Dick Lindhout

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.

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.

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.

Summary: 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.

Pathogenic variants in the PCDH19 gene are associated with epilepsy, intellectual disability (ID) and behavioural disturbances. Only heterozygous females and mosaic males are affected, likely due to a disease mechanism named cellular interference. Until now, only four affected mosaic male patients have been described in literature. Here, we report five additional male patients, of which four are older than the oldest patient reported so far. All reported patients were selected for genetic testing because of developmental delay and/or epilepsy. Custom-targeted next generation sequencing gene panels for epilepsy genes were used. Clinical data were collected from medical records. All patients were mosaic in blood for likely pathogenic variants in the PCDH19 gene. In most, clinical features were very similar to the female phenotype, with normal development before seizure onset, which occurred between 5 and 10 months of age, clustering of seizures and sensitivity to fever. Four out of five patients had mild to severe ID and behavioural problems. We reaffirm the similarity between male and female PCDH19-related phenotypes, now also in a later phase of the disorder (ages 10–14 years).

Summary: 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.