As a large population of patients with epilepsy ages, risk of hyponatremia has become an important clinical concern, in which monitoring of serum sodium levels when receiving antiseizure medications or antipsychotics (ASMs) may help identify and minimize the risk of hyponatremia in patients with epilepsy.

“Although hyponatremia is a frequent problem associated with epilepsy, to our knowledge, the number of cases and annual incidence rates have not been previously reported,” wrote the researchers of the study. “In our cohort, during the 15-year study period, the overall incidence remained unchanged in pediatric and adult patients but increased significantly in older adult patients.”

The retrospective cohort study is published in Heliyon Open Access.

The study enrolled a total of 26,179 patients with serum sodium levels measured between January 2006 and December 2020, and included 14,620 patients who were enrolled in a previous study between January 2006 to December 2017.

The researchers obtained patient information, including age, sex, body weight, clinical symptoms, concomitant ASM treatment, ASM dose and concentration, and other laboratory information. Furthermore, serum sodium level was measured multiple times in most patients and used the lowest sodium level for patients with a changed ASM regimen during the study period. Moderate to severe hyponatremia was defined as serum sodium levels less than 130 mEq/L.

Patients were grouped by age: 0 to 15 years (n = 8598), 16 to 64 years (n = 16,476), and 65 years and older (n = 1105), in which the researchers measured potential risk factors, the incidence rate between patients with and without hyponatremia, factors with a significant influence on developing hyponatremia, and performed a logistic regression analysis and multiple logistic regression analysis to calculate the crude odds ratio and adjusted odds ratios.

The analysis revealed that between 2006 to 2020, 677 (2.6%) patients developed moderate to severe hyponatremia, with an incidence of 3.1 per 1000 person-years (95% CI, 2.2-3.9) in the pediatric group, 19.8 per 1000 person-years (95% CI, 18.7-20.9) in the adult group, and 50.4 per 1000 person-years (95% CI, 43.3-57.5) in the older adult group.

Additionally, the incidence of hyponatremia increased from 36.8 in 2007 to 58.5 in 2020 in the older adult group. However, the incidence rate remained unchanged in the adult group and tended to decrease in the pediatric group.

Furthermore, the use of carbamazepine, valproate, phenytoin, phenobarbital, benzodiazepines, and antipsychotics were found to be significant risk factors for hyponatremia, with carbamazepine, benzodiazepine, and antipsychotics found to induce hyponatremia in adult patients in a dose-dependent manner. Lastly, the researchers found that concomitant use of zonisamide reduced the risk of hyponatremia.

However, the researchers acknowledged some limitations to the study. First, it was retrospective in design and could not evaluate factors such as dietary habits, water consumption, hypothyroidism, hypopituitarism, diarrhea, and vomiting. Additionally, it did not examine the effect of other medications that may be associated with hyponatremia, including oxcarbazepine, eslicarbazepine, tricyclic antidepressants, or selective serotonin reuptake inhibitors.

Despite these limitations, the researchers believe the study demonstrates the effect of ASM polypharmacy was associated with an increased risk of moderate-to-severe hyponatremia and suggests how this risk can be reduced based on these findings.

“Because the population of patients with epilepsy is currently aging, hyponatremia will become an increasingly important concern in clinical settings,” wrote the researchers. “Our findings can contribute to minimizing the risk of hyponatremia in epilepsy patients.”


Yamamoto Y, Ohta A, Usui N, Imai K, Kagawa Y, Takahashi Y. Incidence trends and risk factors for hyponatremia in epilepsy patients: a large-scale real-world data study. Heliyon. 2023;9(8):e18721. doi:10.1016/j.heliyon.2023.e18721