Carbamazepine and oxcarbazepine induced hyponatremia

Abstract

Epilepsy affects about 1 % of people and is mainly treated with anti-seizure medication (ASM). The use of carbamazepine (CBZ) and oxcarbazepine (OXC) as first-line ASM in treating focal epilepsy is limited by hyponatremia. This thesis describes the association between CBZ or OXC and hyponatremia and the clinical impact that carbamazepine- and oxcarbazepine-induced hyponatremia (COIH) has on people with epilepsy. We assessed the occurrence of COIH in a large cohort of people with epilepsy and looked for possible determinants. Over 2,600 people were included from our tertiary epilepsy centre in the Netherlands, and we collected data on sodium level measurements in people who (had) used CBZ and OXC. Our main finding was that hyponatremia (Na+ ≤134 mmol/L) occurred in about a quarter of those taking CBZ and almost half of those taking OXC, in line with other studies. Severe hyponatremia (Na+ ≤128 mmol/L) occurred in 7% in the CBZ group and 22% in the OXC group. Age over 40 years, high serum levels of CBZ and OXC and concomitant use of other ASMs were the main risk factors for hyponatremia in both treatment groups. Females on OXC were at a higher risk of hyponatremia than males. Symptoms present at hyponatremia, which could not be explained by another clear cause such as overt ASM intoxication or comorbidity were scored and found in almost half of people who had COIH. They lead to hospital admissions in 3%, primarily because of falls. Next we assessed the AEs experienced by people taking CBZ or OXC and whether they could be attributed to COIH. We performed an observational retrospective study collecting data between 2017 and 2019 on serum sodium levels and AEs in 410 people with COIH and 300 with normal sodium levels from our previously described cohort. Our main finding was the occurrence of AEs in 65% of people with hyponatremia compared to 21% with normal sodium levels (OR 7,5, p=<0,001) and in 83% of people with severe hyponatremia compared to 55% in those with mild hyponatremia (p=<0,001). Significant predictors of AEs were the drug (OXC vs CBZ), and the number of concomitant ASMs. Dizziness, tiredness, instability and diplopia were reported more often in the hyponatremia group than in those with normal levels. Finally we searched for genetic factors contributing to COIH. In 1,141individuals of a CBZ/OXC treated cohort genetic data was collected for a genome wide association analysis to scan for common genetic determinants of COIH. From our clinical experience, susceptibility to COIH varies individually. We did not observe any genome-wide significant associations, neither with sodium level in a linear trait, nor with hyponatremia as a dichotomous trait. This finding cannot rule out genetic susceptibility for COIH completely, as rare variants and combinations of genetic variants of smaller effect size may contribute to overall risk. We also assessed the clinical and genetic factors associated with CBZ metabolism. We could not replicate the finding of polymorphisms in CYP3A4 and EPHX1 (gene encoding microsomal epoxide hydrolase) that have been associated with inter-individual variability of CBZ metabolism. Also, no genome-wide significant associations with CBZ metabolic ratio were found. Hyponatremia increases the risk of hospitalisation and causes a variety of seemly mild symptoms. Treatment of COIH, by fluid restriction, dose reduction or substitution of the ASM can relieve symptoms and improve quality of life