The Neuro-Cardio-Respiratory Connection of SUDEP

Virtual Special Editions are collections of targeted papers curated by a Guest Editor. Here Dr. Antonis S. Manolis, Athens University School of Medicine (author of the Editor’s Choice article in Volume 64) talks about Sudden Unexpected Death in Epilepsy.

Sudden unexpected death in epilepsy (SUDEP) preferentially targeting young people is the leading cause of epilepsy-related premature mortality. 1 Its annual rate ranges between 0.3 and 6 cases per 1000 adult persons with epilepsy and 1 case per 4500 children. SUDEP accounts for 8–17% of deaths in people with epilepsy. The etiology of SUDEP remains unknown. However, several risk factors have been identified;1-3 among them, the presence of recurrent generalized tonic-clonic seizures and seizure severity have been considered the most important risk factors and the most effective measure of SUDEP prevention appears to be seizure control.1-5

The current special edition comprises a collection of articles selected for their focus on SUDEP and its pathophysiology. In the article featured in this Virtual Special Edition (VSE) (volume 64) (“Sudden unexpected death in epilepsy: The neuro-cardio-respiratory connection”) we discuss the apparent major pathogenetic link of SUDEP related to the epilepsy-produced disruption of the functional connectivity of certain brain structures associated with the central autonomic control of cardio-respiratory function (neuro-cardio-respiratory connection).1 In this review article we also indicate that studies on neuroimaging and molecular genetics may provide insights into the pathogenetic mechanisms and the causes of SUDEP and identify potential biomarkers for risk stratification of patients susceptible to SUDEP.1 The reviews by Jones et al,2 Aurlien et al,3 Langan et al4 and Annegers et al5 included in this VSE complement our review on important relevant issues of SUDEP. Jones et al2 discuss the progress made on SUDEP over the last 25 years; Aurlien et al3 focus on the role of antiepileptic drugs on SUDEP; Langhan et al4 review the risk factors associated with SUDEP; Annegers et al5 discuss classification, predictors and risk factors of SUDEP.

In an experimental rat model, Mameli et al6 showed that a neurogenic trigger could be responsible of SUDEP when it simultaneously disrupts both cardio-pulmonary and metabolic functions; however, in this model, not all animals we affected leaving room for a hypothesis of susceptible animals characterized by a “low threshold of excitability”.

An important issue remains with the overlap of symptoms and manifestations between SUDEP and certain cardiac syndromes leading to sudden cardiac death. Particularly, cardiac channelopathies, such as long QT syndrome, may manifest epileptiform activity during episodes of potentially malignant ventricular tachyarrhythmias, such as polymorphic ventricular tachycardia in the form of torsade de pointes that may lead to sudden death. A recent study by Gonzalez et al7 explored the occurrence of epilepsy and/or EEG abnormalities in patients with LQT1 (n=15) or LQT2 (n=20) and healthy controls (n=20). They reported that 71% of the patients had loss of consciousness, 44% in combination with convulsions. EEG was abnormal in 34% of patients and 10% of controls (p < 0.05). Two patients had epileptiform or sharp activity. The fronto-parietal directed transfer function connectivity was significantly altered in patients compared to controls. The authors concluded that seizure-like episodes and EEG abnormalities were common in patients with congenital LQT syndrome, although they could not find firm evidence of epilepsy, giving credence to the notion that congenital LQT syndrome is a cardiocerebral channelopathy.

Similarly, ictal bradyarrhythmias have been reported in 2–7%, with ictal asystole occurring in 0.3–3% of seizure patients, more commonly resulting from apnea rather than occurring as a primary event. Shih et al8 conducted a retrospective study comprising 1606 consecutive patients admitted for video-EEG monitoring with a diagnosis of "possible seizures" and showed a low rate of significant primary cardiac bradyarrhythmias and asystole of 0.3% (4/1433) with one subject dying during the evaluation. Shmuely et al 9 presented a nice review of the various cardiac arrhythmias occurring during and after seizures which may be likely or unlikely associated with SUDEP. The authors indicate that arrhythmias in epilepsy may not only result from seizure activity but also from a shared genetic susceptibility (“epilepsy genes”: several genetic ion channel mutations seem to be co-expressed in the brain and in the heart, and might thus cause seizures and cardiac arrhythmias), while several antiepileptic drugs (AEDs) could have a proarrhythmic potential triggering various brady- or tachy-arrhythmias.1,3,9 Furthermore, epilepsy may be associated with or trigger various cardiac conditions, such as cardiac channelopathies, ischemia, Takotsubo cardiomyopathy.9

Finally, as we emphasize in our review paper 1 and also as deduced from the review of relevant articles collected in this VSE of Seizure-Journal of European Epilepsy, 2-9 advancing our knowledge on the pathophysiologic mechanisms of SUDEP is a most important first step towards preventing and reducing its incidence. For now, among the potential mechanisms involved in SUDEP, the epilepsy-related disruption of the central autonomic control leading to cardio-respiratory dysfunction predominates, with resultant respiratory and/or cardiac arrest.1