To the Editors: Hindocha and colleagues report the combination of a recognized inherited generalized epilepsy syndrome with an apparent increased risk of Sudden unexpected death in epilepsy (SUDEP). What is unusual about their families is that the epilepsy syndrome is due to a novel mutation, one that results in abnormal sodium channel function. Their hypothesis is that this channelopathy may predispose both to the epilepsy and to a cardiac arrhythmia, and that this channelopathy caused the SUDEP. This suggestion is not new. Epilepsy is a disorder of neuronal function, involving abnormal channel function. Many cardiac arrhythmias are also associated with abnormal channel function, so it might be reasonable to conclude that patients with epilepsy may also be prone to cardiac arrhythmias—and this condition might then predispose them to SUDEP. There is considerable debate as to what causes SUDEP, and such evidence that exists suggests that the final process may involve central cardiorespiratory depression. (Bird et al., 1997; So et al., 2004). Autopsy studies have failed to find any likely pathogenic cardiac abnormalities in SUDEP cases (P-Codrea Tigaran et al., 2005), including in the conduction system (almost by definition); however, a molecular liability to arrhythmias is unlikely to be revealed by a standard autopsy. If a cardiac arrhythmia is responsible for SUDEP, then this condition could be either a tachyarrhythmia or a bradyarrhythmia. Many of the cardiac channelopathies appear to result in a predisposition to tachyarrhythmias, but it is well recognized that patients with epilepsy are prone to bradyarrhythmias. Indeed, most epilepsy monitoring units recognise that occasional patients with epilepsy may have significant bradycardias accompanying their seizures, most often during secondarily generalized convulsions (Britton et al., 2006). Rugg-Gunn and colleagues found 7 of 20 surgery candidates had bradycardias, three potentially fatal (Rugg-Gunn et al., 2004). These patients tend to have temporal lobe seizures, typically intractable to medication, and may have abnormal heart rate variability (HRV), a marker of autonomic dysfunction, and perhaps especially seen in those taking carbamazepine (Tomson et al., 1998). A particularly significant factor in Hindocha's paper is the observation that this family has a missense mutation in the SCN1A gene. The product of this gene, Nav1.1, may have a role in pacemaker function of the sinoatrial node, and blocking this protein slows the heart and increases HRV. However, most patients who die of SUDEP do not have rare genetic epilepsies. They are, in fact, a remarkably homogeneous group, usually composed of young adults with fairly frequent secondarily generalized seizures—who are found dead in bed one morning. Many will have symptomatic localization-related epilepsy, and the genetic influence will be a contributory liability to seizures rather than the sole cause of the epilepsy. The SUDEP will therefore be a stochastic event in an individual who is in someway vulnerable, with possibly a genetic contribution to that vulnerability. To understand this mechanism, we need a better grasp of what actually happens at the time of the SUDEP. HRV studies show that this group of young people with epilepsy may be prone to autonomic instability, and they also appear to liable to brady- (not tachy-) arrhythmias. In Manchester we are in the process of implanting 200 patients who collapse during seizures. This study may show not only how many of such patients have cardiac disorders, but also will help our understanding of the cardiac arrhythmias of those with epilepsy, and could potentially capture a SUDEP. However, it is quite possible that the actual mechanism is a malfunction of central respiratory drive. If so, then the current interest in cardiac arrhythmias, as proposed by Hindocha et al., and which is shared by our unit, may well turn out to be misguided.
Read full abstract
Dec 13, 2020
Kosuke Otsuka + 8
Open Access