People with epilepsy may die unexpectedly without a clear structural or pathological cause for death. We call this SUDEP. Often, but not always, there is evidence to suggest an epileptic seizure around the time of death. SUDEP is a category not a condition. It may represent more than one entity and different mechanisms may operate in different individuals. A final common pathway for death is cardiorespiratory compromise. Understanding mechanisms involved is necessary to formulating prevention strategies.

A number of studies suggest that SUDEP is largely a peri-ictal event. These include case-control studies and accounts of witnessed deaths and detailed circumstances of death. They also include incidence studies showing an association with less well controlled epilepsy, particularly where there is a history of generalised tonic clonic seizures.

Risk factors identified so far, however, only tell part of the story. Sometimes individuals with infrequent seizures die, while others with more frequent and apparently more severe seizures do not. Some may be more at risk because of social factors, lifestyle or sub-optimal management; others may have additional biological susceptibility.

Of particular interest are risk factors we can influence or prevent, such as tonic clonic seizures. One study also identified polytherapy and frequent treatment changes as independent risk factors. While these risk factors may still be surrogate markers for epilepsy severity, theoretically, both could make SUDEP more likely. Medication changes, prescribed or otherwise, particularly if abrupt, could result in instability, while (poly)therapy could, theoretically, affect post ictal respiratory depression and/or cardiac autonomic function. Of note, however, is that one study found untreated epilepsy to be a risk factor, with those who had never had drug therapy at increased risk.

Another consistent observation is that most deaths occur in bed, presumably from sleep. Again, are nocturnal seizures different pathophysiologically – for example, associated with increased vagal tone or respiratory depression – or is it simply that assistance is not to hand, as Delasiauve wrote a century and a half ago? There is some evidence to suggest that he was at least partly right. A study looking at position in death found 71% prone and only 4% supine. Another case control study showed decreased risk associated with using listening devices or sharing the room with someone capable of giving assistance. Respiratory compromise frequently occurs in more severe seizures. Central and obstructive apnoea, excess bronchial and oral secretions, pulmonary oedema and hypoxia are all well documented. That assistance in the community provides some protection favours a role for respiratory factors which, to some extent, can be influenced by relatively unskilled intervention such as airway protection, re-positioning or stimulation.

Primary or secondary cardiac mechanisms are also likely to be important. One can postulate a number of hypotheses, which are not mutually exclusive:

• That malignant cardiac tachy/brady arrhythmias or cardiac failure occur secondary to the ictal discharge and/or apnoea/hypoxia. A study of long-term cardiac rhythm monitoring using an implanted device resulted in 4/19 patients with intractable epilepsy being paced because of recorded periods of asystole, thought to have occurred in a very small proportion of seizures reported.

• That long-term cardiac changes secondary to uncontrolled epilepsy may occur. Pathological studies provide limited support for this.

• That, theoretically, the same underlying process which causes epilepsy could predispose to sudden cardiac death in a proportion of people with epilepsy. For example, ion channel disorders are implicated in genetic epilepsies and in conditions predisposing to sudden cardiac death; many are co-expressed in heart and brain.

• That some individuals with epilepsy may have a co-existing unrelated ‘mild’ genetic susceptibility to sudden death, through cardiac conduction/ion channel disorders, which then manifests because of uncontrolled seizures. Advances in the studies of complex minor genetic susceptibility may further research into SUDEP.

Strategies to reduce SUDEP include focusing on seizure prevention, optimising medical and surgical management and assistance during seizures, aided by future advances in seizure prediction/detection. Further research into mechanisms exploring the above hypotheses may also lead to specific interventions. An analogy between SIDS and SUDEP is often drawn. Success in preventing some potential SIDS cases followed advice on optimal positioning of infants. More recently individual susceptibility in a small proportion of cases (‘SIDS’ genes which include channelopathies) is being addressed. How important these turn out to be remains to be seen. Many lessons can be learnt from the SIDS story.

Written by: Lina Nashef
Kings College Hospital, London, UK

Reprinted with the permission of Epilepsy Australia-the national coalition of Australia epilepsy associations and Epilepsy Bereaved UK.