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 seizures, in particular convulsive seizures (termed 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; exactly why SUDEP occurs is currently unknown, however, though 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

To examine the effectiveness of treatments designed to prevent SUDEP.

Methods

We searched electronic databases and contacted experts in the area to find relevant randomised or non-randomised (observational) studies for the review. 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.

The evidence is current to February 2019.

Results

Out of 818 records found in our searches, we were able to include four observational studies. We found several studies that measured how sensitive devices are at detecting GTCS at night, but these studies did not measure SUDEP and so weren't relevant to this review.

Three studies investigated whether having a supervising person sharing a bedroom with the patient and using special precautions such as regular checking throughout the night or a listening device prevented SUDEP. Two of the three studies which included 202 people who had died of SUDEP and 836 people with epilepsy who were alive found these measures did prevent SUDEP. The third study of 60 SUDEP deaths and 240 controls looked at whether increasing night-time supervision for patients in two residential units above regular checks to include bed monitors and listening devices prevented SUDEP. This study did not show any additional preventative effect. However the same study did show that the centre with the most SUDEP deaths had the lowest level of supervision. The studies did not report on changes in anxiety, depression, quality of life and number of hospital attendances.

The fourth study looked at the effect of giving information to people with epilepsy about SUDEP and whether it improved the taking of antiepileptic medication and the impact on mood and anxiety. The study followed patients up for six months after being given the information (or not) and did not demonstrate any effect on the taking of medication or mood and anxiety. There were no deaths in the study so the effect of giving information and impact on risk of SUDEP is unknown.

Certainty of the evidence

We judged the certainty of the evidence from this review to be very low as the included studies were not randomised, and information about supervision measures to prevent SUDEP was not available in up to 40% of the people within the studies who did not experience SUDEP.

Conclusions

We found limited, very low-certainty 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 limited, very low-certainty evidence that supervision at night reduces the incidence of 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: 

This is an updated version of the original Cochrane Review, published in 2016, Issue 7.

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-resistant 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); and 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: 

For the latest update we searched the following databases without language restrictions: Cochrane Register of Studies (CRS Web, 4 February 2019); MEDLINE (Ovid, 1946 to 1 February 2019); SCOPUS (1823 to 4 February 2019); PsycINFO (EBSCOhost, 1887 to 4 January 2019); CINAHL Plus (EBSCOhost, 1937 to 4 February 2019); ClinicalTrials.gov (5 February 2019); and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP, 5 February 2019). 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 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 1277 records from the databases and search strategies. We found 10 further records by searching other resources (handsearching). We removed 469 duplicate records and screened 818 records (title and abstract) for inclusion in the review. We excluded 785 records based on the title and abstract and assessed 33 full-text articles. We excluded 29 studies: eight studies did not assess interventions to prevent SUDEP; eight studies were review articles, not clinical studies; five studies measured sensitivity of devices to detect GTCS but did not directly measure SUDEP; six studies assessed risk factors for SUDEP but not interventions for preventing SUDEP; and two studies did not have a control group.

We included one cohort study and three case-control studies of serious to critical risk of bias. The 6-month prospective cohort study observed no significant effect of providing patients with SUDEP information on drug compliance and quality of life, anxiety and depression levels. The study was too short and with no deaths observed in either group to determine a protective effect. Two case control studies reported a protective effect for nocturnal supervision against SUDEP. However due to significant heterogeneity, the results could not be combined in meta-analysis. One study of 154 SUDEP cases and 616 controls reported an unadjusted odds ratio (OR) of 0.34 (95% CI 0.22 to 0.53; P < 0.0001). The same study demonstrated the protective effect was independent of seizure control, suggesting that nocturnal supervision is not just a surrogate marker of seizure control. The second case-control study of 48 SUDEP cases and 220 controls reported an unadjusted OR of 0.08 (95% CI 0.02 to 0.27; P < 0.0001). The third case-control study of residential care centre patients who were already receiving physical checks more than 15 minutes apart throughout the night did not report any protective effect for additional nocturnal supervision (physical checks < 15 minutes apart; use of listening devices; dormitory setting; and use of bed sensors). However the same study did ascertain a difference between centres: the residential centre with the lowest level of supervision had the highest incidence of SUDEP. The case-control studies did not report on quality of life or depression and anxiety scores.

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