Carbamazepine in KCNQ2-DEE: New Insights from Research & Mouse Models

Carbamazepine is often considered a first-line treatment for patients with KCNQ2 developmental and epileptic encephalopathy (KCNQ2-DEE). It is effective in reducing or stopping seizures. However, its effect on cognitive outcomes is still under discussion.

A recent study evaluated the long-term oral administration of carbamazepine in a mouse model with Kcnq2 dysfunction. Mice were treated from weaning for 70 days. During this period, seizures were monitored, and weekly blood samples were collected. At three months of age, cognitive abilities were assessed using the Water T-maze and Barnes maze tests. Brain tissue was analyzed to measure carbamazepine and carbamazepine-epoxide concentrations.

Results:

  • After 70 days of treatment, only 1 out of 12 Kcnq2-DEE mice treated with carbamazepine experienced a seizure, compared to 8 out of 13 mice receiving the vehicle.
  • The efficacy of carbamazepine on seizures was progressive and correlated with carbamazepine-epoxide accumulation in the brain.
  • Cognitive abilities of treated mice were comparable to wild-type mice.

Information from discussions with Dr. Laurent Villard and Aila Coulmann on behalf of KCNQ2 e.V.:

  • Q: Could similar cognitive improvements be observed with other sodium channel blockers or openers like Lacosamide, Oxcarbazepine, or Phenytoin?

A: These compounds have not been tested in our model. Experiments are time-consuming and expensive, with each drug requiring a dedicated research program.

  • Q: Are other sodium channel modulators being tested in KCNQ2 loss-of-function patients/mouse models?

A: Our KCNQ2 knock-in mouse model shows both spontaneous seizures and neurodevelopmental deficits. Most other published models do not show a strong cognitive phenotype, making efficacy assessment difficult.

  • Q: What makes CBZ unique regarding cognitive effects?

A: We are developing a new research project to investigate the cellular and molecular consequences of CBZ treatment – in the mouse model and in iPSC-derived patient neurons. This may reveal what happens in cells, networks, and the brain under CBZ and identify potential new targets for future treatments.

  • Q: Should CBZ be considered the preferred treatment for patients with loss-of-function mutations?

A: CBZ is the preferred option to control seizures. Its impact on cognitive outcomes still requires clinical investigation, and several research groups are already focusing on this.

Publication:

https://www.nature.com/articles/s41598-023-40472-w

Disclaimer:

This article is for informational purposes only and does not constitute medical advice. Treatment decisions must always be made together with treating physicians.