Treatments to prevent Sudden Unexpected Death in Epilepsy (SUDEP)

Background

Sudden Unexpected Death in Epilepsy (SUDEP) is defined as sudden, unexpected, witnessed or unwitnessed, non-traumatic or non-drowning death of people with epilepsy, with or without evidence of an epileptic seizure, and for whom a postmortem examination reveals no other cause of death. SUDEP is the most common epilepsy-related cause of death, with around 1 to 2 deaths per 1000 patients per year. Frequent generalised tonic-clonic seizures (GTCS), male gender, young age of first seizure, long duration of epilepsy, and taking multiple antiepileptic drugs are all thought to increase the risk for SUDEP, however exactly why SUDEP occurs is currently unknown. However, it is thought to be related to heart failure, breathing difficulties, and brain damage following GTCS.

With the correct antiepileptic treatment regimen around 70% of people with epilepsy can become free of all seizures. However, around one-third of people with epilepsy will continue to have seizures despite taking multiple antiepileptic drugs. Continuing seizures place patients at risk of SUDEP and can be associated with depression and lower quality of life. Strategies to try to prevent SUDEP include reducing the number of GTCS a patient has (by considering epilepsy surgery or making lifestyle changes), examining for heart and breathing problems during and following seizures, supervising patients at night or using safety pillows to prevent breathing difficulties. Drugs that increase the brain chemical serotonin and reduce the brain chemicals adenosine and opioids may also help prevent breathing difficulties.

Objective

The aim of this review was to examine the effectiveness of treatments designed to prevent SUDEP.

Methods

The last search for trials for this review was performed in November 2015. We searched electronic databases and contacted experts in the area to find relevant randomised or non-randomised (observational) studies for the review. Our outcomes of interest were: number of deaths due to SUDEP; number of other deaths not related to SUDEP; changes in anxiety, depression, and quality of life; and number of hospital attendances.

Results

Out of 592 records found in our searches, we were able to include one observational study. We found several studies that measured how sensitive devices are at detecting GTCS at night, but these studies did not measure SUDEP and so were not relevant to this review.

The one included study identified 154 people who had experienced SUDEP and then compared them to 616 people with epilepsy who had not experienced SUDEP. The study found that fewer people experienced SUDEP who had a supervising person sharing a bedroom with them or who used special precautions such as regular checking throughout the night or a listening device used than those who did not use these measures of supervision.

This study did not provide any information on number of other deaths not related to SUDEP; changes in anxiety, depression, and quality of life; and number of hospital attendances.

Quality of the evidence

We judged the quality of the evidence from this review to be very low as the only included study was not randomised, and information about supervision measures to prevent SUDEP was not available for 40% of the people with epilepsy who did not experience SUDEP.

Conclusions

We found very limited, low-quality evidence that supervision at night prevents SUDEP. Further research is needed to identify if other treatments, such as seizure detection devices, safety pillows, and drug interventions working on serotonin, adenosine, and opiate levels in the brain are effective in preventing SUDEP in people with epilepsy.

Authors' conclusions: 

We found very low-quality evidence of a preventative effect for nocturnal supervision against SUDEP. Further research is required to identify the effectiveness of other current interventions, for example seizure detection devices, safety pillows, SSRIs, early surgical evaluation, educational programmes, and opiate and adenosine antagonists in preventing SUDEP in people with epilepsy.

Read the full abstract...
Background: 

Sudden Unexpected Death in Epilepsy (SUDEP) is defined as sudden, unexpected, witnessed or unwitnessed, non-traumatic or non-drowning death of people with epilepsy, with or without evidence of a seizure, excluding documented status epilepticus and in whom postmortem examination does not reveal a structural or toxicological cause for death. SUDEP has a reported incidence of 1 to 2 per 1000 patient years and represents the most common epilepsy-related cause of death. The presence and frequency of generalised tonic-clonic seizures (GTCS), male sex, early age of seizure onset, duration of epilepsy, and polytherapy are all predictors of risk of SUDEP. The exact pathophysiology of SUDEP is currently unknown, although GTCS-induced cardiac, respiratory, and brainstem dysfunction appears likely. Appropriately chosen antiepileptic drug treatment can render around 70% of patients free of all seizures. However, around one-third will remain drug refractory despite polytherapy. Continuing seizures place patients at risk of SUDEP, depression, and reduced quality of life. Preventative strategies for SUDEP include reducing the occurrence of GTCS by timely referral for presurgical evaluation in people with lesional epilepsy and advice on lifestyle measures; detecting cardiorespiratory distress through clinical observation and seizure, respiratory, and heart rate monitoring devices; preventing airway obstruction through nocturnal supervision and safety pillows; reducing central hypoventilation through physical stimulation and enhancing serotonergic mechanisms of respiratory regulation using selective serotonin reuptake inhibitors (SSRIs); reducing adenosine and endogenous opioid-induced brain and brainstem depression.

Objectives: 

To assess the effectiveness of interventions in preventing SUDEP in people with epilepsy by synthesising evidence from randomised controlled trials of interventions and cohort and case-control non-randomised studies.

Search strategy: 

We searched the following databases: Cochrane Epilepsy Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL, Issue 11, 2015) via the Cochrane Register of Studies Online (CRSO); MEDLINE (Ovid, 1946 onwards); SCOPUS (1823 onwards); PsycINFO (EBSCOhost, 1887 onwards); CINAHL Plus (EBSCOhost, 1937 onwards); ClinicalTrials.gov; and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We used no language restrictions. The date of the last search was 12 November 2015. We checked the reference lists of retrieved studies for additional reports of relevant studies and contacted lead study authors for any relevant unpublished material. We identified duplicate studies by screening reports according to title, authors' names, location, and medical institute, omitting any duplicated studies. We identified any grey literature studies published in the last five years by searching: Zetoc database; ISI Proceedings; International Bureau for Epilepsy (IBE) congress proceedings database; International League Against Epilepsy (ILAE) congress proceedings database; abstract books of symposia and congresses, meeting abstracts, and research reports.

Selection criteria: 

We aimed to include randomised controlled trials (RCTs), quasi-RCTs, and cluster-RCTs; prospective non-randomised cohort controlled and uncontrolled studies; and case-control studies of adults and children with epilepsy receiving an intervention for the prevention of SUDEP. Types of interventions included: early versus delayed pre-surgical evaluation for lesional epilepsy; educational programmes; seizure-monitoring devices; safety pillows; nocturnal supervision; selective serotonin reuptake inhibitors (SSRIs); opiate antagonists; and adenosine antagonists.

Data collection and analysis: 

We aimed to collect data on study design factors and participant demographics for included studies. The primary outcome of interest was the number of deaths from SUDEP. Secondary outcomes included: number of other deaths (unrelated to SUDEP); change in mean depression and anxiety scores (as defined within the study); clinically important change in quality of life, that is any change in quality of life score (average and endpoint) according to validated quality of life scales; and number of hospital attendances for seizures.

Main results: 

We identified 582 records from the databases and search strategies. We found 10 further records by searching other resources (handsearching). We removed 211 duplicate records and screened 381 records (title and abstract) for inclusion in the review. We excluded 364 records based on the title and abstract and assessed 17 full-text articles. We excluded 15 studies: eight studies did not assess interventions to prevent SUDEP; five studies measured sensitivity of devices to detect GTCS but did not directly measure SUDEP; and two studies assessed risk factors for SUDEP but not interventions for preventing SUDEP. One listed study is awaiting classification.

We included one case-control study at serious risk of bias within a qualitative analysis in this review. This study of 154 cases of SUDEP and 616 controls ascertained a protective effect for the presence of nocturnal supervision (unadjusted odds ratio (OR) 0.34, 95% confidence interval (CI) 0.22 to 0.53) and when a supervising person shared the same bedroom or when special precautions, for example a listening device, were used (unadjusted OR 0.41, 95% CI 0.20 to 0.82). This effect was independent of seizure control. Non-SUDEP deaths; changes to anxiety, depression, and quality of life; and number of hospital attendances were not reported.

Share/Save