An insufficient effect of lamotrigine leading to fatal seizures
Aurlien D, Tauböll E, and Gjerstad L (2008) An insufficient effect of lamotrigine leading to fatal seizures. Acta Neurol Scand p. 293
IN RESPONSE TO: Lamotrigine in idiopathic epilepsy – Increased risk of cardiac death? Link to Article]
Abstract: We agree that the cause of death in the four cases we have described is not clear. That is why the title of our paper ends with a question mark.
We also agree that uncontrolled seizures could be a possible explanation to these deaths, as we express in the sentence ‘an insufficient effect of lamotrigine leading to fatal seizures’ under the discussion.
Post-ictal apnea may clearly be another option, but this implies the common denominators (idiopathic epilepsy, lamotrigine (LTG) monotherapy, female gender and young age) as a coincidence. Nevertheless, a post-ictal apnea may have contributed to the development of a post-ictal acidosis which may increase the risk of long QT time.
Our intention was to focus on whether LTG may increase the risk of cardiac death in certain subgroups of patients. The fact that no increase in the rate of SUDEP has been found among patients with localization-related epilepsy may not exclude an increased risk in idiopathic epilepsy.
Danielsson et al. did not demonstrate a safe lower serum concentration of LTG. As the authors suggest the Ikr blocking effect of LTG may be clinically significant in the presence of other factors that increase the risk of arrhythmia (drug–drug interactions resulting in high serum concentrations, concomitant use of other Ikr blocking drugs and seizure-induced acidosis).
In our cases, a seizure-induced acidosis may have been a contributing factor. As we suggest in the paper, a cardiac predisposition to arrhythmia in individual patients with idiopathic epilepsy may be another and female gender a third contributing factor.
We highly welcome the GSK study SCA104648 where no increase in the QTc was found at monotherapy up to 400 mg/day. However, this study was carried out among healthy volunteers and it remains to see if the QT time increases in patients with epilepsy, or in certain subgroups. Animal studies may also add important information. Thus, more studies are needed to explore the effect of LTG on cardiac function.
Response to critics of Aurlien et al. Concedes that causes of death in that study were unknown. Suggests that safe levels of AEDs in healthy controls established in drug testing may not apply to epilepsy patients if ion channel mutations predispose to arrhythmias.