SUDEP

Lliwen A. Jones,  Rhys H. Thomas.  Sudden death in epilepsy: Insights from the last 25 years.  Seizure: European Journal of Epilepsy,   Article in press.

Highlights

• SUDEP is the leading cause of mortality in chronic refractory epilepsy.

• Pathophysiology remains poorly understood but risk factors identified.

• No proven intervention for its prevention.

• Increasing awareness and research in the last 25 years.

• Several promising future research avenues to minimise SUDEP impact.  

Abstract

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of mortality in patients with refractory epilepsy, and as such has been a major research focus over the last 25 years. The earliest SUDEP research papers were published in Seizure, as have scores of SUDEP papers since. In this review we discuss the efforts to try and describe the pathophysiological basis of SUDEP, the drive to discover the clinical risk factors that increase the likelihood of SUDEP, and the motivation to increase awareness of SUDEP. These three areas are the prime factors that, when answered, will allow us to better mitigate against SUDEP and help individuals monitor their personal risk. The field has benefited from strong definitions, multinational collaboration, the use of cutting edge genetic analysis, and ensuring that bereaved families are able to take part in research when this is appropriate. Clearly there is much that we do not know and yet, has any area of epilepsy research come so far in the last 25 years?

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From the article:

Termed as Sudden Unexpected Death in Epilepsy (SUDEP), this was defined in 1997 by Nashef :

“Sudden, unexpected, witnessed or unwitnessed, non-traumatic and non-drowning death in patients with epilepsy, with or without evidence of a seizure and excluding documented status epilepticus, in which post-mortem examination does not reveal a toxicologic or anatomic cause for death.” 

SUDEP is the leading cause of mortality in patients with chronic refractory epilepsy, estimated to cause 10–50% of deaths. The topic has attracted increasing amounts of interest from both the scientific and epilepsy community since its definition. Given the sudden and devastating nature of SUDEP, most often affecting young people between the ages of 20 and 40, better knowledge of its pathophysiology and associated risk factors is crucial so that attempts at treatment and prevention can be made…

Despite vigorous efforts, the pathophysiology of SUDEP today remains little better understood than when first described in the literature. The publication of several SUDEP epidemiological studies, case series of witnessed and monitored SUDEP and human and animal epilepsy research however, have provided data from which possible SUDEP mechanisms have been proposed …

The most common proposed mechanism reported in other studies is that of seizure-induced respiratory dysfunction.  Although the majority of patients are found in the prone position, the face is usually tilted to one side and the airway is not completely obstructed. A case series of witnessed deaths reported that most patients experienced breathing difficulties before death. This may be due to a combination of obstructive and central apnoea ultimately leading to asystole. The persistence of hypoxia and hypercapnia after respiratory effort has been restored or increased has suggested the possibility of intrinsic pulmonary dysfunction. The evidence remains circumstantial with post-mortem examination showing pulmonary oedema in many SUDEP cases but not significant enough to cause death …

Another proposed mechanism is that of seizure related cardiac arrhythmia. There are many case reports of patients receiving cardiac pacemakers as a result of postictal bradycardia and asystole. Genetic mutations in ion channels have also been studied as a potential cause for SUDEP, particularly long QT syndrome (LQTS) . A study of 61 people with SUDEP (the majority with definite SUDEP) were studied with exome sequencing and four had mutations in genes known to contribute to LQTS; two with  KCNH2  , one  KCNQ1  and a fourth with  SCN5A  . A further nine had variants in candidate genes for cardiac arrhythmia; that is to say genes coding for ion channels that may contribute to LQTS, Brugada syndrome or catecholaminergic polymorphic ventricular tachycardia. An ultra-rare variant in  SCN5A  has previously been identified in in a young woman with SUDEP.  It remains unclear whether patients with LQTS and epilepsy are at increased risk of SUDEP, and this mechanism is unlikely to be the primary cause of SUDEP in the majority of patients.

Other proposed mechanisms include that prolonged PGES leads to electrocerebral shutdown, leading to cardiorespiratory dysfunction. This was proposed in the MORTEMUS study, but studies have been inconsistent in determining the role played by PGES in SUDEP. A study by Shen et al. explored the possibility that adenosine may play a role in centrally-induced cardiorespiratory dysfunction, suggesting that adenosine receptor antagonists such as caffeine may have a protective effect against SUDEP when given at seizure onset. 

The significant but non-modifiable risk factors for SUDEP appear to be male sex, history of GTCS, younger age of onset, longer duration of epilepsy, symptomatic aetiology,  and associated learning disability. Although fixed, the knowledge of these risk factors are useful for clinicians when counselling patients for SUDEP. More importantly for the drive to minimise the risk of SUDEP, several modifiable risk factors have also been identified. Consistently reported are higher frequency of GTCS, and antiepileptic drug (AED) polytherapy , although it is recognised that AED polytherapy may be a surrogate for seizure frequency. Identification that the seizure frequency may increase in the months prior to a SUDEP has implications for SUDEP surveillance and healthcare system delivery. The majority of SUDEP cases occur at night and several studies have reported that a lack of night-time surveillance as a risk factor for SUDEP. Inconsistently reported is the use of lamotrigine and carbamazepine; further research is required to establish their roles as potential SUDEP risk factors ..

There remains no effective evidence-based treatment or prevention against SUDEP. The mainstay of management has been in addressing the modifiable risk factors to reduce SUDEP risk. This includes promoting AED compliance to reduce the incidence of GTCS and making patients and families aware of the potential consequences of uncontrolled nocturnaL . The use of a safety checklist has gained interest since it was first proposed and has subsequently been developed in to a smart-phone app . Patient education is important in promoting adherence to AEDs, avoiding factors that may trigger seizures, appropriately reacting to clusters of seizures and being aware of the interaction of other drugs with AEDs. Lattice pillows have been proposed as an intervention to reduce the risk of airway obstruction, but there have been no studies to evaluate their use in epilepsy. Nocturnal supervision has been found to be protective against SUDEP in one study, possibly suggesting that nocturnal seizure alarms may have a role in improving night-time supervision . The use of selective serotonin reuptake inhibitors (SSRI), opiate receptor inhibitors, adenosine receptor inhibitors, cardiac pacemakers and implantable cardiac defibrillators (ICD) have also been proposed as future targets for SUDEP prevention but there have been no trials examining the benefits of these in the prevention of SUDEP.

Within the hospital setting, several interventions are recommended to reduce the duration of seizures, respiratory dysfunction and EEG suppression. These include repositioning of the patient, oral suctioning and oxygen administration as well as prompt administration of AED if indicated. The MORTEMUS study also showed that in near-SUDEP cases, resuscitation was prompt whereas in the SUDEP cases it was delayed suggesting that close monitoring of patients in hospital with the use of direct supervision, ECG, EEG and oxygen saturations may reduce the risk of SUDEP…

Through the above, a better understanding of SUDEP may lead to effective prevention strategies. It is chilling to recognise that most people with epilepsy who die a SUDEP death, die alone. More research is required particularly for the role of nocturnal supervision of epilepsy patients, as though it is currently suggested in the literature that supervision is protective, to routinely advise this could have a deleterious effect on the quality of life of epilepsy patients and should not be undertaken lightly without substantive evidence for its recommendation. Nocturnal seizure alarms appear to be a promising alternative and these warrant further research to determine whether offer any protection against SUDEP. Further research is also required to determine the effectiveness of SSRIs, opiate and adenosine receptor inhibitors, cardiac pacemakers and ICDs in the prevention of SUDEP. We hope that reducing the treatment gap and ensuring the highest quality epilepsy care for everyone may reduce SUDEP rates; already there is evidence that successful epilepsy surgery reduces mortality, in part, by lowering SUDEP rates .