome, but these observations provide a signal that withdrawal of, or switch from, VPA during the first trimester could lead to loss of seizure control, and highlight the need for a specifically designed prospective observational study.

Remarkable Phenytoin Sensitivity in 4 Children with SCN8A-related Epilepsy: A Molecular Neuropharmacological Approach.

Mutations in SCN8A are associated with epilepsy and intellectual disability. SCN8A encodes for sodium channel Nav1.6, which is located in the brain. Gain-of-function missense mutations in SCN8A are thought to lead to increased firing of excitatory neurons containing Nav1.6, and therefore to lead to increased seizure susceptibility. We hypothesized that sodium channel blockers could have a beneficial effect in patients with SCN8A-related epilepsy by blocking the overactive Nav1.6 and thereby counteracting the effect of the mutation. Herein, we describe 4 patients with a missense SCN8A mutation and epilepsy who all show a remarkably good response on high doses of phenytoin and loss of seizure control when phenytoin medication was reduced, while side effects were relatively mild. In 2 patients, repeated withdrawal of phenytoin led to the reoccurrence of seizures. Based on the findings in these patients and the underlying molecular mechanism we consider treatment with (high-dose) phenytoin as a possible treatment option in patients with difficult-to-control seizures due to an SCN8A mutation.

Complex SCN8A DNA-abnormalities in an individual with therapy resistant absence epilepsy.

BACKGROUND: De novo SCN8A missense mutations have been identified as a rare dominant cause of epileptic encephalopathy. We described a person with epileptic encephalopathy associated with a mosaic deletion of the SCN8A gene. METHODS: Array comparative genome hybridization was used to identify chromosomal abnormalities. Next Generation Sequencing was used to screen for variants in known and candidate epilepsy genes. A single nucleotide polymorphism array was used to test whether the SCN8A variants were in cis or in trans. RESULTS: We identified a de novo mosaic deletion of exons 2-14 of SCN8A, and a rare maternally inherited missense variant on the other allele in a woman presenting with absence seizures, challenging behavior, intellectual disability and QRS-fragmentation on the ECG. We also found a variant in SCN5A. CONCLUSIONS: The combination of a rare missense variant with a de novo mosaic deletion of a large part of the SCN8A gene suggests that other possible mechanisms for SCN8A mutations may cause epilepsy; loss of function, genetic modifiers and cellular interference may play a role. This case expands the phenotype associated with SCN8A mutations, with absence epilepsy and regression in language and memory skills.