Cardiac investigations in genetic epilepsy

Research Published November 24 2021
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A rare and tragic consequence of epilepsy is Sudden Unexpected Death in Epilepsy (SUDEP), which occurs after a seizure. The mechanisms involved, whether respiratory, cardiac or cerebral, are not yet fully understood. However, this risk is very low, about 1 per 1000 patients with epilepsy. A study led by Alexandre Bacq in Stéphanie Baulac’s (Inserm) “Genetics and Pathophysiology of Epilepsy” team at the Institut du Cerveau, looked at cardiac functions in a cohort of patients at risk of SUDEP and using mouse models of SUDEP. The results, published in Annals of Neurology, have a direct impact on the management of patients, suggesting that certain heavy cardiac examinations could be avoided, and pave the way for new research on the brain mechanisms in SUDEP.

In 2019, Stéphanie Baulac’s team at the Brain Institute had highlighted that the risk of sudden death is higher in drug-resistant epilepsy linked to mutations in the DEPDC5 gene, a player in the mTOR signalling pathway. Other epilepsy genes are associated with SUDEP, including those coding for ion channels. Mutations in these genes result in cardiac defects. Is this the case in patients with a DEPDC5 mutation?

To answer this question, Alexandre Bacq and colleagues assembled a cohort of patients with a DEPDC5 mutation – considered to be at risk of SUDEP – and collected electrocardiogram (ECG), holter (24-hour ECG up to 8 days), and structural investigations by transthoracic echography. No major cardiac abnormalities were identified in the 16 patients studied. Three of these patients subsequently died of SUDEP. The researchers had access to the post-mortem heart tissue of one of them and did not observe any abnormalities such as fibrosis or thrombosis.

In order to further explore the mechanisms at play during SUDEP and to ‘counteract’ the limitations of the human study, the researchers turned to the study of the heart and brain of a genetic mouse model of DEPDC5 deficiency. To do this, they generated a new model of epilepsy and SUDEP that mimics the human genetic etiology. As in patients, the rodents show no cardiac predisposition or variations in heart rate in the basal state. During the fatal seizure, the cardiac arrhythmia classically found during an epileptic seizure is not present at the beginning of the cerebral crisis.

These findings have a first direct consequence on the management of patients with a DEPDC5 gene mutation at high risk of SUDEP, by suggesting that burdensome cardiac examinations for patients could be limited. If the DEPDC5 gene mutation is not associated with cardiac dysfunction, what is the origin of SUDEP? The answer may lie in the brain, for example in the brainstem, which controls cardiorespiratory functions. Future research on brain activity during SUDEP should help to elucidate the mechanisms behind this tragic consequence of epilepsy.


Bacq A, Roussel D, Bonduelle T, Zagaglia S, Maletic M, Ribierre T, Adle-Biassette H, Marchal C, Jennesson M, An I, Picard F, Navarro V, Sisodiya S and Baulac. Cardiac investigations in sudden unexpected death in DEPDC5-related epilepsy. Annals of Neurology. Oct 24. doi: 10.1002/ana.26256

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