Elsevier

The Lancet

Volume 353, Issue 9156, 13 March 1999, Pages 888-893
The Lancet

Articles
Risk factors for sudden unexpected death in epilepsy: a case control study

https://doi.org/10.1016/S0140-6736(98)05114-9Get rights and content

Summary

Background

Sudden unexpected death is substantially more common in people with epilepsy than in the general population. Our objective was to investigate the association between some clinical variables and sudden unexpected death in epilepsy (SUDEP) to identify risk factors.

Methods

This nested case-control study was based on a cohort of people aged between 15 and 70 years, who, during 1980–89, had been admitted to and discharged with a diagnosis of epilepsy from any hospital in the county of Stockholm. The study population was followed up through the National Cause of Death Register until Dec 31, 1991. Cases were individuals who had died, with a diagnosis of epilepsy registered on the death certificate, and who after review of medical and necropsy records were found to meet our SUDEP criteria. Three control participants, who were living epilepsy patients matched for age and sex, were selected from the same cohort for each case. All medical records were examined. Clinical data were collected and analysed on a predesigned protocol.

Findings

57 SUDEP cases were included, of whom 91% had undergone necropsy. The relative risk of SUDEP increased with number of seizures per year. The estimated relative risk was 10·16 (95% Cl 2·94–35·18) in patients with more than 50 seizures per year, compared with those with up to two seizures per year. The risk of SUDEP increased with increasing number of antiepileptic drugs taken concomitantly—9·89 (3·20–30·60) for three antiepileptic drugs compared with monotherapy. Other major risk factors were early-onset versus late-onset epilepsy (7·72 [2·13–27·96]), and frequent changes of antiepileptic drug dosage compared with unchanged dosage (6·08 [1·99–18·56]). The association between SUDEP risk and early onset, and SUDEP risk and seizure frequency, was weaker for female than for male patients, whereas frequent dose changes showed a stronger association in female patients.

Interpretation

Our data suggest that SUDEP is a seizure-related event, although the pathophysiological substrate that predisposes individuals to SUDEP may be established at an early age, and there may be some sex differences. Improvement of seizure control and possibly the avoidance of polytherapy may be ways to reduce the risk of SUDEP.

Introduction

People with epilepsy have an increased risk of sudden unexpected death. The incidence of sudden unexpected death in epilepsy (SUDEP) depends on the population under study; it ranges from 1 per 100 patient-years in therapy-resistant epilepsy-surgery candidates to 1 per 1000 in studies based on prevalent cases and to 3·5 per 10 000 in investigations based on incident cases,1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 as summarised by O'Donaghue and Sander.14

Although several suggestions have been made, the physiological mechanisms underlying SUDEP remain unclear.15, 16, 17, 18 Without established explanations for SUDEP, the analysis of possible risk factors becomes important. Previous studies have suggested that low age, being male, remote symptomatic epilepsy, intractability (poor response to treatment), alcoholism, treatment non-compliance, and recent head trauma are associated with increased risk. However, the value of these observations is limited because in general the studies lack relevant control groups, comprise few cases, and are often based on selected populations of patients. Nashef and Brown19 have already emphasised the need for case-control studies.

We have done a population-based, nested, case-control study of SUDEP within a large cohort of adult epilepsy patients in Stockholm, Sweden. Our aim was to investigate the association between some clinical characteristics and SUDEP, focusing mainly on risk factors suggested by previous investigators.

Section snippets

Study population

We have described our study population in more detail previously.20 In brief, all participants were aged between 15 and 70 years, were living in Stockholm, and, at least once between 1980 and 1989, were admitted to hospital and discharged with a diagnosis of epilepsy, identifiable on the Stockholm County Inpatient Register. We thus identified a study population of 6880 people, and estimated that more than 60% of the adult epilepsy population in Stockholm is included in this cohort.20 The study

Results

We found a significantly low RR for SUDEP associated with cerebrovascular disease, and a low RR for SUDEP associated with heart disease (though it did not reach significance). We also found an increased risk associated with injuries (other than injuries to the central nervous system) and with dementia (table 2).

Seizure frequency was the factor most strongly associated with an increased risk of SUDEP (table 3). Fewer cases (1·8%) than controls (31·6%) were seizure-free during the last year of

Discussion

Previous information on risk factors for SUDEP comes from selected cohorts such as case series from epilepsy referral centres,1, 2, 5 from residences for patients with intractable epilepsy,3, 4 from coroner's offices,12, 24 and, in a few cases, from larger cohort studies.6, 7, 11 The paucity of studies allowing comparison with a relevant control group within the study has been underlined elsewhere.19, 25 The few available case-control studies have compared small numbers of SUDEP cases from

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